Lactoferrin for oral Inhalation use for the treatment of a disease caused by a SARS-coronavirus The present invention relates to a composition comprising lactoferrin for inhalation use as an antiviral agent, preferably for use in the treatment of viral infections of the respiratory system and of symptoms or disorders deriving from, or relating to, said viral infections, preferably SARS-coronavirus viral infections (e.g. COVID-19). In addition, the present invention relates to a device for the administration - through the inhalation route - of said composition comprising lactoferrin and the use thereof in said methods for the treatment of viral infections.

Viral infections of the respiratory tract, as the name says, are infectious diseases caused by viruses that affect the organs of the upper and/or lower respiratory system (nose, pharynx, larynx, trachea, bronchi and lungs). Preferably, the present invention relates to viral infections caused by at least one virus of the species severe acute respiratory syndrome coronavirus, abbreviated as SARS-CoV. Said viruses of the SARS- CoV species are positive-strand RNA viruses (group IV of the Baltimore classification), belonging to the genus of Betacoronavirus.

A virus of the species severe acute respiratory syndrome coronavirus is the virus that caused the 2002- 2003 SARS epidemic in China, referred to as SARS-CoV strain. It was first discovered in November 2002 in the Chinese province of Guangdong. From November 1, 2002 to August 31, 2003, the virus infected 8,096 people in about thirty countries, causing 774 deaths, mainly in China, Hong Kong, Taiwan and all of Southeast Asia. Toward the end of 2019, a second virus of the species severe acute respiratory syndrome coronavirus, called SARS-CoV-2 strain or, alternatively, 2019-nCoV, caused a new SARS epidemic in China and the rest of the world, more commonly known as COVID-19 ( COronaVInis Disease 19, also known as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) or coronavirus disease 2019, also known as coronavirus syndrome 2019).

The Applicant, addresses and solves the problem of the treatment of viral infections, preferably viral infections of the respiratory tract (upper and lower respiratory tract), in particular viral infections of the respiratory tract caused by at least one virus of the species severe acute respiratory syndrome coronavirus (such as SARS-CoV, SARS-CoV-2/2019-nCoV strain - whose disease is known as COVID-19 - or SARS-CoV-like), by providing compositions for inhalation use comprising lactoferrin or a derivative thereof and, optionally, N-acetylcysteine and/or hyaluronic acid or a salt thereof, for use in methods for the treatment of said viral infections or symptoms or disorders related thereto.

Lactoferrin, also known as lactotransferrin, is a multifunctional globular protein. Lactoferrin belongs to the transferrin family and it has a molecular mass of about 80 KDa, with two binding sites for the ferric ion (Fe ³⁺ ), similarly to the transferrin itself. Lactoferrin is never saturated with iron and its ferric content varies. Lactoferrin has antimicrobial activity, bactericidal, fungicidal and against various viruses. It is hypothesised that the antimicrobial activity of lactoferrin is related to its affinity for Fe ³⁺ , therefore to its high ability to compete in the free state with iron-dependent microorganisms, and to a direct action on the external membrane of Gram-negative bacteria. The combination of lactoferrin with ferric ion in mucosal secretions modulates the activity and aggregative ability of bacteria and viruses toward cell membranes. This is due to the fact that some bacteria and viruses require iron in order to carry out cell replication and lactoferrin, on the contrary, removes it from the surrounding environment, preventing the proliferation of said bacteria and viruses. Patent document KR 20180120204 A describes a composition comprising lactoferrin for use in the treatment of viral respiratory infections, preferably human rhinovirus (HRV) infections and human influenza viruses; according to an embodiment, said composition may be administered using an inhaler; said composition may be in the form of dry powder. Lactoferrin exhibits antiviral activity against DMA and RNA viruses, including rotavirus, respiratory syncytial virus, herpes virus and HIV. The antiviral effect of lactoferrin lies in the early stage of infection. Lactoferrin prevents the virus from entering into the host cell by blocking cell receptors or binding directly to virus partides. Specifically, the antiviral effed of lactoferrin mainly lies in its ability to bind to glycosaminoglycans of the plasma membrane. Furthermore, it is known in the literature that ladoferrin partidpates in the host's immune response against acute invasion of severe acute respiratory syndrome coronavirus (SARS-CoV) by improving NK cell activity and by stimulating neutrophil aggregation and adhesion. Furthermore, it has been hypothesised that lactoferrin can play a protective role in the host's defence against SARS-CoV infection by binding to HSPGs (HSPG, heparan sulfate proteoglycans, widely distributed) and by blocking the preliminary interaction between SARS-CoV and host cells, given that HSPGs are essential molecules of the cell surface involved in the entry of SARS-CoV cells.

In the context of the present invention, the expression lactoferrin derivatives is used to indicate any multifunctional peptide or globular protein deriving from lactoferrin which shows similar antiviral effects, for example apolactoferrin or lactoferridn. Ladoferridn is a lactoferrin derivative with known antibacterial activity, apolactoferrin is lactoferrin in which the N-terminal lobe (or apoladoferrin) takes an open conformation. The compositions of the invention, based on lactoferrin or a derivative thereof and, optionally, N- acetylcysteine or a salt thereof and/or hyaluronic acid or a salt thereof, formulated for inhalation use, preferably in the form of dry powders for inhalation, are effective as antiviral agents, in particular in the treatment of viral infections of the respiratory trad and of the symptoms or disorders related thereto, in particular infections caused by at least one virus of the spedes severe acute respiratory syndrome coronavirus (such as the SARS-CoV, SARS-CoV-2 or SARS-CoV-like strain).

The compositions of the invention, based on lactoferrin or a derivative thereof and, optionally, hyaluronic acid or a salt thereof, can be formulated, by adding spedfic excipients and additives, as solutions or emulsions or dispersions suitable to be atomised and administered - using a spray device or the like - into the nose, into the throat and mouth for inhalation, oral or nasal use. Said sprayable compositions are effective as antiviral agents, in particular in the treatment of viral infections of the respiratory tract and of the symptoms or disorders related thereto in particular infections caused by at least one virus of the spedes severe acute respiratory syndrome coronavirus (such as SARS-CoV, SARS-CoV-2 or SARS-CoV- like).

The compositions of the invention, based on lactoferrin or a derivative thereof and, optionally, N- acetylcysteine or a salt thereof and/or hyaluronic acid or a salt thereof, have no significant side effects and they can be administered to all categories of subjects in need, induding the elderly, pregnant or breastfeeding women, paediatric subjects (0-12 years), subjeds with respiratory or cardiovascular complications or diabetes or other complications that may pose a risk or danger in the event of a viral infection, for example immunocompromised subjects due to congenital or acquired disease or under treatment with immunosuppressants or subjects who have undergone transplant surgery.

Furthermore, the compositions of the invention, based on lactoferrin and, optionally, N-acetylcysteine and/or hyaluronic acid, are easy to prepare and cost-effective.

It is known that the administration through the inhalation route allows a rapid onset (absence of first pass through the stomach and liver) and absence of side effects of damage to the stomach (for example, pain, bleeding, ulcers and/or indigestion) potentially present in oral (gastro-enteral) administration of the drug. Therefore, the administration of lactoferrin and, optionally, N-acetylcysteine and/or hyaluronic acid through the inhalation route can be advantageous with respect to the dassical oral administration in tablets and of high interest for patients with disorders assodated with said viral infections. In particular, the subject can self-administer the required dose of lactoferrin and, optionally, N-acetylcysteine and/or hyaluronic acid through the inhalation route, which leads to an almost immediate blood bioavailability of ladoferrin and, optionally, N-acetylcysteine and/or hyaluronic acid in the subject As a matter of fact, the administration of active substances through the inhalation route leads said substances into the lungs and, therefore, to the absorption thereof into the bloodstream in a significantly faster way as compared to an oral gastro-enteric administration (e.g. an oral tablet).

However, the administration of powdered drugs through the inhalation route can entail problems of coughing in the subject to whom they are administered, problems of low dosages due to limited capadty of emission of the inhalers, problems of packing of the powders, drawbacks related to a just a small portion of the administered active ingredient reaching the pulmonary pathways, difficulty on the part of the subject to use inhalers, difficulty in regulating the dosage by the subject in case of multidose inhalers, problems related to bacterial sterility in case of multi-purpose inhalers.

In order to overcome the aforementioned drawbacks, the Applicant developed a device (in short, device of the invention) comprising a single-dose inhaler, preferably a single-dose disposable inhaler, coupled with a single-dose container (for example a cartridge or a blister) comprising the composition of the invention which is effective for the administration of lactoferrin and, optionally, N-acetylcysteine and/or hyaluronic acid in powder form to a subject in need through the inhalation route .

The device of the invention is simple to construct and cost-effective. Furthermore, the device of the invention is easy to use by any type of subject, including subjects with respiratory difficulties, for example asthmatic subjects, children and the elderly. The easy use of the device of the invention allows to improve the adherence of the subject to the therapy. Furthermore, when the device of the invention is of the disposable type, it is free from bacterial sterility-related problems. Lastly, if the capsule/container (for example a cartridge or a blister) comprising the active ingredient (i.e. lactoferrin and, optionally, N-acetyl cysteine and/or hyaluronic acid) is inserted into the inhaler by the manufacturer of the device of the present invention, instead of being inserted by the user subject, the use of the device of the invention is even simpler and more immediate for the subject in need.

These and other objects, which will be dear from the detailed description that follows, are attained by the by the compositions, by the mixtures, by the device and by the inhaler of the present invention due to the technical characteristics present in the description and daimed in the attached daims.

FIGURES

Figure 1 is an upper perspective view of the inhaler seen from the distal end thereof; Figure 2 is a lower perspective view of the inhaler seen from the distal end thereof; Figure 3 is a top plan view of the inhaler;

Figure 4 is a view similar to the preceding one with the cartridge mounted on the inhaler;

Figure 5 is a sectional view of the inhaler along the longitudinal centreline plane thereof, with the cartridge mounted thereon; Figure 6 is a view similar to the preceding one with the cartridge open for dispensing the powder comprising the composition of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Forming an object of the present invention is a composition for inhalation use (in short, composition of the invention) for use as an antiviral agent, in a subject in need, preferably for use in a method for the preventive and/or curative treatment of viral infections of the respiratory system and of symptoms or disorders deriving from or relating to said viral infection in subjects in need, wherein said composition comprises:

(i) a mixture M (in short, mixture M of the invention) comprising or, alternatively, consisting of lactoferrin or an acceptable pharmaceutical grade derivative thereof; and, optionally,

(ii) at least one acceptable pharmaceutical grade additive and/or excipient.

Forming an object of the present invention is a method for the preventive and/or curative treatment of viral infections of the respiratory system, and of related symptoms or disorders, in a subject in need by administration through the inhalation route (oral or by mouth) of a therapeutically effective amount of said composition of the present invention comprising lactoferrin.

In an embodiment, the composition of the invention comprises said mixture M of the invention comprising lactoferrin or a derivative thereof and, furthermore, N-acetylcysteine (NAC) or an acceptable pharmaceutical grade salt thereof.

In the context of the present invention, an acceptable pharmaceutical grade salt of N-acetyl cysteine (in short, NAC) includes all the salts known in the art and/or to the man skilled in the art and suitable for the use of the present invention. A preferred example of an acceptable pharmaceutical grade N-acetylcysteine salt is the L-lysine salt of N-acetylcysteine (NAL). N-acetylcysteine is the substance identified by the lUPAC name 2R-acetamido-3-sulfanylpropanoic acid, CAS example: 616-91-1. N-acetylcysteine is a derivative of N-acetylate of the cysteine amino acid which has an antioxidant and mucolytic activity. Antioxidants are substances that slow or prevent the oxidation of other substances. Mucolytics are substances that make the mucus secreted by the respiratory system more fluid and facilitate the work of ejecting the mucus by the bronchi and trachea. It is known that the major determinants of viscosity and elasticity of the secretions of the respiratory system are fucomudns and IgG immunoglobulins. N-acetylcysteine, in particular, is characterised by the capadty to split the sulphur bridges in proteins: in the case of mucus, N-acetylcysteine depolymerises the mucoprotein complexes (glycoprotein agglomerates) into smaller units, provided with lower viscosity, and it exerdses an important mucolytic and fluidifying effect on the mucosal and mucopurulent secretions effect.

In an embodiment, the mixture M of the composition of the invention - besides lactoferrin or a derivative thereof and, optionally, N-acetylcysteine (NAG) or a salt thereof - further comprises hyaluronic acid (HA) or an acceptable pharmaceutical grade salt thereof.

For example, the mixture M of the composition of the invention comprises or, alternatively, consists of lactoferrin or a derivative thereof and hyaluronic acid, or an acceptable pharmaceutical grade salt thereof. Alternatively, the mixture M of the composition of the invention comprises, alternatively, consists of lactoferrin, or a derivative thereof, N-acetylcysteine and hyaluronic acid, or further comprises hyaluronic acid or an acceptable pharmaceutical grade salt thereof.

Hyaluronic acid (for example CAS 9004-61-9) is a non-sulfated glycosaminoglycan and devoid of protein core. Hyaluronic acid and the salts thereof are macromolecules. In particular, hyaluronic acid or the salt thereof, preferably sodium hyaluronate, in the context of the present invention preferably has an average molecular weight comprised from 20 kDa to 4000 kDa (for examplelOO kDa, 500 kDa, 1500 kDa, 1000 kDa, 2000 kDa, or 3000 kDa), preferably comprised from 50 kDa to 1500 kDa, even more preferably comprised from 150 kDa to 1000 kDa. In the context of the present invention, the expression hyaluronic acid salt is preferably used to indicate a salt of an alkaline or alkaline earth metal, such as for example sodium, potassium, magnesium or caldum; preferably the hyaluronic acid salt is the sodium salt (sodium hyaluronate).

The hyaluronic acid that can be used in the context of the present invention may be linear or branched and of plant origin (for example obtained through microbial fermentation of a plant substrate, such as soy), a biotechnology process consisting in allowing particular yeasts or bacteria that produce it spontaneously to ferment

The presence of hyaluronic acid in the composition of the invention combined with N-acetylcysteine or a salt thereof boosts the mucolytic efficacy of N-acetylcysteine (decrease in mucus viscosity and ease of expectoration/elimination of the mucus for the subject suffering from mucus hyper-production).

Preferably, the viral infection treated using the composition of the invention is an infection caused by a virus of the family Coronaviridae, subfamily: Coronavirinae, genus: Betacoronavirus, spedes: severe acute respiratory syndrome coronavirus (in short, SARS-CoV or SARS-coronavirus); preferably selected from the following strains: (I) severe acute respiratory syndrome coronavirus (SARS-CoV), (II) severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2 or virus responsible for the COVID-19 or 2019- nCoV disease), and (III) severe acute respiratory syndrome coronavims-like (SARS-CoV-like or SL-CoV); preferably (II) severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) or virus responsible for the COVID-19 disease.

In short, in the context of the present invention these viruses (e.g. (I), (II) and (III)) are referred to as "viruses of the spedes SARS-coronavirus" or simply 'SARS-coronavirus·.

Symptoms or disorders deriving from or relating to said viral infection of the respiratory tract, preferably coronavirus infection as defined above (e.g. SARS-CoV, SARS-CoV-2, SARS-CoV-like) may be: severe acute respiratory syndrome (SARS), respiratory complications, asthma, chronic obstructive pulmonary disease (CORD), bronchitis, emphysema, cystic fibrosis, cough, pertussis, pneumonia, pleuritis, bronchiolitis, cold, sinusitis, rhinitis, tracheitis, pharyngitis, laryngitis, acute laryngotracheobronchitis, epiglottitis, bronchiectasis, difficulty breathing, dyspnoea (breathlessness, shortness of breath,) fever, fatigue, musde ache and/or pain, nasal congestion, runny nose, sore throat, gastrointestinal symptoms such as for example nausea and diarrhoea, renal insufficiency, loss of appetite and/or general feeling of malaise.

The compositions of the invention, according to any one of the described embodiments, may be for use as adjuvants of further antiviral therapeutic approaches or for the treatment of the disease caused by a SARS-coronavirus.

The composition of the present invention, comprising lactoferrin or a derivative thereof and, optionally, N- acetylcysteine or a salt thereof and/or hyaluronic add or a salt thereof, is formulated for inhalation use, preferably in the form of dry powder for inhalation by mouth (oral inhalation); more preferably in the form of dry powder for inhalation by mouth (oral inhalation) using an oral inhalation device actuated by the subject treated through aspiration (by mouth) and wherein said inhalation device does not comprise propellant gases.

The composition of the invention formulated for inhalation use may comprise at least one acceptable pharmaceutical grade additive and/or excipient suitable for said formulation of the composition in the form of dry powder for inhalation by mouth and known to the man skilled in the art, wherein said at least one additive and/or excipient may comprise at least one first carrier and/or at least one second carrier and/or at least one further additive and/or excipient other than said first and second carriers, as defined below. Said first carrier is selected from: lactose, mannose, a dextran and mixtures thereof.

The composition of the invention in the form of dry powder for inhalation (oral) may comprise: (i) the mixture M comprising, or alternatively, consisting of lactoferrin or a derivative thereof; (ii) as additive and/or excipient; said at least one first carrier selected from lactose, a dextran, mannitol and mixtures thereof (preferably lactose). Preferably, the composition of the invention comprises or, alternatively, consists of lactoferrin and lactose.

Alternatively, the composition of the invention in the form of dry powder for inhalation (oral) may comprise: (i) the mixture M comprising or, alternatively, consisting of lactoferrin or a derivative thereof, and N- acetylcysteine or a salt thereof; (ii) as additive and/or excipient; said at least one first carrier selected from lactose, a dextran, mannitol and mixtures thereof (preferably lactose). Preferably, the composition of the invention comprises or, alternatively, consists of lactoferrin, N-acetylcysteine or a salt thereof and lactose.

Said at least one first carrier, for example lactose, may be present in the composition of the invention in a percentage by weight from 1% to 80% (for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, Or 75%) with respect to the total weight of the mixture M or of the composition, preferably from 5% to 50%, more preferably from 10% to 40%.

In an embodiment, the mixture M (lactoferrin or a derivative thereof and, optionally, N-acetylcysteine or a salt thereof): said at least one first carrier ( e.g . lactose) by weight ratio is comprised in the range from 10:1 to 1:10 (for example, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9), preferably from 5:1 to 1:5, more preferably from 2:1 to 1:2.

Lactose (lUPAC name β-D-galactopyranosyl (1→4) D-glucopyranose, CAS 63- 42- 3) is a disaccharide and a dextrorotatory reducing sugar. The lactose molecule consists of a D-galactose and of a D-glucose molecule linked by a glyosidic bond (acetal) β(1 - 4). The aldehyde group of the glucose unit is responsible for the reducing properties of lactose. Lactose is added to the inhalation powders of the present invention to improve the efficiency at which the DPI empties after respiratory activation, the turbulence, the dispersion of the active ingredient (lactoferrin and, optionally, N-acetylcysteine) in the small airways and so as to avoid the aggregation of powder particles to be inhaled. The lactose particles have a particle diameter such that they cannot penetrate into the deep parts of the respiratory system, hence most of the lactose settles in the oropharynx before moving on to the stomach after being swallowed.

Said second carrier is a stearate selected from among the group comprising or, alternatively, consisting of: magnesium stearate, zinc stearate, calcium stearate, sodium stearate, lithium stearate, sodium stearyl fumarate, sodium stearoyl lactylate and mixtures thereof; more preferably magnesium stearate.

The composition of the invention in the form of dry powder for inhalation (oral) may comprise: (i) the mixture M comprising or, alternatively, consisting of lactoferrin or a derivative thereof; (ii) as additive and/or excipient, said at least one second carrier selected from magnesium stearate, zinc stearate, calcium stearate, sodium stearate, lithium stearate, sodium stearyl fumarate, sodium stearoyl lactylate and mixtures thereof (preferably magnesium stearate).

Alternatively, the composition of the invention in the form of dry powder for inhalation (oral) may comprise: (i) the mixture M comprising or, alternatively, consisting of lactoferrin or a derivative thereof; (ii) as additive and/or excipient, said at least one first carrier selected from lactose, a dextran, mannitol and mixtures thereof (preferably lactose) and furthermore said at least one second carrier selected from magnesium stearate, zinc stearate, calcium stearate, sodium stearate, lithium stearate, sodium stearyl fumarate, sodium stearoyl lactylate and mixtures thereof (preferably magnesium stearate). Preferably, the composition of the invention comprises or, alternatively, consists of lactoferrin, lactose and magnesium stearate.

Furthermore, the composition of the invention in the form of dry powder for inhalation (oral) may comprise: (i) the mixture M comprising or, alternatively, consisting of lactoferrin or a derivative thereof, N- acetylcysteine or a salt thereof; (ii) as additive and/or excipient, said at least one second carrier selected from magnesium stearate, zinc stearate, calcium stearate, sodium stearate, lithium stearate, sodium stearyl fumarate, sodium stearoyl lactylate and mixtures thereof (preferably magnesium stearate). Preferably, the composition of the invention comprises or, alternatively, consists of lactoferrin, N- acetylcysteine or a salt thereof and magnesium stearate.

Alternatively, the composition of the invention in the form of dry powder for inhalation (oral) may comprise: (i) the mixture M comprising or, alternatively, consisting of lactoferrin or a derivative thereof, N- acetylcysteine or a salt thereof; (ii) as additive and/or excipient, said at least one first carrier selected from lactose, a dextran, mannitol and mixtures thereof (preferably lactose) and furthermore said at least one second carrier selected from magnesium stearate, zinc stearate, calcium stearate, sodium stearate, lithium stearate, sodium stearyl fumarate, sodium stearoyl lactylate and mixtures thereof (preferably magnesium stearate). Preferably, the composition of the invention comprises or, alternatively, consists of lactoferrin, N-acetylcysteine or a salt thereof, lactose and magnesium stearate.

Thus, the composition in the form of dry powder for inhalation (oral) of the present invention may comprise, as at least one additive and/or excipient, said at least one second carrier (e.g. a stearate, preferably magnesium stearate) alternatively to said first carrier or in addition to said at least one first carrier (e.g. lactose). Said at least one second carrier, for example magnesium stearate, may be present in the mixture M or in the composition of the invention in a percentage by weight from 0.05% to 60% (for example, 0.1%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or 55%) with respect to the total weight of the mixture M or of the composition, preferably from 0.1% to 30%, more preferably from 0.1% to 10%.

When composition of the invention in the form of dry powder for inhalation (oral) comprises both said at least one second carrier (e.g. magnesium stearate) and said at least one first carrier (e.g. lactose), the sum of said at least one first and one second carrier may be present in the mixture M or in the composition of the invention in a percentage by weight from 1% to 80% (for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70% or 75%) with respect to the total weight of the mixture M or of the composition, preferably from 5% to 50%, more preferably from 10% to 40%. Said at least one further acceptable pharmaceutical grade additive and/or excipient other than said at least one first and one second carrier, if present in the composition of the invention in the form of dry powder for inhalation (oral), is selected from the group comprising or, alternatively, consisting of: maltodextrin, leucine, sodium citrate and mixtures thereof, or any other additive and/or excipient known to the man skilled in the art Preferably, the composition of the invention or the mixture M of the invention in the form of dry powder suitable for inhalation through the oral route has an average particle diameter or volume median geometric diameter (in short, VMGD) comprised in the range from 0.5 μm to 50 μm, preferably from 0.5 μm to 20 μm, more preferably from 0.5 μm to 5 μm or from 1 μm to 5 μm or from 0.5 μm to 3 μm or from 1 μm to 3 μm, for example about 0.5 μm, 1 μm, 2 μm, 3 μm, 4 μm, 5 μm (±0,5 μm). The average particle diameter or the volume median geometric diameter (in short, VMGD) of the dry powder of the composition or mixture M of the present invention formulated for inhalation are measured according to standard methods and equiμment known to the man skilled in the art, in particular according to technologies known in the field of powders for inhalation through the oral route.

The composition of the invention or the mixture M of the invention, comprising lactoferrin or a derivative thereof and, optionally, N-acetylcysteine or a salt thereof and/or hyaluronic acid or a salt thereof, and, optionally, said at least one first carrier and/or said at least one second carrier (for example lactose and/or magnesium stearate), may be in the form of micronized dry powder.

In the context of the present invention, the expression 'dry powder* is used to indicate a powder having a low moisture content, for example a powder having a content comprised in the range from 0.01% to15% (for example, 0.05%, 0.1%, 0.5%, 1%, 5%, or 10%) by weight with respect to the total weight of the powder, preferably from 0.1% to 10%, more preferably from 0.5% to 5%.

The composition of the invention and/or the mixture M of the invention are produced in a form suitable for inhalation (oral), preferably dry powder for inhalation (oral), through processes known to the man skilled in the art in the field of inhalable drugs or products. For example, the composition of the invention can be prepared through a process for the mechanical mixing of the individual components. Furthermore or alternatively, the composition of the invention can be prepared through a spray-drying process.

The composition of the invention for inhalation use, preferably in the form of dry powder for inhalation by mouth (oral), is effective as an antiviral agent, in particular in the treatment of infections of the respiratory tract caused by a SARS-coronavirus, preferably SARS-CoV-2 or strain responsible for the COVID-19 disease, in daily doses of lactoferrin comprised in the range from 5 mg to 1000 mg or from 5 mg to 500 mg, preferably from 10 mg to 300 mg, more preferably from 10 mg to 200 mg, for example from 10 mg to 100 mg, from 10 mg to 90 mg, from 10 mg to 80 mg, from 10 mg to 70 mg, from 10 mg to 60 mg, from 10 mg to 50 mg, from 10 mg to 180 mg, from 10 mg to 160 mg, from 10 mg to 140 mg, from 10 mg to 120 mg.

The aforementioned daily doses can be administered to the subject in need in a single dose (one dose) or in repeated doses, for example two, three or four daily doses.

The composition of the invention may be administered using an inhaler suitable for inhalation of dry powder known in the art (DPIs, dry powder inhalers), such as single-dose or multidose inhaler, disposable (single use- single dose) inhaler or inhaler reusable after each dose.

Forming an object of the present invention is a device for delivering a composition through the inhalation route (in short, device of the present invention, such as an inhaler plus the composition of the present invention) wherein said device comprises: - a dry powder inhaler (in short, inhaler of the present invention) having the characteristics reported below and in patent document EP3386575B1 incorporated for reference in the present description in the parts describing the inhaler, such as from [0024] to [0041] and from Figure 1 to Figure 8; and The composition of the invention according to any one of the embodiments described in the present invention comprised in the cartridge (C) housed in or to be housed in said inhaler, wherein said composition comprises: (i) the mixture M comprising or, alternatively, consisting of lactoferrin or a derivative thereof and, optionally, N-acetylcysteine or an acceptable pharmaceutical grade salt thereof and/or hyaluronic acid or an acceptable pharmaceutical grade salt thereof; and, optionally, said composition further comprises (ii) at least one acceptable pharmaceutical grade additive and/or excipient (i.e. a first carrier and/or a second carrier and/or a further additive other than said first and second carriers), wherein said composition is in the form of dry powder for administration by inhalation (oral) preferably having the characteristics defined in the present invention, such as volume median geometric diameter (VMGD), by weight percentages, by weight ratios etc.

Said composition of the invention for inhalation (oral) in the form of dry powder, comprising lactoferrin or a derivative thereof and, optionally N-acetyl cysteine and/or hyaluronic acid and/or additives, is comprised in a cartridge (C) housed - temporarily at the time of use or permanently (i.e. from manufacturing) - in said inhaler of the present invention to obtain the device of the present invention. Preferably, the device of the present invention comprises said cartridge (C) permanently incorporated in the inhaler (i.e. from manufacturing). Said cartridge (C), comprising the composition of the present invention and housed in the inhaler of the present invention to form the device of the present invention, may alternatively be referred to as a blister or container.

Before the administration of the composition of the invention to a subject in need using the device of the present invention through an oral aspiration action by said subject (without the aid of propellant gases), said composition is transferred from the cartridge (C) housed in the inhaler of the present invention to a region of said inhaler (such as, for example, an inner fall region (5) in Figure 1). Said transfer of the composition of the invention from the cartridge (C) to a region of the inhaler may for example occur after the breakage of a surface of said cartridge (C), wherein said surface is faced toward the region of the inhaler where the composition is to be transferred (e.g. a pierceable surface of a blister). Said breakage of a surface of the cartridge (C) (or blister) can be carried out by exerting pressure - by the user of the device - on a surface of the cartridge (C) (or blister) opposite to the surface to be pierced, for example by applying pressure using the hand or the finger.

The single-dose inhaler of the invention is preferably a single-dose disposable inhaler. The single-dose inhaler of the invention is actuated by the subject through oral aspiration and it does not comprise propellant gases.

Embodiments (FRns) of the single-dose inhaler, preferably single-dose disposable, of the present invention are as follows: FR1. Inhaler for medicinal products in powder form (dry powder compositions for inhalation) consisting of a substantially pipe-shaped hollow body having a first portion (1) for housing a cartridge (C) (or blister) of said medicinal product in powder form (i.e. composition of the present invention) and a second portion (2) connected substantially perpendicularly to said first portion (1) for dispensing the medicinal product by means of a primary air flow (FP) carrying the powder from an inner fall region (5), located at the bottom of said first portion (1), along a dispensing duct (3) whose end is suitable to be placed in the mouth of the patient, said dispensing duct (3) being divided horizontally by a partitioning septum (4) into an upper duct (3a) which dispenses said primary air flow (FP) and a lower duct (3b) which dispenses a powder-free secondary air flow (FS), the suctioning of the air forming the primary flow (FP) being carried out through at least three air intakes (7) formed in the first portion (1) which are preferably arranged symmetrically with respect to the longitudinal centreline plane of the inhaler, the suctioning of the air forming the secondary flow (FS) being carried out through an air intake (8) obtained at the distal end of said lower duct (3b), the inhaler being characterised in that said base for supporting the cartridge (C) includes a plurality of horizontal support surfaces (9) projecting into the first portion (1), oriented flow channels (11) formed in the support base which extend between said at least three air intakes (7) and inner powder foil region (5). FR2. Inhaler according to FR1, characterised in that the longitudinal axes of the channels (11) extending from side air intakes (7) form a 55º±20% angle (a) with the centreline plane.

FR3. Inhaler according to one of the preceding FRs, characterised in that said horizontal support surfaces (9) projecting into the first portion (1) are formed on a plane corresponding to the top part of the upper duct (3a) so that a distal portion (9') of the latter is also part of the support base.

FR4. Inhaler according to one of the preceding FRs, characterised in that the connection between the internal powder fall region (5) and the upper duct (3a) is obtained by means of a grid (6).

FRS. Inhaler according to one of the preceding FRs, characterised in that it further comprises three vertical septa (14) extending over the entire height of the grid (6) and partition it into four air inlet regions, said vertical septa (14) being preferably arranged so that said inlet regions have the same width.

FRS. Inhaler according to one of the preceding FRs, characterised in that the partitioning septum (4) is shorter than the dispensing duct (3), preferably by a distance (d) comprised between 4 and 7 mm.

FR7. Inhaler according to one of the preceding FRs, characterised in that the first portion (1) comprises a perimeter wall (12) extending above the support base and it is provided with coupling means for locking the cartridge (C) onto the inhaler.

FR8. Inhaler according to one of the preceding FRs, characterised in that, at each support surface (9), the perimeter wall (12) has an elastic region (12a) with reduced thickness having a central triangular tooth (12b) projecting thereinto, said tooth (12b) being obtained with an inclined surface extending from the top part of the wall (12) toward the support base and with a lower horizontal base so as to form a chute for the insertion of the cartridge (C) from above and an undercut for the locking thereof onto the base of support. FR9. Inhaler according to one of the preceding FRs, characterised in that the air intake (8) of the lower duct (3b) is partitioned into a plurality of air inlet regions, preferably having the same width, by one or more elongated septa (15), preferably not more than seven, extending below the powder fall region (5).

FR10. Inhaler according to one of the preceding FRs, characterised in that the minimum inlet section of the upper duct (3a) is 25.6 mm ² ±20%, the minimum inlet section of the lower duct (3b) is 14.3 mm ² ±20%, and the ratio between said sections may vary in the range from 1:1 to 9:1. FR11. Inhaler according to one of the preceding FRs, characterised in that the air intakes (7) for the primary air flow (FP) consist of projections, preferably semi-circular, obtained in the lower wall of the first portion (1) below the support base. FR12. Disposable single dose device for the inhalation of lactofemn or a derivative thereof and, optionally,

N-acetylcysteine or a salt and/or hyaluronic acid or a salt thereof in powder form, characterised in that it comprises an inhaler according to one of daims 9 to 11 and a self-pierdng cartridge comprising the dry powder composition of the invention locked on the support base of said inhaler, said cartridge (C) having a symmetrical longitudinal plan shape substantially corresponding to the shape of said support base and a region (P) designed to receive the pressure of a patient's fingers to open the cartridge (C), said region (P) being aligned to the longitudinal symmetry plane of the cartridge (C).

The administration of the compositions of the invention, comprising lactoferrin or a derivative thereof and, optionally, N-acetylcysteine or a salt thereof and/or hyaluronic acid or a salt thereof, in the form of dry powder for inhalation (oral) by means of the delivery device of the invention, actuated by the aspiration of the subject in need, it is such as to make effective the administration of the dose effective and to maximize the intrinsic effectiveness of the compositions of the invention itself.

The composition of the invention in the form of dry powder for inhalation (oral), according to any one of the embodiments defined in the present invention, shows a good ftowability, a good uniformity of distribution of the active ingredient and an appropriate chemical and physical stability prior to use.

Furthermore, when inhaled using the inhaler of the invention actuated by means of a single aspiration action by the subject to whom the composition is administered, the composition of the invention in the form of dry powder for inhalation creates a good inhalable fraction and an accurate therapeutically active dose of the active ingredient.

The expression "good flowability" refers to a composition that can be easily handled during the preparation method and it is capable of guaranteeing an accurate and reproducible administration of the therapeutically effective dose when administered using the device of the invention by means of the aspiration action of the subject The flow characteristics can be evaluated by measuring the Carr index; a Carr index lower than 25 is usually used to indicate good flow characteristics.

The expression "distribution uniformity" refers to a composition in which, when mixing, the uniformity of the content of the active ingredient, expressed as the relative standard deviation (RSD), is lower than 5%.

The expression "chemically stable" refers to a formulation that meets the ICH Q1 A guidelines referring to "Stability testing of novel active substances (and medicinal products)". The expression "physically stable" refers to a formulation in which if several components of the dry powder particles of the composition of the invention are present, these components substantially do not separate during the method for preparing the dry powder and/or over the time comprised between the preparation and the use of the composition.

The tendency to separate can be evaluated according to Staniforth et al., J. Pharm. Pharmacol., 34.700- 706, 1982, which is wholly incorporated herein for reference, and it is considered acceptable if the distribution of the active ingredient in the dry powder composition after the test, expressed as the relative standard deviation (RSD), does not change significantly with respect to that of the composition prior to the test

The expression "inhalable fraction" refers to an index of the particle percentage of active ingredient which reaches the lungs (deep area) in a subject The inhalable fraction, also referred to as the fine particle fraction (FRF), is evaluated using appropriate in viiro apparatus such as Multistage Cascade Impactor or Multi Stage Liquid Impinger (MLSI) according to the procedures indicated in common pharmacopeia. FRF is calculated from the ratio between the dispensed dose and the fine particle mass (of fine particle dose, in short FPD). An inhalable fraction greater than 30% is an index of good inhalation performance. The expression "accurate therapeutically active dose of the active ingredient" refers to a composition in which the change between the average dispensed daily intake and the average emitted dose is equal to or lower than 15%, preferably lower than 10%.

In the context of the present invention, the expressions "active agent" and 'active ingredienf are synonyms and they refer to lactoferrin or a derivative thereof, and, optionally, to N-acetylcysteine or acceptable pharmaceutical or food grade salts thereof and/or hyaluronic acid and acceptable pharmaceutical or food grade salts thereof.

Unless specified otherwise, the expression composition or mixture or other comprising a component at an amount 'comprised in a range from x to y* is used to indicate that said component can be present in the composition or mixture or other at all the amounts present in said range, even though not specified, extremes of the range comprised.

Unless specified otherwise, the indication that a composition or mixture 'comprises' one or more components or substances means that other components or substances can be present besides the one, or the ones, indicated specifically. In the context of the present invention, the expression 'treatment method* is used to indicate an intervention on a subject in need, comprising the administration of a therapeutically effective amount (established by the man skilled in the art based on standard methods and instruments) of a composition or mixture of substances with the aim of eliminating, reducing/decreasing or preventing a disease or ailment and symptoms or disorders thereof. In the context of the present invention, the term 'subject/s' is used to indicate human or animal subjects, preferably mammals (e.g. pets such as dogs, cats, horses, sheep or cattle). Preferably, the compositions of the invention are for use in treatment methods for human subjects.

Preferred embodiments of the present invention FRn are reported below. FR1. A composition for use in a method of treating a viral infection of the respiratory system, and related symptoms or disorders, wherein said viral infection is caused by a virus of the family Coronaviridae, subfamily: Coronaviiinae, genus: Betacoronavirus, spedes: severe acute respiratory syndrome coronavirus (SARS), wherein said composition comprises (i) a mixture M comprising or, alternatively, consisting of lactoferrin or an acceptable pharmaceutical grade derivative thereof; and, optionally,

(ii) at least one acceptable pharmaceutical grade additive and/or excipient; and wherein said composition is for use through the inhalation route and wherein the composition is formulated in the form of dry powder for inhalation by mouth.

FR2. The composition for use according to FR1, wherein said virus belonging to the species severe acute respiratory syndrome coronavirus is selected from the strains: severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2 or 2019-nCoV), and severe acute respiratory syndrome coronavirus-like (SARS-CoV-like or SL-CoV); preferably severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) responsible for the COVID 19 disease.

FR3. The composition for use according to any one of the preceding FRs, wherein the mixture M further comprises N-acetylcysteine or an acceptable pharmaceutical grade salt thereof.

FR4. The composition for use according to any one of the preceding FRs, wherein the mixture M further comprises hyaluronic acid or an acceptable pharmaceutical grade salt thereof. FR5. The composition for use according to any one of the preceding FRs, wherein the composition comprises said at least one acceptable pharmaceutical grade additive and/or excipient, and wherein said at least one additive and/or excipient comprises at least one first carrier seleded from: ladose, mannose, a dextran and mixtures thereof, preferably ladose.

FR6. The composition for use according to FRS, wherein said at least one additive and/or excipient further comprises at least one second carrier selected from a stearate, preferably selected from: magnesium stearate, zinc stearate, caldum stearate, sodium stearate, lithium stearate, sodium stearyl fumarate, sodium stearoyl lactylate and mixtures thereof, more preferably magnesium stearate.

FR7. The composition for use according to any one of the preceding FRs, wherein said composition or mixture M has a volume median geometric diameter (VMGD) comprised in the range from 1 μm to 50 μm, preferably from 1 μm to 20 μm, more preferably from 1 μm to 5 μm.

FR8. A device for delivering a composition through the inhalation route, wherein said device comprises:

- a cartridge (C) comprising the inhalation composition according to any one of FRs 1 to 7, wherein said composition comprises

(i) the mixture M comprising or, alternatively, consisting of lactoferrin or an acceptable pharmaceutical grade salt thereof; and, optionally,

(ii) at least one acceptable pharmaceutical grade additive and/or excipient; and

- a dry-powder inhaler comprising a substantially pipe-shaped hollow body comprising a first portion (1) for housing a cartridge (C) of said inhalation composition according to any one of daims FRs 1 to 7, and a second portion (2) connected to said first portion (1) for dispensing the powder composition by means of a primary air flow (FP) carrying the powder from an inner fall region (5), located at the bottom of said first portion (1), along a dispensing duct (3) whose end is suitable to be placed in the mouth of a subject, said dispensing duct (3) being divided horizontally by a partitioning septum (4) into an upper duct (3a) which dispenses said primary air flow (FP) and a lower duct (3b) which dispenses a powder-free secondary air flow (FS), the suctioning of the air forming the primary flow (FP) being carried out through at least three air intakes (7) formed in the first portion (1) which are preferably arranged symmetrically with respect to the longitudinal centreline plane of the inhaler, the suctioning of the air forming the secondary flow (FS) being carried out through an air intake (8) obtained at the distal end of said lower duct (3b), the inhaler being characterised in that said base for supporting the cartridge (C) includes a plurality of horizontal support surfaces (9) projecting into the first portion (1) and oriented flow channels (11) formed in the support base which extend between said at least three air intakes (7) and inner powder fall region (5). FR9. The device according to FR8, for use in a method for the treatment of a viral infection of the respiratory system, wherein said viral infection is caused by a virus of the family Coronaviridae, subfamily: Coronaviiinae, genus: Betacoronavirus, species: severe acute respiratory syndrome coronavirus (SARS), preferably selected from the strains: severe (SARS-CoV), severe acute respiratory syndrome coronavirus- 2 (SARS-CoV-2 or virus responsible for the COVID-19 or 2019-nCoV disease), and severe acute respiratory syndrome coronavirus-like (SARS-CoV-like or SL-CoV); preferably severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) or virus responsible for the COVID-19 disease.

FR10. The composition for use according to any one of FRs 2 to 7 or the device for use according to FR9, wherein said symptoms and/or disorders deriving from or relating to said viral infection of the respiratory system are selected from: severe acute respiratory syndrome (SARS), respiratory complications, asthma, chronic obstructive pulmonary disease (CORD), bronchitis, emphysema, cystic fibrosis, cough, pertussis, pneumonia, pleuritis, bronchiolitis, cold, sinusitis, rhinitis, tracheitis, pharyngitis, laryngitis, acute laryngotracheobronchitis, epiglottitis, bronchiectasis, difficulty breathing, dyspnoea, breathlessness, shortness of breath, fever, fatigue, muscle ache and/or pain, nasal congestion, runny nose, sore throat, gastrointestinal symptoms, nausea, diarrhoea, renal insufficiency, loss of appetite, general feeling of malaise.