CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority under 35 U.S.C. § 119 from the following European patent applications: EP 20177451.0 filed on May 29, 2020; EP 20184767.0 filed on Jul. 8, 2020; EP 20195740.4 filed on Sep. 11, 2020; and EP 21171333.4 filed on Apr. 29, 2021. The disclosures of the foregoing applications are incorporated herein by reference in their entirety.

SEQUENCE LISTING

The entire content of a Sequence Listing titled “Sequence_Listing.txt,” created on Nov. 16, 2021 and having a size of 15 kilobytes, which has been submitted in electronic form in connection with the present application, is hereby incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

The present invention relates to novel uses of an anti-histamine drug compound for treating viral infections, particularly methods and compounds for treating Coronaviridae infections (e.g., SARS virus or MERS virus), adenovirus infections, human Respiratory Syncytial Viral infections and influenza infections.

BACKGROUND OF THE INVENTION

Coronaviruses are single-stranded RNA viruses, about 120 nanometers in diameter. They are prone to mutation and recombination and are therefore highly diverse. There are about 40 different varieties and they mainly infect human and non-human mammals and birds. They reside in bats and wild birds, and can spread to other animals and hence to humans.

There are four main genera (alpha, beta, gamma, and delta-coronavirus) based on their genomic structure. Alpha- and beta-coronaviruses infect only mammals, usually causing respiratory symptoms in humans and gastroenteritis in other animals. Until December of 2019, only six different coronaviruses were known to infect humans. Four of these (HCoV-NL63, HCoV-229E, HCoV-0043 and HKU1) usually caused mild common cold-type symptoms in immunocompetent people and the other two have caused pandemics in the past two decades. In 2002-2003, the severe acute respiratory syndrome coronavirus (SARS-CoV) caused a SARS epidemic that resulted in a 10% mortality. Similarly, the Middle East respiratory syndrome coronavirus (MERS-CoV) caused a pandemic in 2012 with a 37% mortality rate.

In late 2019 and early 2020, a novel coronavirus, SARS-coronavirus 2 (SARS-CoV-2), which is closely related to SARS-CoV, was discovered to be the cause of a large and rapidly spreading outbreak of respiratory disease, including pneumonia. Since the novel coronavirus was recognized, the disease it caused was termed coronavirus disease 2019 (CoVID-19).

The SARS-related coronaviruses are covered by spike proteins that contain a variable receptor-binding domain (RBD). This RBD binds to angiotensin-converting enzyme-2 (ACE-2) receptor found in the heart, lungs, kidneys, and gastrointestinal tract, thus facilitating viral entry into target cells.

The original virus strain spread from Wuhan is considered as the “wild-type” virus, which soon gave rise to variants, i.e. mutants that evolved through natural selection based on higher infectivity. In early March 2020, a variant with D614G mutation in the spike protein (B.1 variant) were identified in Europe, which soon replaced the original Wuhan strain globally. Subsequently, SARS-CoV-2 variants B.1.1.7 (also known as 201/501Y.V1, VOC 202012/01) and B.1.351 (also known as 20H/501Y.V2) were identified in the United Kingdom and South Africa, respectively, and have since spread to many countries. These variants harbor diverse mutations in the gene encoding the spike protein. One of these is in the receptor binding domain (RBD which binds human ACE2) at position 501, where the amino acid asparagine (N) has been replaced with tyrosine (Y) (mutation N501Y). The B.1.1.7 variant also has several other mutations, including: 69/70 deletion and likely leads to a conformational change in the spike protein, and P681H, near the S1/S2 furin cleavage site. The combination of these mutations leads to higher receptor binding, more efficient spread and higher disease-causing potential compared to the original version that emerged in Wuhan in China in 2019. The B.1.351 variant has in addition to the N501Y, also the E484K and K417N mutations, but not the 69/70 deletion. Several lines of evidence suggest that this variant emerged due to immune pressure i.e. as an escape from the human immune response resulting from natural infection, or passive immune therapy or active immunization with different vaccines. The E484K mutation seems to be responsible for reduced vaccine effectiveness. This mutation (along with 16 other mutations N501Y and K417T) was also detected in the Brazilian variant, designated as P.1. Variant P.1. caused widespread infection in Brazil and was later detected globally. This mutant is suspected to cause more severe disease in younger people, lead to higher mortality and evade immune response induced by the previous variant and some of the vaccines.

The mutant B.1.617 was first detected and spread in India. It has 13 mutations from those 3 are of concern regarding immune evasion: E484Q, L452R and P681R. The lineage B.1.618 became one of the dominant mutants in West Bengal, it carries the deletion of two amino acids (H146del and Y145del), as well as the E484K and D614G mutations in the spike protein. It is speculated to possess higher infectivity and pose a threat for evading natural or vaccine induced immunity.

It is highly likely that wide-spread vaccination will induce the emergence of further variants with different combination of the currently known and new mutations.

The accelerated global vaccination together with the simultaneous intense spread of the virus poses a huge evolutionary pressure for the emergence of escape mutants. All vaccines, almost exclusively, rely on triggering an immune response against the spike protein. Furthermore, according to the current view, a neutralizing immune response against the receptor binding domain of the spike protein is considered to be the major contributor to protection. Based on these two facts, among the naturally emerging virus variants those will be selected that express mutated spike proteins affording a selective advantage (higher binding to the receptor and/or evasion of the neutralizing immune response). Subsequent variants may accumulate several successive mutations, with higher overall virulence/transmissiblity and/or with a higher likelihood of immune evasion. It is envisioned that besides those mentioned above additional new virus variants will emerge with the potential need of second-generation vaccines for optimal protection against them.

Therefore, antiviral compounds active against the, by now dominant UK (B1.1.7) variant and the SA (B.1.351) variant as well as against other emerging variants that are associated with greatly reduced vaccine-induced protection, are highly relevant, both for prevention and treatment.

Adenoviruses are large non-enveloped viruses with a double-stranded DNA genome. The family Adenoviridae contains six genera with broad host specificity of viruses. All seven human adenovirus families (A to G) belong to the Mastadenovirus genus. Currently, the human viruses are classified into 88 different (sero)types, which are responsible to cause various mucosal infections. Types within families B (HAdV-B) and C (HAdV-C) are responsible for upper respiratory tract infections, HAdV-F (mainly types 40 and 41) and HAdV-G (mainly type 52) types cause gastroenteritis. Conjunctivitis is associated with HAdV-B and HAdV-D. These mucosal infections are usually self-limiting but can be more severe in an immunocompromised host. Adenovirus serotype 14 is an emerging pathogen that cause outbreaks of severe respiratory infections that could be lethal even in immunocompetent hosts.

Adenoviruses exhibit a classical icosahedral capsid made of 240 hexon and 12 penton proteins. The penton bases are associated with protruding fibers that bind to the host cell receptors: CD46 (family B) and coxsackie/adenovirus receptor (CAR, for all other families). This initial binding is followed by the interaction of the penton base viral structures with αV integrins, which stimulates endocytosis of the virus particles. Intracellularly, the capsid is destabilized, the endosome is degraded, and the viral DNA enters the nucleus through the nuclear pore. After associating with histone proteins the host transcription machinery is used for viral gene expression without the integration of the viral genome into the host genome. Viral proteins are expressed in an early (mainly regulatory proteins) and late (structural proteins) separated by the genome replication. Finally, the viral genomes are packaged into the protein shell and released from the host cell upon a virus induced lysis procedure.

Adenoviruses are relatively resistant to disinfectants and detergents (non-encapsulated), and survive long on surfaces and in water. There are no proven antiviral drugs to treat adenoviral infections, so treatment is largely directed at the symptoms. Currently, there is no adenovirus vaccine available to the general public, but a vaccine was used by the US military for types 4 and 7. Recently, engineered adenoviruses were successfully used in gene therapy and as viral vectors for heterologous vaccine antigen delivery (Ebola and Covid).

Human Respiratory Syncytial Virus (hRSV) is an enveloped virus with a negative-sense, single-stranded RNA genome. The genome is linear and has 10 genes encoding for 11 proteins. RSV is divided into two antigenic subtypes, A and B, with 16 and 22 clades (or strains), respectively.

RSV is highly contagious and can cause outbreaks from both community and hospital transmission. Each year, approximately 30 million acute respiratory illnesses and over 60,000 childhood deaths are caused RSV worldwide. Transmission occurs through contaminated aerosol droplets encountering mucosal surfaces of the nose, mouth, or eyes. Infection of the ciliated cells of the upper airways is followed by spread to the lower airways. It is among the most common childhood infections of various severity ranging from mild upper respiratory tract infection through bronchiolitis to viral pneumonia, which in the most severe cases may require mechanical ventilation. Immunocompromised individuals (including pre-term infants) have a higher risk for more severe diseases outcome. Therapeutic options are usually limited to supportive care, although ribavirin has been licensed for RSV infections in children. Vaccines are not available (despite significant development efforts), however, passive immunization with monoclonal antibodies (palivizumab) has become available as a choice for prophylaxis.

Influenza, commonly called “the flu”, is an infectious disease caused by influenza viruses. In each season (winter months in the Northern hemisphere) 5-15% of the population contracts influenza, with approx. 3-5 million severe cases. Over half a million deaths occur annually among high-risk groups, including young children, the elderly, and people with chronic health conditions. Following a 1-4 days incubation period, the onset of symptoms is sudden including fever, chills, headaches, muscle pain or aching, loss of appetite, fatigue, and confusion. Pneumonia may be caused by the primary viral infection or by a secondary bacterial infection, such as by the pneumococcus orS. aureus. Transmission of influenza is mediated by aerosol droplets. The primary infection site is the upper airways followed by progression to the lower airways and invasive infection.

There are four types (species) of influenza viruses: A, B, C and D. Seasonal epidemics (i.e. flu season) is caused by human influenza A (IAV) and B (IBV) viruses, while C and D are rarely associated with symptomatic infections in humans. Influenza A viruses are divided into subtypes based on two proteins on the surface of the virus: hemagglutinin (H) and neuraminidase (N). Although there are potentially 198 different influenza A subtype combinations, currently H1N1 and H3N2 types circulate worldwide. Influenza B viruses are not divided into subtypes, but instead are further classified into two lineages: B/Yamagata and B/Victoria. Based on these, seasonal flu vaccines usually contain two A (an H1N1 and an H3N2) and one or two B strains in combination. Influenza viruses have a negative-sense, single-stranded RNA genome that is segmented. Both IAV and IBV contain 8 segments, that could combine with the genome of other influenza viruses upon co-infection of the same cell. This process (called reassortment) give rise to progeny with significantly altered viral antigen composition. Such reassortant virus variants are novel to the human population and may give rise to pandemics (e.g., the Spanish flu in 1918, H1N1). Reassortment may also occur between viruses specific to different hosts. For instance, the “swine flu” pandemic in 2009 was caused by a triple reassortant virus carrying a combination of swine-, avian- and human-specific virus sequences (H1N1. Similarly, avian influenza strains, which are common in wild-water birds occasionally infect humans (“avian or bird flu”, H5N1). Upon reassortment of such avian viruses with human influenza viruses may give rise to variants enabling human-to-human spread, and therefore, have the potential to cause global pandemics.

Therapy of individuals of lower risk groups mainly focuses on symptomatic treatment (fever) and isolation. Patients suffering in severe or progressive clinical illness associated with suspected or confirmed influenza virus infection are treated with antiviral drugs (e.g., oseltamivir or other neuraminidase inhibitors) and supportive therapy (e.g. anti-inflammatory drugs). High risk groups (elderly, pregnant women, immunocompromised, associated chronic diseases) should receive annual seasonal flu vaccines as prophylaxis.

Azelastine, a phthalazine derivative, is an antihistamine available as an intranasal spray for the treatment of allergic and vasomotor rhinitis and as an ophthalmic solution for the treatment of allergic conjunctivitis. It is a racemic mixture, though there is no noted difference in pharmacologic activity between enantiomers, and was first granted FDA approval in 1996.

Gysi et al. (“Network Medicine Framework for Identifying Drug Repurposing Opportunities for COVID-19”, arXiv:2004.07229 [q-bio.MN] dated 15 Apr. 2020) discloses a network-based toolset to COVID-19 to arrive at certain drug candidates based on their likely efficacy for COVID-19 patients, among them Azelastine, yet without any indication whether the antihistamine would have a direct impact on the virus underlying the disease.

Hasanain Abdulhameed Odhar et al. (Bioinformation 2020, 16(3):236-244) describe molecular docking and dynamics simulation of FDA approved drugs with the main protease from 2019 novel coronavirus. Drugs were ranked according to their minimum binding activity to main protease crystal of 2019-nCoV, with Azelastine being ranked less preferred than Conivaptan.

Xia Xiao et al. (bioRxiv Jul. 6, 2020, D01:10.1101/2020.07.06.188953) describe antiviral activity of a series of compounds against 0043, among them Azelastine as an anti-histamine.

Fu et al. (Cell Prolif. 2014, 47:326-335) disclose azelastine hydrochloride targeting sodium taurocholate co-transporting polypeptide (NTCP) in hepatitis B virus (HBV) therapy. NTCP is a transmembrane protein highly expressed in human hepatocytes that mediates the transport of bile acids, which plays a key role in HBV entry into hepatocytes.

M. W. Simon (Pediatric Asthma, Allergy & Immunology, 2003, Vol. 16:275-282) describes azelastine as a potent and selective second-generation histamine H1receptor antagonist that downregulates expression of the intracellular adhesion molecule-1 (ICAM-1) receptor, which plays an important role in human rhinovirus, Coxsackie type A viruses, adenovirus type 5, human parainfluenza virus type 2 and 3, and respiratory syncytial virus mucosal attachment as well as mobilization of immune effector cells.

SUMMARY OF THE INVENTION

It is the objective of the present invention to provide new antiviral treatments, medicinal and pharmaceutical products which can be used to prevent from virus infection and/or virus spread, in particular in subjects that have been exposed to or infected with a virus, or who are at risk of being infected. The objective is solved by the subject of the present claims and as further described herein.

The following items are embodiments of the invention described herein:

1. A method of treating a subject in need of anti-Coronavirus treatment comprising prophylactic or therapeutic treatment, with an antiviral effective amount of an Azelastine compound, wherein the antiviral effective amount is 0.1-500 μg per dose.

2. The method of item 1, wherein said anti-Coronavirus treatment is against one or more β-coronaviruses or SARS viruses Coronaviruses selected from SARS-CoV-2, MERS-CoV, SARS-CoV-1, HCoV-0043, HCoV-HKU1, and/or against one or more α-coronaviruses, such as HCoV-NL63, HCoV-229E or PEDV, and/or against one or more naturally-occurring variants or mutants of any of the foregoing.

3. The method of item 2, wherein said one or more viruses are naturally-occurring SARS-CoV-2, SARS-CoV-2 variants or mutants.

4. The method of item 3, wherein said SARS-CoV-2 variants or mutants comprise one or more mutations of the SARS-CoV-2 S-protein, preferably K417N, L452R, N501Y, D614G, P681H, P681R, E484K, E484Q, or 69/70 deletion in SEQ ID NO:4.

5. The method of item 3, wherein said SARS-CoV-2 variants or mutants are selected form the group consisting of B.1.1.7 (UK variant), B.1.351 (South African), P.1 (Brazilian), B.1.617 (Indian), B.1.618 (Bengal) mutants.

6. The method of item 1, wherein a disease condition is treated which is caused by or associated with an infection by any one or more of 6-coronaviruses or SARS viruses selected from SARS-CoV-2, MERS-CoV, SARS-CoV-1, HCoV-0043, HCoV-HKU1, and/or any one or more of α-coronaviruses, such as HCoV-NL63, HCoV-229E or PEDV, and/or any one or more of naturally-occurring variants or mutants of any of the foregoing.

7. The method of item 6, wherein said one or more viruses are naturally-occurring SARS-CoV-2, SARS-CoV-2 variants or mutants.

8. The method of item 7, wherein said SARS-CoV-2 variants or mutants comprise one or more mutations of the SARS-CoV-2 S-protein, or K417N, L452R, N501Y, D614G, P681H, P681R, E484K, E484Q, or 69/70 deletion in SEQ ID NO:4.

9. The method of item 7, wherein said SARS-CoV-2 variants or mutants are selected form the group consisting of B.1.1.7 (UK variant), B.1.351 (South African), P.1 (Brazilian), B.1.617 (Indian), B.1.618 (Bengal) mutants.

10. The method of item 1, wherein the antiviral effective amount is effective in preventing infection of susceptible cells by the Coronavirus.

11. The method of item 1, wherein the Azelastine compound is applied into the subject's nose in an antiviral effective amount of 1-1000 μg per nostril.

12. The method of item 1, wherein a pharmaceutical preparation is administered comprising the Azelastine compound and a pharmaceutically acceptable carrier.

13. The method of item 12, wherein said pharmaceutical preparation is a medicinal product or a drug product.

14. The method of item 12, wherein said pharmaceutical preparation is formulated for local administration or systemic administration.

15. The method of item 14, wherein said local administration comprises application to the upper and lower respiratory tract, nasal, pulmonary, intraoral, ocular, or dermal application.

16. The method of item 14, wherein said systemic administration comprises intravenous, intramuscular, subcutaneous, intradermal, transdermal, or per os (“through the mouth”, oral) administration.

17. The method of item 12, wherein said pharmaceutical preparation is administered to the subject as a spray, a powder, a gel, an ointment, a cream, a foam, or a liquid solution, a lotion, a gargle solution, an aerosolized powder, an aerosolized liquid formulation, granules, capsules, drops, tablet, syrup, lozenge, or a preparation for infusion or injection.

18. The method of item 1, wherein the Azelastine compound is administered as the sole antiviral substance, or wherein treatment is combined with a further treatment with one or more active substances.

19. The method of item 18, wherein said one or more active substances are selected from the group consisting of antiviral, anti-inflammatory and antibiotic substances.

20. The method of item 1, wherein the subject has been infected or is at risk of being infected with said Coronavirus.

21. The method of item 1, wherein the subject is at risk of or suffering from a disease condition which is common cold, infection of the nose, sinusitis, throat and larynx, bronchiolitis, diarrhea, rash on skin, pneumonia, and/or acute respiratory distress syndrome (ARDS).

22. The method of item 1, wherein the subject is a human being, dog, cat, horse, camelid, cattle or pig.

23. Use of an Azelastine compound as an antiviral substance in a medicinal product for treating a biological surface to prevent from Coronavirus infection and/or Coronavirus spread.

24. The use of item 23, wherein the biological surface is a mucosal surface which is infected or at risk of being infected with one or more different Coronaviruses.

25. The method of item 23, wherein said Coronavirus is any one or more of β-coronaviruses or SARS viruses selected from SARS-CoV-2, MERS-CoV, SARS-CoV-1, HCoV-0043, HCoV-HKU1, and/or any one or more of α-coronaviruses, such as HCoV-NL63, HCoV-229E or PEDV, and/or any one or more of naturally-occurring variants or mutants of any of the foregoing.

26. The method of item 25, wherein said one or more viruses are naturally-occurring SARS-CoV-2, SARS-CoV-2 variants or mutants.

27. The method of item 26, wherein said SARS-CoV-2 variants or mutants comprise one or more mutations of the SARS-CoV-2 S-protein, or K417N, L452R, N501Y, D614G, P681H, P681R, E484K, E484Q, or 69/70 deletion in SEQ ID NO:4.

28. The method of item 26, wherein said SARS-CoV-2 variants or mutants are selected form the group consisting of B.1.1.7 (UK variant), B.1.351 (South African), P.1 (Brazilian), B.1.617 (Indian), B.1.618 (Bengal) mutants.

29. The method of item 23, wherein said medicinal product is formulated for topical use, or for application to the upper and lower respiratory tract, nasal, pulmonary, intraoral, ocular, or dermal application.

30. The method of item 23, wherein said medicinal product is used as a solution, dispersion, dry powder, or aerosolized liquid or powder.

31. The method of item 23, wherein the Azelastine compound is applied in an antiviral effective amount.

32. The method of item 31, wherein the antiviral effective amount is 1 ng-1000 ng/cm2.

33. The use of an Azelastine compound as viral disinfectant.

The invention further provides for an Azelastine compound in an antiviral effective amount for use as an antiviral substance in a pharmaceutical preparation for use in prophylactic or therapeutic treatment of a subject in need of antiviral treatment.

Specifically, the Azelastine compound is Azelastine, or a pharmaceutically acceptable salt thereof, such as Azelastine hydrochloride.

According to a specific aspect, the pharmaceutical preparation is a medicinal product or a drug product. Specifically, the pharmaceutical preparation comprises the Azelastine compound and a pharmaceutically acceptable carrier.

Specifically, the subject is need of antiviral treatment targeting a respiratory virus, such as influenza virus, respiratory syncytial virus, adenovirus, coronavirus, or upper respiratory tract virus, such as rhinovirus.

A respiratory virus is herein specifically understood to be a virus causing respiratory disease. Though some of the target viruses further described herein may not only cause a respiratory disease, but also affect other body parts, such viruses are herein still understood to be a “respiratory virus”. Specifically, the antiviral treatment is targeting one or more human viruses, in particular a human respiratory virus, such as selected from the virus families Coronaviridae, Adenoviridae, Paramyxoviridae or Orthomyxoviridae.

Specifically, a disease condition is treated which is caused by or associated with an infection by one or more of:

a) Coronaviridae viruses, preferably selected from the group consisting of a β-coronavirus, such as SARS-CoV-2, MERS-CoV, SARS-CoV-1, HCoV-0043, HCoV-HKU1, and an α-coronavirus, such as HCoV-NL63, HCoV-229E or PEDV, including naturally-occurring variants or mutants of any of the foregoing, or

b) Adenoviridae, preferably human Adenoviruses, such as HAdVB, HAdVC, or HAdVD;

c) human respiratory syncytial viruses (RSV), such as RSV subtype A or B; or

d) influenza viruses, such as human influenza viruses, preferably influenza virus A (IVA), such as H1N1, H3N3, or H5N1, or influenza virus B (IVB), or influenza virus C (IVC), or influenza virus D (IVD).

Specifically, a disease condition is treated which is caused by or associated with an infection by one or more Coronaviridae viruses, in particular one or more different Coronaviridae viruses.

According to a specific aspect, said Coronaviridae viruses are preferably selected from the group consisting of a 6-coronavirus, such as SARS-CoV-2, MERS-CoV, SARS-CoV-1, HCoV-0043, or HCoV-HKU1, or an α-coronavirus, such as Humane Coronavirus NL63 (HCoV-NL63, New Haven coronavirus), HCoV-229E or Porcine epidemic diarrhea virus (PEDV), including naturally-occurring variants or mutants of any of the foregoing.

Specifically, said one or more different Coronaviridae viruses referred to herein are naturally-occurring SARS-CoV-2 variants or mutants, in particular those that comprise one or more mutations of the spike protein (SARS-CoV-2 S-protein), such as any one or more of the following mutations: K417N, L452R, N501Y, D614G, P681H, P681R, E484K, E484Q, or 69/70 deletion.

Specifically, the spike protein comprises or consists of the amino acid sequence identified as SEQ ID NO:4 (sequence provided inFIG. 5, NCBI accession number QII57161.1, SARS-CoV-2, S-protein).

Preferably said one or more different Coronaviridae viruses are naturally-occurring SARS-CoV-2 variants or mutants selected from the group consisting of the UK (B1.1.7) variant, the South African (B.1.351) variant, the Brazilian (P.1) variant, the Indian (B.1.617) variant and the Bengal (B.1.618) variant.

The preparations, methods and uses described herein are specifically comprising an azelastine compound in an antiviral effective amount. Such antiviral effective amount may target one specific virus or more than one different viruses, virus mutants or virus variants, such as further described herein.

The target virus of an antiviral effect is particularly understood as the virus which is (directly or indirectly) related to the indication for the treatment described herein, in particular the treatment for prophylaxis or therapy of a disease condition or disease that is caused or otherwise associated by such target virus.

Specifically, the target of the preparations, methods and uses described herein, and in particular the target of an antiviral effect described herein, can be any one or more different virus species, virus mutants or virus variants e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 different virus species, mutants or variants.

Specifically, the target can be any two or more viruses e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 different virus species, virus mutants or virus variants, wherein at least 2, 3, or 4 of the viruses are of different virus families, such as selected from the families:

a) Coronaviridae (6-coronavirus, such as SARS-CoV-2, MERS-CoV, SARS-CoV-1, HCoV-0043, HCoV-HKU1; or α-coronavirus, such as HCoV-NL63, HCoV-229E or PEDV, including naturally-occurring variants or mutants of any of the foregoing);

b) Adenoviridae (such as Adenoviruses or human Adenoviruses e.g., HAdVB, HAdVC, or HAdVD);

c) Paramyxoviridae (such as RSV or human RSV e.g., hRSV subtype A or B); or

d) Orthomyxoviridae (such as influenza viruses or human influenza viruses, preferably influenza virus A (IVA), such as H1N1, H3N3, or H5N1, or influenza virus B (IVB), or influenza virus C (IVC), or influenza virus D (IVD)).

Specifically, such viruses listed in a) to d) above are herein referred to as exemplary “respiratory viruses”.

According to a specific example, the target can be at least one virus selected from a) and at least one virus selected from b), c), or d). Specifically, the target can be at least one β-coronavirus, such as a SARS virus, in particular SARS-CoV-2, and at least one influenza virus.

Specifically, the target can be at least one β-coronavirus, such as a SARS virus, in particular SARS-CoV-2, and at least one Adenovirus HAdVB, HAdVC, or HAdVD.

Specifically, the target can be at least one β-coronavirus, such as a SARS virus, in particular SARS-CoV-2, and at least one hRSV subtype A or B.

According to a specific example, the target can be at least one virus selected from d) and at least one virus selected from a), b), or c).

Specifically, the target can be at least one influenza viruses or human influenza viruses, and at least one Adenovirus HAdVB, HAdVC, or HAdVD.

Specifically, the target can be at least one influenza viruses or human influenza viruses, and at least one hRSV subtype A or B.

According to a specific example, the target can be at least one virus selected from b) and at least one virus selected from a), c), or d).

Specifically, the target can be at least one Adenovirus HAdVB, HAdVC, or HAdVD, and at least one hRSV subtype A or B.

According to a specific example, the target can be at least one virus selected from a) and at least one virus selected from b), and optionally at least one virus selected from c), or d). Specifically, the target can be at least one β-coronavirus, such as a SARS virus, in particular SARS-CoV-2, and at least one influenza virus, and optionally at least one one Adenovirus HAdVB, HAdVC, or HAdVD, and/or at least one hRSV subtype A or B.

The invention further provides for an azelastine compound (as further described herein) in an antiviral effective amount for use as an antiviral substance in a pharmaceutical preparation for the prophylactic or therapeutic treatment of a disease condition caused by or associated with an infection by one or more different viruses which are Coronaviridae viruses, preferably selected from the group consisting of a β-coronavirus, such as SARS-CoV-2, MERS-CoV, SARS-CoV-1, HCoV-0043, or HCoV-HKU1, or an α-coronavirus, such as HCoV-NL63, HCoV-229E or PEDV, including naturally-occurring variants or mutants of any of the foregoing, for example, any one or more of the naturally-occurring SARS-CoV-2 variants or mutants referred to herein, preferably selected from the group consisting of the UK (B1.1.7) variant, the SA (B.1.351) variant, the Brazilian (P.1) variant, the Indian (B.1.617) variant and the Bengal (B.1.618) variant.

Specifically, the disease condition associated with or caused by a target virus, or a respiratory virus described herein, in particular wherein the target virus is a virus of the Coronaviridae, Adenoviridae, Paramyxoviridae, or Orthomyxoviridae family, is common cold, infection of the nose, sinusitis, throat and larynx, bronchiolitis, diarrhea, rash on skin, or pneumonia, acute respiratory distress syndrome (ARDS). Specifically, a disease condition can be a symptom associated with any one or more of the foregoing. Specifically, a symptom to be treated can be any of coughing, sore throat, runny nose, sneezing, headache, and fever.

According to a specific aspect, the antiviral effective amount is effective in preventing infection of susceptible cells by the virus, thereby treating the disease condition. Specifically, susceptible cells are within or at a biological surface or a subject.

According to a specific aspect, the antiviral effective amount is 0.1-500 μg/dose, preferably below any one of 100, 90, 80, 70, 50, 50, 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1 or 1 μg/dose. Specifically, the number of doses is up to 1 to 10 per day.

According to a specific aspect, the antiviral effective amount is 15 μg-150 μg per dose, preferably less than 100 μg, or less than 50 μg.

Specifically, the antiviral effective amount may be even less, such as less than any one of 50, 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1% of the amount ranging 15 μg-150 μg. Such lower amounts have particularly been proven to be effective with coronaviruses (or viruses of the family Coronaviridae), and/or viruses other than coronaviruses (or other than viruses of the family Coronaviridae), such as viruses of the families Adenoviridae, Paramyxoviridae, or Orthomyxoviridae.

For example, the antiviral effect targeting any of the target viruses described herein has proven to be highly effective with 0.1%, i.e. 2.39 mM) and 5× reduced (0.02%, i.e. 478 microM) dose of a commercial azelastine nasal spray preparation, thereby reducing viral load in humans.

For example, the anti-influenza virus effect has proven to be highly effective at 5× dilution (0.02%, i.e. 478 microM) and 10× dilution (0.01%, i.e. 239 microM) of a commercial azelastine preparation (being 0.1%, 2.39 mM).

For example, the anti-RSV effect has proven highly effective from a range of 0.4-6.4 microM in vitro.

According to a specific aspect, said pharmaceutical preparation is formulated for local administration, such as for topical or topical mucosal administration, preferably for application to the upper and lower respiratory tract, nasal, pulmonary, intraoral, ocular, or dermal use, or for systemic administration, preferably by intravenous, intramuscular, subcutaneous, intradermal, transdermal, or oral administration. Typically, for parenteral administration, intravenous or peroral administration is preferred.

According to a specific aspect, said pharmaceutical preparation is administered to a subject as a spray, such as a nose spray, a powder, such as an instant powder or powder for inhalation, or by a healthcare device, such as e.g., comprising a surface or fabric impregnated with the Azelastine compound for inhalation, a gel, an ointment, a cream, a foam, or a liquid solution, a lotion, a gargle solution, an aerosolized powder, an aerosolized liquid formulation, granules, capsules, drops, tablet, syrup, lozenge, an eye drop, or a preparation for infusion or injection.

Specifically, antiviral formulations and administration forms are provided, such as for veterinary and for human use. Specifically, the formulations comprise a predetermined amount of the Azelastine compound as active ingredient; e.g., as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.

According to a specific aspect, the Azelastine compound is used in an antiviral effective amount to provide a peak concentration (or maximum concentration) in blood or plasma, which is about 0.01-2 μg/mL, or up to any one of 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 μg/mL

According to a specific aspect, the Azelastine compound is used in a formulation at a concentration of 1 μM-10 mM, preferably up to any one of 1 mM, 100 μM, 90 μM, 80 μM, 70 μM, 60 μM, or 50 μM. According to a specific embodiment, the concentration is 3-50 μM.

Specifically, a liquid solution or dispersion is used for nasal administration, such as by nose drops or a nasal spray, preferably wherein the antiviral effective amount is 1-1000 μg per nostril, preferably 1-500 μg per nostril, or up to any one of 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, more preferably up to 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 5, 4, 3, 2 or 1 μg per nostril.

Specifically, a dose can be administered by nasal administration which is about 2-2000 μg per dose, preferably 2-1000 μg per dose, or up to any one of 400, 380, 360, 340, 320, 300, 280, 260, 240, 220, more preferably up to 200, 180, 160, 140, 120, 100, 80, 60, 40, 20, 10, 5, 4, 3, or 2 μg per dose.

A formulation is preferably applied as a nasal spray, nasal drops, an aerosol such as an aerosolized liquid or powder e.g., as a throat spray or for intrapulmonary administration, or as eye drops.

Exemplary formulations may contain the Azelastine compound as an active ingredient in an amount of, for example, 0.001 to 2% (w/w), such as about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.05%, 0.1%, 0.15%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, or 2.0% (w/w).

Specifically, a volume of 100-1000 μL per dose can be applied in a sprayable formulation, e.g., up to 500 μL spray volume. According to a specific example, a nasal spray may deliver a volume of about 100-150 μL per spray. Typically, two sprays are applied per nostril one or twice daily.

When using a spray, a metered spray is preferably used to administer a certain spray volume or dose per puff.

Formulations suitable for intrapulmonary administration may have a particle size in the range of 0.1 to 500 microns, which can be administered by inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the Azelastine compound. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds used in the treatment or prophylaxis of lung inflammation or lung diseases.

Specifically, a liquid solution or dispersion is used for parenteral administration, such as by infusions or injections, preferably wherein the antiviral effective amount provides a dose of about 1-500 mg.

Specifically, a single loading dose of about 1-500 mg may be administered parenterally, followed by maintenance doses of about 10-200 mg, or about 100 mg, or about 200 mg, e.g., by daily administration for 1-10 days, or until a certain clinical response has been achieved.

Specifically, a tablet, gel or lozenge is used for oral administration, preferably wherein the antiviral effective amount is 1 μg-12 mg per dose, preferably up to any one of 5, 4, 3, 2, or 1 mg; or up to 100 μg per dose.

Specifically, a tablet comprising the Azelastine compound may be used which can be administered once to three times a day.

Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, such as sucrose, acacia or tragacanth, pastilles comprising the Azelastine compound in an inert basis such as gelatin and glycerin, sucrose, or acacia, or mouthwashes comprising the Azelastine compound in a suitable liquid carrier.

When formulated in a topically applied gel or ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, active ingredients may be formulated in a cream with an oil-in-water cream base.

Formulations suitable for topical administration to the eye may include eye drops, gel or cream, wherein the Azelastine compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent or oil/water emulsion.

According to specific examples, such formulations for a topical administration in the mouth, or a topically applied formulation such as a gel or ointment, may comprise the Azelastine compound in a concentration of, for example, 0.001 to 20% (w/w), such as about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.05%, 0.1%, 0.15%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 9, or 20% (w/w).

According to a specific aspect, treatment with the Azelastine compound can be combined with a further treatment administering an Azelastine compound (which can be the same or a different compound) in another administration form. For example, treatment with an intranasal or throat spray comprising Azelastine Hydrochloride can be combined with a tablet comprising an Azelastine compound (which can be Azelastine Hydrochloride or different from Azelastine Hydrochloride).

According to a specific aspect, the Azelastine compound is administered as the sole antiviral substance, or wherein treatment is combined with a further treatment such as an additional antiviral, anti-inflammatory and/or antibiotic treatment e.g., comprising administration of one or more antiviral substances or agents, and/or one or more anti-inflammatory and/or antibiotic substances or agents, by one or more different preparations and/or one or more different routes of administration.

Specifically, the Azelastine compound can be combined with one or more additional active therapeutic agents in a unitary dosage form for simultaneous, co-administration or sequential administration to a subject. The combination therapy may e.g., be administered as a simultaneous, parallel or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.

According to a specific aspect, a subject is treated who has been infected or is at risk of being infected with said virus, preferably a human being, or a non-human mammal, such as a dog, cat, horse, camelids, cattle or pig.

Specifically, the subject is or has been exposed to a virus, or is otherwise at risk of being infected with the virus.

Specifically, the subject has a weakened immune system and is at a higher risk of developing a viral disease or increased severity of viral disease.

Specifically, the subject has been determined or diagnosed of being infected with the virus.

In specific embodiments, a subject is treated which is a diseased subject or patient suffering from Coronaviridae virus-caused disease, e.g., a SARS virus-caused disease, upon getting in contact with the pathogen, such as COVID19, or COVID19-associated pneumonia.

In further specific embodiments, a subject is treated which is a diseased subject or patient suffering from an influenza virus-caused disease, e.g., influenza.

The invention further provides for the Azelastine compound as described herein for use as an antiviral substance in a medicinal product for treating a biological surface to prevent from virus infection and/or virus spread.

According to a specific aspect, said medicinal product is formulated for topical use, preferably for application to the upper and lower respiratory tract, nasal, pulmonary, intraoral, ocular, or dermal use.

Topical application typically refers to the surface of the skin, a wound, and/or mucosal cells or tissues (e.g., alveolar, buccal, lingual, masticatory, or nasal mucosa, etc.).

According to a specific aspect, said medicinal product is used in a formulation suitably used for topical administration, in particular mucosal administration, such as a spray, solution, dispersion, dry powder, or aerosolized liquid or powder.

According to a specific aspect, the Azelastine compound is applied to a biological surface in an antiviral effective amount, preferably wherein the amount is 1 ng-1000 ng per cm2, preferably 10-800 ng/cm2, or up to any one of 800, 700, 600, 500, 400, 300, 200, 100, 90, 80, 70, 60, 50 ng/cm2.

Any of the medicinal products suitably used for topical treatment as described herein can be used for treating the biological surface.

According to a specific aspect, the biological surface comprises or consists of a mucosal surface which is infected or at risk of being infected with said virus.

The invention further provides for the use of an Azelastine compound as described herein, as viral disinfectant, in particular suitable for treating a biological surface, or a non-biological surface, such as sanitary devices face masks, etc. Specifically, animate or non-animate surfaces can be treated using the disinfectant.

Specifically, the viral disinfectant is an antiviral preparation, such as a medicinal product.

According to specific aspect, the invention provides for an Azelastine compound as described herein, for use in preventing or treating a Coronaviridae viral infection, in particular a SARS virus infection, in a human or non-human mammal.

According to specific aspect, the invention provides for an Azelastine compound as described herein, for use in preventing or treating a Coronaviridae viral infection, in particular a SARS virus infection, in a human or non-human mammal.

According to specific aspect, the invention provides for an Azelastine compound as described herein, for use in preventing or treating an Adenoviridae viral infection, in particular a HAdVB, HAdVC, or HAdVD virus infection in a human being.

According to specific aspect, the invention provides for an Azelastine compound as described herein, for use in preventing or treating a Paramyxoviridae viral infection, in particular a human RSV virus infection, in a human being.

According to specific aspect, the invention provides for an Azelastine compound as described herein, for use in preventing or treating a Orthomyxoviridae viral infection, in particular an influenza virus infection, in a human or non-human mammal.

According to a specific aspect, a kit is provided which comprising one or more individual dosage units of the Azelastine compound as further described herein, and directions for their use in treating a Coronaviridae viral infection or a Coronaviridae virus-caused disease, in a human or non-human mammal.

According to another specific aspect, a kit is provided which comprising one or more individual dosage units of the Azelastine compound as further described herein, and directions for their use in treating an Adenoviridae viral infection, in particular a HAdVB, HAdVC, or HAdVD virus infection in a human being.

According to another specific aspect, a kit is provided which comprising one or more individual dosage units of the Azelastine compound as further described herein, and directions for their use in treating a Paramyxoviridae viral infection, in particular a human RSV virus infection, in a human being.

According to another specific aspect, a kit is provided which comprising one or more individual dosage units of the Azelastine compound as further described herein, and directions for their use in treating a Orthomyxoviridae viral infection, in particular an influenza virus infection, in a human or non-human mammal.

According to a specific aspect, the invention provides for an antiviral pharmaceutical preparation comprising the Azelastine compound as further described herein and a pharmaceutically acceptable carrier.

Specifically, the pharmaceutical preparation is provided for medical use, in particular, for use in the prophylactic or therapeutic treatment of a disease condition caused by Coronaviridae virus such as COVID19.

Specifically, the pharmaceutical preparation is provided for medical use, in particular, for use in the prophylactic or therapeutic treatment of a disease condition caused by a Coronaviridae virus and/or an Adenoviridae virus and/or a Paramyxoviridae virus and/or a Orthomyxoviridae virus.

According to a specific aspect, the invention further provides for methods of treating a subject being infected or at risk of being infected with one or more different viruses such as one or more of Coronaviridae viruses and/or Adenoviridae viruses and/or Paramyxoviridae viruses and/or Orthomyxoviridae viruses, comprising administering an antiviral effective amount of the Azelastine compound, and respective medicinal products or pharmaceutical preparations as further described herein.

According to a further specific aspect, the invention provides for an antiviral preparation of the Azelastine compound as described herein (such as a medicinal product, pharmaceutical preparation or disinfectant) and methods of producing such antiviral preparation comprising formulating an antiviral effective amount of the Azelastine compound with a pharmaceutically acceptable carrier to produce an antiviral preparation, in particular a medicinal product or pharmaceutical preparation.

The topical administration of any of the antiviral preparations as described herein (such as a medicinal product, pharmaceutical preparation or disinfectant) to a biological surface is preferably such that upon a certain contact time of e.g. 10 minutes to 24 hours, and/or up to 24, 18, 12, 6, 5, 4, 3, 2, or 1 hour(s), contacting results in at least a 0.5-fold (by half) reduction, or 1-log, 2-log, 3-log, 4-log, 5-log reduction in a virus on said surface.

