Treatment of viral diseases

Abstract

The present invention provides a method of treating a viral disease, disorder, or condition in a subject, the method comprising administering to said subject by inhalation a medically active liquid in a nebulized form, wherein the medically active liquid comprises remdesivir or a pharmaceutically acceptable salt thereof, and wherein the medically active liquid is administered in a nebulized form using an inhalation device.

Description

[Technical Field]

[0001] The present invention relates to the field of methods for treating viral infections or viral diseases, disorders, or conditions in a subject by administering to the subject a medically active liquid in aerosolized form via inhalation, wherein the medically active liquid comprises remdesivir or a pharmaceutically acceptable salt thereof, and the medically active liquid is administered in aerosolized form using an inhalation device. More specifically, the present invention relates to the treatment of viral infections, such as coronavirus infections, or viral diseases, disorders, or conditions, such as respiratory or pulmonary diseases, disorders, or conditions induced by or resulting from coronavirus infections. [Background technology]

[0002] Nebulizers or other aerosol generators for liquids are known in the art. These devices are used, inter alia, in medicine and therapy. They function as inhalation devices for administering an active ingredient in the form of an aerosol, i.e., small droplets embedded in a gas. Such inhalation devices are known, for example, from European Patent No. 0,627,230. The essential components of such inhalation devices are a reservoir containing the liquid to be aerosolized, a pumping device for generating a pressure high enough to atomize the liquid, and an atomizing device in the form of a nozzle. The pumping device draws the liquid from the reservoir in discrete amounts, i.e., not continuously, and delivers it to the nozzle. The pumping device operates without a propellant and generates pressure mechanically.

[0003] Remdesivir is an antiviral drug approved by the FDA in May 2020 for emergency use to treat suspected or laboratory-confirmed coronavirus disease COVID-19 in adults and children hospitalized with severe illness. Remdesivir has been shown to have antiviral effects against the novel coronavirus first detected in 2019, called SARS-CoV-2 (also known as 2019-nCoV), which caused the COVID-19 disease outbreak. See, for example, Wang, M. et al., Cell Research, Vol. 30, 269-271 (2020, doi:10.1038 / s41422-020-0282-0). In addition to COVID-19, remdesivir is being investigated for the treatment of other viral infections. For example, remdesivir has been shown to have antiviral effects against various viral infections, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), Ebola virus (EBOV), Marburg virus, respiratory syncytial virus (RSV), Nipah virus (NiV), and Hendra virus. See, for example, Warren, TK et al., Nature, Vol. 531, 381-385 (2016); Lo, MK et al., Sci. Rep., Vol. 7, 43395 (2017); Sheahan, TP et al., Sci. Transl. Med., Vol. 9, ea113653 (2017); and Sheahan, TP et al., Nature Communications, Vol. 11, 222 (2020, doi:10.1038 / s41467-019-13940-6). U.S. Patent No. 7,544,712 discloses methods for treating coronavirus infections, including severe acute respiratory syndrome and transmissible porcine gastroenteritis virus infections, by oral, intranasal, or parenteral administration of various compounds. Despite these efforts, a soluble liquid formulation of remdesivir has not been developed for pulmonary delivery via inhalation to treat a viral infection or viral disease or condition, such as a respiratory disease or condition.Such formulations advantageously deliver drugs to patients in more precise doses non-invasively through the highly permeable, large surface area of ​​the lung.

[0004] It is therefore an object of the present invention to provide a method for treating a viral infection or viral disease, disorder or condition in a subject in a particularly precise, effective and patient-friendly manner. Further objects of the present invention will become apparent based on the following description, examples and claims of the invention. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] European Patent No. 0,627,230 [Patent Document 2] U.S. Patent No. 7,544,712 [Non-patent literature]

[0006] (Non-patent document 1) Wang, M. et al., Cell Research, Vol. 30, 269-271 (2020, doi:10.1038 / s41422-020-0282-0) (Non-Patent Document 2) Warren, TK et al., Nature, Vol. 531, 381-385 (2016) (Non-patent document 3) Lo,MKet al,Sci.Rep.,Vol.7,43395(2017);Sheahan,TPet al.,Sci.Transl.Med.,Vol.9,eaal3653(2017) (Non-patent document 4) Sheahan, TPet al., Nature Communications, Vol. 11, 222 (2020, doi:10.1038 / s41467-019-13940-6) Summary of the Invention

[0007] In a first aspect, the present invention relates to a method of preventing or treating a viral infection or viral disease, disorder, or condition in a subject, the method comprising administering to the subject by inhalation a medically active liquid in a nebulized form, wherein the medically active liquid comprises remdesivir or a pharmaceutically acceptable salt thereof, and wherein the medically active liquid is administered in a nebulized form using an inhalation device. In some embodiments, the viral disease, disorder, or condition is a respiratory or pulmonary disease, disorder, or condition. In a further aspect, the present invention provides a medically active liquid comprising remdesivir or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of a viral infection or viral disease, disorder, or condition in a subject, wherein the medically active liquid is administered to the subject in a nebulized form by inhalation using an inhalation device. In some embodiments, the viral disease, disorder, or condition is a respiratory or pulmonary disease, disorder, or condition.

[0008] In a further aspect, the present invention provides use of remdesivir or a pharmaceutically acceptable salt thereof for preparing a medically active liquid for preventing or treating a viral disease, disorder, or condition in a subject, wherein the medically active liquid is administered to the subject in a nebulized form by inhalation using an inhalation device. In some embodiments, the viral disease, disorder, or condition is a respiratory or pulmonary disease, disorder, or condition.

[0009] In yet a further aspect, the present invention provides use of an inhalation device for preventing or treating a viral infection or viral disease, disorder, or condition in a subject, wherein a medically active liquid is administered in nebulized form using the inhalation device, and the medically active liquid comprises remdesivir or a pharmaceutically acceptable salt thereof. In some embodiments, the viral disease, disorder, or condition is a respiratory or pulmonary disease, disorder, or condition. [Brief explanation of the drawings]

[0010] [Figure 1]1 shows an embodiment of an inhalation device that can be used before its first use in the method of the present invention.

[0011] [Figure 2] 2 shows an inhalation device similar to that of FIG. 1 but without the outlet valve.

[0012] [Figure 3] 2 shows the embodiment of FIG. 1 with a filled pump chamber.

[0013] [Figure 4] 2 shows the inhalation device of FIG. 1 during initial operation;

[0014] [Figure 5] The situation at the end of the first operation is shown.

[0015] [Figure 6] The situation after refilling the pump chamber is shown.

[0016] [Figure 7] 1 shows the results of the average particle size distribution of Example 1.

[0017] [Figure 8] 1 shows the results of the average particle size distribution of Example 2. DETAILED DESCRIPTION OF THE INVENTION

[0018] In a first aspect, the present invention provides a method of treating or preventing a viral infection or viral disease, disorder, or condition in a subject, the method comprising administering to the subject by inhalation a medically active liquid in a nebulized form, wherein the medically active liquid comprises remdesivir or a pharmaceutically acceptable salt thereof, and wherein the medically active liquid is administered in a nebulized form using an inhalation device. In some embodiments, the viral disease, disorder, or condition is a respiratory or pulmonary disease, disorder, or condition.

[0019] In a second aspect, the present invention provides a medically active liquid comprising remdesivir or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a viral infection or viral disease, disorder, or condition in a subject, wherein the medically active liquid is administered to the subject in a nebulized form by inhalation using an inhalation device.

[0020] As used herein, the term "treatment" means the administration of a compound or composition to a subject to at least ameliorate, reduce, or inhibit existing signs or symptoms of an infection, disease, disorder, or condition experienced by the subject.

[0021] As used herein, the term "prevention" refers to the prophylactic administration of a formulation to a subject who does not exhibit signs or symptoms of an infection, disease, disorder, or condition, but who is expected or anticipated to be likely to exhibit such signs or symptoms in the absence of prevention. Prophylactic treatment may at least alleviate or partially ameliorate the expected symptoms or symptoms.

[0022] As used herein, the term "effective amount" refers to the administration of a sufficient amount of the relevant compound or composition to prevent the onset of symptoms of the condition being treated, or to stop the worsening of symptoms, or to treat and alleviate symptoms, or at least reduce the severity of symptoms. The effective amount will vary in a manner understood by those skilled in the art with respect to the patient's age, sex, weight, etc.

[0023] As used herein, the term "subject" or "individual" or "patient" can refer to any subject for whom treatment is desired, particularly a vertebrate subject, and even more particularly a mammalian subject.Suitable vertebrates include, but are not limited to, primates, birds, livestock animals (e.g., sheep, cows, horses, donkeys, pigs), laboratory animals (e.g., rabbits, mice, rats, guinea pigs, hamsters), companion animals (e.g., cats, dogs), and captive wild animals (e.g., foxes, deer, dingoes).Preferred subjects, individuals, or patients are humans.

[0024] As used herein, the term "medically active" refers to a compound that has pharmacological activity that ameliorates symptoms associated with a viral infection or viral disease, disorder or condition, such as a respiratory disease, disorder or condition.

[0025] Further definitions are provided in the ensuing discussion.

[0026] For the avoidance of doubt, it should be noted that all embodiments and features of the invention described below, and combinations thereof, whether referred to as "specific," "particular," "preferred," "advantageous," or in any other manner, can refer to all aspects of the invention summarized above and further described below.

[0027] As used herein, the term "remdesivir" refers to the compound also known as GS-5734, Chemical Abstracts Service (CAS) number [1809249-37-3]. Remdesivir has a molecular weight of 602.6 g / mol and the following structure: TIFF0007761592000001.tif98120

[0028] The term "remdesivir" also includes any pharmaceutically acceptable salts of remdesivir.

[0029] The present invention provides methods and medically active liquids for use in treating or preventing a viral infection or viral disease, disorder, or condition in a subject. In some specific aspects, the disease, disorder, or condition is associated with, caused by, or mediated through a viral infection, such as a coronavirus, or specifically the disease COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In some embodiments, the viral disease, disorder, or condition is a respiratory or pulmonary disease, disorder, or condition.

[0030] Generally speaking, a viral disease, disorder, or condition according to the present invention can be induced by or result from a viral infection, can be a disease, disorder, or condition of the immune system, cardiovascular system, endocrine system, gastrointestinal tract, renal system, respiratory system, central nervous system, or can be a cancer or other malignancy caused by or associated with a viral pathogen. A viral disease according to the present invention can also be a viral infection or viral disease, disorder, or condition that responds to inhibition of viral replication.

[0031] More specifically, the viral disease, disorder or condition referred to herein may be induced by or result from a viral infection and may be a disease, disorder or condition of the immune system, an inflammatory disease, disorder or condition or an autoimmune disease, disorder or condition, a disease, disorder or condition of the cardiovascular system, a cancer, tumor or other malignancy, a disease, disorder or condition of the renal system, a disease, disorder or condition of the gastrointestinal tract, a disease, disorder or condition of the respiratory system, a disease, disorder or condition of the endocrine system and / or a disease, disorder or condition of the central nervous system (CNS).

[0032] According to certain of these embodiments, the methods and medically active liquids for use according to the present invention allow for the treatment of viral infections in patients or subjects, which may be selected from a wide variety of viral infections, including coronaviruses, influenza viruses such as H1N1 influenza or avian influenza H5N1, rhinoviruses such as human rhinoviruses (HRV), adenoviruses such as human adenoviruses (HAdV), severe acute respiratory syndrome viruses (SARS) such as severe acute respiratory syndrome coronavirus (SARS-CoV or SARS-CoV-2), Middle East respiratory syndrome viruses such as Middle East respiratory syndrome coronavirus (MERS-CoV), Zika virus (ZIKV), Japanese encephalitis virus (JEV), hepatitis C virus (HCV), Ebola virus (EBOV), chikungunya virus (CHIKV), Epstein-Barr virus (EBV), Marburg virus, respiratory syncytial virus (RSV), Nipah virus (NiV), Hendra virus, and human immunodeficiency virus (HIV). In some embodiments, viral infections include severe acute respiratory syndrome viruses (SARS), such as severe acute respiratory syndrome coronavirus (SARS-CoV or SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), Ebola virus (EBOV), Marburg virus, respiratory syncytial virus (RSV), Nipah virus (NiV), and Hendra virus. However, in certain embodiments, the viral infection prevented or treated by the methods of the present invention is an infection caused by a coronavirus. In some embodiments, the viral infection is a lung infection, such as a lower respiratory tract infection (e.g., pneumonia).

[0033] In further specific embodiments, the viral infection treated or prevented by the methods and medically active liquids for use according to the present invention is a SARS-CoV or SARS-CoV-2 viral infection. SARS-CoV-2 viral infection is believed to be the cause of the pandemic disease COVID-19. Thus, in specific embodiments, the methods and medically active liquids for use according to the present invention allow for the treatment of viral infections and / or diseases, disorders, or conditions associated with or caused by such viral infections in subjects or patients diagnosed with COVID-19.

[0034] In further specific embodiments described above, the disease, disorder, or condition treated or prevented in accordance with the present invention is a lower respiratory tract infection affecting at least a portion of the lower respiratory tract of a subject, particularly a human, such as one or both lungs of the subject or patient (e.g., pneumonia). According to these embodiments, the respiratory disease, disorder, or condition may be a pulmonary disease, disorder, or condition, although the term "pulmonary" means that such a disease affects or involves one or both lungs of the subject or patient. In some embodiments, the respiratory disease, disorder, or condition or viral disease, disorder, or condition may be induced by or result from a viral infection.

[0035] Specifically, the viral disease, disorder, or condition treated or prevented in accordance with the present invention is Severe Acute Respiratory Syndrome (SARS), more specifically SARS-CoV-2 viral infection. In other specific embodiments, the viral disease, disorder, or condition treated or prevented in accordance with the present invention is Middle East Respiratory Syndrome (MERS), more specifically Middle East Respiratory Syndrome coronavirus infection.

[0036] In certain embodiments, as outlined above, the subject treated by the method according to the present invention is preferably a human or a warm-blooded animal, particularly a human.In some embodiments, the subject is diagnosed with a viral infection, for example, a coronavirus infection, particularly an infection caused by SARS or MERS coronavirus.In further specific embodiments, the subject is diagnosed with COVID-19.

[0037] In further specific embodiments, the viral disease, disorder, or condition treated or prevented in accordance with the present invention may be a disease, disorder, or condition resulting from or caused by an initial infection with a viral pathogen, including, but not limited to, inflammatory or inflammatory processes caused by such infection, such as pneumonia caused by infection with a coronavirus, e.g., SARS-CoV or SARS-CoV-2.

[0038] The method according to the present invention comprises administering by inhalation to a subject a medically active liquid in a nebulized form, wherein the medically active liquid comprises remdesivir or a pharmaceutically acceptable salt thereof, and wherein the medically active liquid is administered in a nebulized form using an inhalation device.

[0039] In certain embodiments, the antiviral active agent administered by and contained in the medically active liquid according to the present invention is remdesivir or a pharmaceutically acceptable salt thereof. Without being bound by any theory, in further embodiments, remdesivir or a pharmaceutically acceptable salt thereof administered by and contained in the medically active liquid may inhibit the replication of SARS-CoV or SARS-CoV-2.

[0040] In some embodiments, remdesivir is administered as a pharmaceutically acceptable salt. In other embodiments, remdesivir is administered as a solvate. In some specific embodiments, the solvate may contain one or more solvent molecules, for example, one or more water or alcohol molecules.

[0041] In some embodiments, remdesivir or a pharmaceutically acceptable salt thereof can be used as a medically active liquid, such as administered in a nebulized form according to the present invention. However, in alternative embodiments, the medically active liquid, or in other words, liquid pharmaceutical composition, administered by a method according to the present invention and comprising remdesivir or a pharmaceutically acceptable salt thereof, is preferably formulated as a composition that is suitable and adapted for use in inhalation, in other words, a composition that can be nebulized or atomized for inhalation and that is physiologically acceptable for inhalation by a subject, particularly a human.

[0042] The medically active liquid or pharmaceutical composition administered by inhalation according to the present invention can be in the form of a dispersion, e.g., a suspension having a liquid continuous phase and a solid dispersed phase, or in the form of a solution. In some embodiments, the medically active liquid or pharmaceutical composition is in the form of a solution in which remdesivir is substantially dissolved in the solution. In some embodiments, a solution or solid dispersion of remdesivir is administered to a subject by inhalation to treat a viral infection or viral disease, disorder, or condition, such as a respiratory or pulmonary disease, disorder, or condition.

[0043] In some embodiments, remdesivir is available as a lyophilizate or lyophilized solid that is reconstituted with a solvent to produce a medically active liquid that is administered to a subject.

[0044] In some embodiments, the medically active liquid may contain a solvent as a solvent or continuous phase, or in other words, a liquid vehicle. In some embodiments, a suitable solvent or liquid vehicle may be an aqueous solvent, a non-aqueous solvent, or a mixture of an aqueous solvent and a non-aqueous solvent. In some preferred embodiments, the solvent is a non-aqueous solvent. In certain embodiments, the physiologically acceptable solvent includes, but is not limited to, an alcohol, particularly an alcohol having 2 to 4, or preferably 2 or 3, carbon atoms, such as ethanol, propanol, or isopropanol, or a glycol, such as ethylene glycol, propylene glycol, or glycerol, or a lipophilic liquid, such as a semi-fluorinated alkane. In some preferred embodiments, the medically active liquid contains 100% alcohol. In some embodiments, the medically active liquid contains 100% ethanol. In some embodiments, the medically active liquid contains 100% glycol. In other embodiments, the medically active liquid contains a mixture of one or more alcohols. In still other embodiments, the medically active liquid contains a mixture of one or more alcohols and one or more glycols. In yet other embodiments, the medically active liquid comprises a mixture of one or more alcohols and water. In yet other embodiments, the medically active liquid comprises a mixture of one or more glycols and water. In yet other embodiments, the medically active liquid comprises a mixture of one or more alcohols, one or more glycols, and water.

[0045] In some embodiments, the solvent system or liquid vehicle of the medically active liquid can include an alcohol as described above, particularly ethanol, propanol, isopropanol, ethylene glycol, or propylene glycol, as the sole or predominant solvent, e.g., 100% by weight of the alcohol. Even in these cases, water may be present as a co-solvent, e.g., in an ethanol solvent system with water, e.g., in an amount of up to about 30% by weight, or up to about 20% by weight, or up to about 10% by weight or less, or alternatively, in an ethylene glycol or propylene glycol system with water, e.g., up to about 30% by weight, up to about 20% by weight, or up to about 10% by weight or less.

[0046] In some embodiments, the medically active liquid containing remdesivir or a pharmaceutically acceptable salt thereof is dispensed in a volume of about 1 μL, 2 μL, 5 μL, 10 μL, or 15 μL, or at least about 20 μL, 25 μL, 30 μL, or 50 μL. In some embodiments, the remdesivir or pharmaceutically acceptable salt thereof is dispensed in a volume of about 15 μL. In some embodiments, the concentration of remdesivir or a pharmaceutically acceptable salt thereof in the medically active liquid is from about 0.1 μg / μL to about 30 μg / μL, or from about 1 μg / μL to about 25 μg / μL, e.g., about 0.10 μg / μL, 0.25 μg / μL, 0.5 μg / μL, 1 μg / μL, 2 μg / μL, 3 μg / μL, 4 μg / μL, 5 μg / μL, 6 μg / μL, 7 μg / μL, 8 μg / μL, 9 μg / μL, or 10 μg / μL. In some embodiments, the concentration of remdesivir or a pharmaceutically acceptable salt in the medically active liquid is selected from the range of about 15 μg / μL, 16 μg / μL, 17 μg / μL, 18 μg / μL, 19 μg / μL, 20 μg / μL, 21 μg / μL, 22 μg / μL, 23 μg / μL, 24 μg / μL, 25 μg / μL, 26 μg / μL, 27 μg / μL, 28 μg / μL, 29 μg / μL, or 30 μg / μL. In other embodiments, the concentration of remdesivir or a pharmaceutically acceptable salt in the medically active liquid is about 16 μg / μL. In still other embodiments, the concentration of remdesivir or a pharmaceutically acceptable salt in the medically active liquid is about 15 μg / μL. In some embodiments, the concentration of remdesivir or a pharmaceutically acceptable salt in the medically active liquid is about 1 μg / μL to about 10 μg / μL or about 10 μg / μL to about 30 μg / μL.

[0047] In some embodiments, remdesivir or a pharmaceutically acceptable salt is dispensed in an amount of about 100 μg to about 300 μg per activation. In other embodiments, remdesivir or a pharmaceutically acceptable salt is dispensed in an amount of about 150 μg to about 300 μg per activation. In other embodiments, remdesivir or a pharmaceutically acceptable salt is dispensed in an amount of about 150 μg to about 230 μg per activation. In other embodiments, remdesivir or a pharmaceutically acceptable salt is dispensed in an amount of about 210 μg to about 250 μg per activation. In other embodiments, remdesivir or a pharmaceutically acceptable salt is dispensed in an amount of about 220 μg to about 230 μg per activation. In other embodiments, remdesivir or a pharmaceutically acceptable salt is dispensed in an amount of about 225 μg per activation.

[0048] In further embodiments, the medically active liquid or liquid pharmaceutical composition may optionally contain one or more physiologically acceptable excipients suitable for inhalation use. Excipients that may be used in the medically active liquid or liquid composition may include, but are not limited to, one or more buffers for adjusting or controlling the pH of the solution, salts, flavoring agents, surfactants, lipids, antioxidants, and cosolvents, all of which may be used to enhance or improve solubility. In some embodiments, the solubilizer is a cyclic oligosaccharide such as cyclodextrin. In certain embodiments, the solubilizer is cyclodextrin.

[0049] Suitable excipients are known to those skilled in the art and are described, for example, in standard pharmacopeias such as the United States Pharmacopoeia or Ph. Eur, or in Handbook of Pharmaceutical Excipients, 6th ed. Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009.

[0050] Exemplary compounds suitable as buffers for adjusting the pH of the pharmaceutical composition after reconstitution include, for example, sodium dihydrogen phosphate dihydrate and / or disodium hydrogen phosphate dodecahydrate, sodium hydroxide solution, basic salts of sodium, calcium, or magnesium, such as citrate, phosphate, acetate, tartrate, lactate, etc., amino acids, acid salts, such as hydrogen phosphate or dihydrogen phosphate, especially sodium, as well as organic and inorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, cromoglycic acid, acetic acid, lactic acid, tartaric acid, succinic acid, fumaric acid, lysine, methionine, acid hydrogen phosphate salts of sodium or potassium, and the additional buffer systems mentioned above. In further specific embodiments, the medically active liquids nebulized and administered according to the present invention may contain one or more additional excipients selected from chelating agents, such as edetate disodium dihydrate, calcium sodium EDTA, preferably edetate disodium dihydrate.

[0051] In yet further specific embodiments, the medically active liquids sprayed and administered according to the present invention may contain one or more preservatives and / or antioxidants. Suitable preservatives include, but are not limited to, parabens, such as benzalkonium chloride (BAC), methylparaben, ethylparaben, propylparaben, sodium benzoate, sorbic acid, and salts thereof. In certain embodiments, the medically active liquids sprayed and administered according to the present invention contain benzalkonium chloride as a preservative. Suitable antioxidants include, but are not limited to, butylated hydroxytoluene (BHT), vitamin A, vitamin E, vitamin C, retinyl palmitate, and the like.

[0052] Additional excipients that may be included in the medically active liquid containing remdesivir or a pharmaceutically acceptable salt thereof administered in accordance with the present invention include, but are not limited to, phosphatidylcholines, such as dilauroylphosphatidylcholine (DLPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylglycerol (DTPA), diethylenetriaminepentaacetic acid, hydrogenated soy phosphatidylcholine (HSPC), multilamellar vesicles, and soy phosphatidylcholine (SPC).

[0053] The medically active liquid comprising remdesivir or a pharmaceutically acceptable salt thereof, administered by inhalation to a subject in need thereof, may, in further embodiments, further comprise at least one additional medically active compound or active pharmaceutical ingredient (API).

[0054] The amount of remdesivir or a pharmaceutically acceptable salt thereof to be contained in the medically active liquid and administered to a patient or subject in need thereof can be determined according to routine experimentation known to those of skill in the art.

[0055] The medically active liquid comprising remdesivir or a pharmaceutically acceptable salt thereof administered according to the methods of the invention can be administered by inhalation using an inhaler or inhalation device, as described in further detail below, in one single dose or in several separate doses, e.g., from 1 to about 6 or 4 doses per day, or 2 or 3 doses per day.

[0056] According to the present invention, a medically active liquid containing remdesivir or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in nebulized form using an inhalation device. As used herein, the term "nebulized form," in reference to the medically active liquid being administered, means that the medically active liquid is present in the form of an aerosol, and the medically active liquid containing remdesivir or a pharmaceutically acceptable salt thereof is present in the form of finely divided particles or droplets dispersed in air or another propellant as the continuous phase.

[0057] In certain embodiments, such aerosols preferably have respirable particles or droplets each having a mass median aerodynamic diameter (measured by laser diffraction) of about 10 μm or less, particularly about 7 μm or less, or about 5 μm or less.

[0058] In a further specific embodiment, remdesivir or a pharmaceutically acceptable salt thereof contained in a medically active liquid is administered to the lungs of a subject, specifically in the form of a respirable aerosol comprising remdesivir or a pharmaceutically acceptable salt thereof.

[0059] In further specific embodiments, the medically active liquid administered by the methods of the present invention may be essentially free of propellants, such as hydrofluoroalkane (HFA) propellants.

[0060] According to the present invention, a medically active liquid containing remdesivir or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof using an inhalation device. As used herein, the term "inhalation device" should be understood in its broadest sense to refer to a device that allows and is compatible with inhalation administration of a medically active liquid, preferably oral inhalation nebulization. Examples of such inhalation devices are known to those skilled in the art and include, but are not limited to, metered dose inhalers (MDIs), nebulizers, vibrating mesh inhalers, and soft mist inhalers (SMIs). Exemplary embodiments of inhalers suitable for administering medically active liquids containing remdesivir or a pharmaceutically acceptable salt thereof are described, for example, in “Inhalation drug delivery devices: technology update” Medical Devices: Evidence and Research 2015:8 131-139; or “Recent advances in aerosolized drug delivery”, A. Chandel et al., Biomedicine & Pharmacotherapy, Vol. 112, April 2019, 108601 (doi.org / j.biopha.2019.108601), or “Pharmaceutical Inhalation Aerosol Technology”, Third Edition, A.J. Hickey et al., May 1, 2019, the contents of each of which are incorporated herein by reference in their entirety.

[0061] In certain embodiments, such nebulization and administration by inhalation of a medically active liquid comprising remdesivir or a pharmaceutically acceptable salt thereof can be accomplished using a handheld inhalation device.

[0062] In further specific embodiments, the inhalation device that can be used to administer a medically active liquid containing remdesivir or a pharmaceutically acceptable salt thereof is a soft mist inhaler. As used herein, the term "soft mist inhaler" refers, in certain embodiments, to a non-powered, ambulatory inhalation device for liquid formulations with low-velocity spray characteristics. In further specific embodiments, such an inhalation device, more specifically, such a soft mist inhaler, includes at least one impingement-type nozzle for atomization / aerosolization of the medically active liquid, as described in more detail below.

[0063] Suitable inhalation devices are known, such as for example the Respimat® inhaler (Boehringer Ingelheim), vibrating membrane nebulizers, such as eFlow® (PARI), Vibrating-Mesh® nebulizers (for example Philips InnoSpire Go).

[0064] A further exemplary suitable inhalation device is known, for example, from document EP 0,627,230, the contents of which are incorporated herein by reference in their entirety. The essential components of this exemplary inhalation device are a reservoir in which the medically active liquid to be aerosolized is contained, a pump device for generating a pressure high enough for atomization, and an atomizing device in the form of a nozzle. The pump device draws the liquid from the reservoir in discrete amounts, i.e., not continuously, and supplies it to the nozzle. The pump device operates without a propellant and generates pressure mechanically.

[0065] Further exemplary embodiments of suitable inhalation devices are described in WO 91 / 14468, the contents of which are incorporated herein by reference in their entirety. In such devices, pressure in a pump chamber connected to a housing is generated by the movement of a movable hollow piston. The piston is movably arranged inside a stationary cylinder or pump chamber. An inlet (arranged upstream) of the hollow piston is fluidly connected to the interior of a reservoir (reservoir pipe section). Its tip (arranged downstream) leads to the pump chamber. A check valve is arranged inside the tip of the piston to prevent backflow of liquid into the reservoir.

[0066] The soft mist inhaler described above has proven to be a very effective means for delivering a medically active liquid or composition or a pharmaceutically active compound contained therein to the lungs of a patient or subject in need thereof. Such soft mist inhalers typically comprise one or more impingement nozzles. Such impingement nozzles are adapted to emit at least two liquid jets that collide and are split into small aerosol droplets of the medically active liquid, which are then atomized. The one or more nozzles are typically fixed to the user-facing side of the housing of the inhaler device so that they are immobile or immovable relative to the housing, or at least to the side or portion of the housing that faces the user (e.g., patient), when the device is in use.

[0067] Specific embodiments of such soft mist inhalers suitable for administering medically active liquids containing remdesivir or a pharmaceutically acceptable salt thereof are described, for example, in International Patent Application Publication No. WO 2018 / 197730, the contents of which are incorporated herein by reference in their entirety. It should be noted, however, that the inhalation device described therein is merely one example of an inhalation device suitable for use in accordance with the present invention and, therefore, should not be construed as limiting the scope of the present invention in any way.

[0068] In certain embodiments of the invention, the inhalation device that may be used to administer the medically active liquid comprising remdesivir or a pharmaceutically acceptable salt thereof is a handheld inhalation device for delivering a nebulized medically active aerosol for inhalation therapy, (a) a housing having a user-facing side; (b) an impingement nozzle for producing an atomized aerosol by the collision of at least two liquid jets, the impingement nozzle being rigidly attached to the user-facing side of the housing so that the nozzle is immovable relative to the housing; (c) a fluid reservoir disposed within the housing; and (d) a pump unit disposed within the housing, an upstream end fluidly connected to a fluid reservoir; a downstream end fluidly connected to the nozzle; the pump unit is adapted to pump fluid from the fluid reservoir to the nozzle; The pump unit is (i) a riser pipe having an upstream end, - adapted to act as a piston in a pump unit, a riser pipe fixedly secured to the user-facing side of the housing so as to be immovable relative to the housing; and (ii) a hollow cylinder located upstream of the riser pipe, the upstream end of the riser pipe being inserted into the cylinder such that the cylinder is longitudinally movable on the riser pipe; (iii) lockable means for storing potential energy when locked and releasing the stored energy when unlocked, the means being disposed outside the cylinder and mechanically coupled to the cylinder, wherein unlocking of the means causes longitudinal propulsive movement of the cylinder toward the downstream end of the pump unit.

[0069] In certain embodiments, such a preferred inhalation device comprises a housing having a user-facing side, an impingement nozzle for generating an atomized aerosol by the collision of at least two liquid jets, a fluid reservoir disposed within the housing, and a pump unit also disposed within the housing. The nozzle may be fixedly secured to the user-facing side of the housing so as to be immovable relative to the housing. The pump unit may have an upstream end fluidly connected to the fluid reservoir and a downstream end fluidly connected to the nozzle. The pump unit is further adapted to pump fluid from the fluid reservoir to the nozzle, and comprises a riser pipe adapted to function as a piston for the pump unit, a hollow cylinder, and lockable means for storing potential energy. The riser pipe is fixedly secured to the user-facing side of the housing so as to be immovable relative to the housing. The hollow cylinder is located upstream of the riser pipe, and the upstream end of the riser pipe is inserted into the cylinder so that the cylinder is longitudinally movable relative to the riser pipe. The lockable means is adapted to store potential energy when locked and to release the stored energy when unlocked. The lockable means is disposed outside of and mechanically coupled to the cylinder such that unlocking the means propels longitudinal movement of the cylinder towards the downstream end of the pump unit.

[0070] As used herein, handheld inhalation device is a portable device that can be conveniently held in one hand and is suitable for delivering nebulized medically active aerosol for inhalation therapy.To be suitable for inhalation therapy, the device must be able to emit medically active aerosol whose particle size is respirable, that is, as outlined above, small enough to be taken up by the lungs of the patient or user.Typically, respirable particles have an aerodynamic mass median diameter of about 10 μm or less, particularly about 7 μm or less, or about 5 μm or less, respectively.In this respect, inhalation device is substantially different from the device that emits spray for oral or nasal administration, such as that disclosed in US Patent Application Publication No. 2004 / 0068222, the contents of which are incorporated herein by reference in their entirety.

[0071] In some embodiments, the mean particle size distribution of the nebulized medically active aerosol comprising remdesivir is about 1.0 μm to about 2.0 μm at Dv10. In other embodiments, the mean particle size distribution of the nebulized medically active aerosol comprising remdesivir is about 2.0 μm to about 4.0 μm at Dv50. In still other embodiments, the mean particle size distribution of the nebulized medically active aerosol comprising remdesivir is about 4.0 μm to about 10.0 μm at Dv90. The terms "Dv10, Dv50, Dv90" refer to the maximum particle size in micrometers (μm), of which 10%, 50%, and 90%, respectively, are present in the sample volume.

[0072] The inhalation device that can be used in the method of the present invention can deliver nebulized aerosol.As used herein, aerosol is a system that has at least two phases, namely, a gas phase and a continuous phase that comprises the dispersed liquid phase in the form of small droplets.Optionally, the liquid phase itself can represent liquid solution, dispersion, suspension or emulsion.

[0073] A suitable nozzle is important for generating aerosol to be atomized. According to the present invention, the nozzle is preferably of an impingement type. This means that the nozzle is adapted to emit at least two liquid jets that collide and break into small aerosol droplets. The nozzle can be fixed firmly to the user-facing side of the housing of the inhalation device so that it is immobile or immovable relative to the housing, or at least the side or part of the housing that faces the user (e.g., patient) when the device is in use.

[0074] A fluid reservoir, which may be disposed within the housing, is preferably adapted to hold or store a medically active liquid from which a nebulized aerosol is generated and delivered by the inhalation device.

[0075] The pump unit, which may be disposed within the housing, is preferably adapted to function as a piston pump, also called a plunger pump, in which the riser pipe functions as a piston or plunger that is longitudinally movable within a hollow cylinder, the inner segment of which the upstream end of the riser pipe moves through may form a pump chamber having a variable volume depending on the position of the riser pipe relative to the cylinder.

[0076] The hollow cylinder comprising the pump chamber may be fluidly connected, directly or indirectly, to a fluid reservoir, such as by an optional reservoir pipe (or reservoir pipe section). Similarly, a riser pipe, having an internal (upstream) end facing the reservoir and which may be housed within the hollow cylinder, may be fluidly connected, directly or indirectly, at its downstream or external end to a nozzle in a liquid-tight manner.

[0077] In this context, the expression "hollow cylinder" refers to a part or member that is hollow in the sense that it has a cylindrical shape or includes an internal cavity with a segment having a cylindrical space. In other words, the external shape of the respective part or member does not have to be cylindrical, as is applicable to other types of piston pumps. Furthermore, the expression "hollow cylinder" does not exclude an operating state of the respective part or member in which the "hollow" space can be filled with a material, for example, a liquid to be sprayed.

[0078] As used herein, longitudinal motion is motion along the major axis of the hollow cylinder, and propulsive motion is motion of the portion in the downstream (or forward) direction.

[0079] In either embodiment, the riser pipe of the pump unit of the inhalation device of the present invention is disposed downstream of the cylinder and is rigidly fixed to the housing or at least a portion of the housing, including the user-facing side of the housing, preferably to the user-facing side of the housing. To avoid any doubt, in this context, rigidly fixed means fixed, directly or indirectly (i.e., via one or more connections), so as to prevent relative movement between the respective parts. Since the nozzle is also rigid with respect to the housing or the respective housing part, the riser pipe is also rigid with respect to the nozzle, and the pumping action is provided by the longitudinal movement of the hollow cylinder. The forward movement of the cylinder, located upstream relative to the riser pipe, results in a decrease in the volume of the pump chamber, and the repulsive movement of the cylinder results in an increase in volume. In other words, the riser pipe maintains its position relative to the housing, and the hollow cylinder can change its position relative to the housing, particularly along its longitudinal axis, to perform a piston-like movement of the immovable riser pipe within the movable cylindrical member.

[0080] This arrangement differs from other impaction-type inhalation devices that rely on a pump unit with a riser pipe in an upstream position and a cylindrical member in a downstream position where the riser pipe is movable and the cylindrical member is fixed to the housing, as disclosed in U.S. Patent Application Publication No. 2012 / 0090603, the contents of which are incorporated herein by reference in their entirety. It should be noted, however, that inhalation devices with this type of pumping may also be suitable for nebulized inhalation administration of medically active liquids according to the methods of the present invention.

[0081] An important advantage of the described preferred suction device is that the passage between the pump chamber and the fluid reservoir can be designed with fewer restrictions regarding its dimensions. For example, it is possible to accommodate a very large inlet valve (also known as a check valve), which is easier to manufacture because it does not need to be accommodated within a narrow riser pipe. Instead, this configuration allows for the use of a check valve whose size is limited only by the internal size of the housing or the dimensions of the means for storing potential energy. In other words, the diameters of the valve, riser pipe, and, if used, reservoir pipe do not need to match each other. Furthermore, because a movable piston does not need to be connected to the fluid reservoir, the components that form the fluid connection to the reservoir can be designed independently of the movable component, i.e., the hollow cylinder, allowing each individual part to be adapted to its individual function. In this respect, the described pump configuration offers greater design flexibility because the movable hollow cylinder, due to its robust structure and dimensions, offers a better opportunity to design a mechanically stable connection with the reservoir than the less robust movable riser pipe. Also, the connection between the hollow cylinder and the fluid reservoir can be designed with a larger diameter to allow for faster flow rates and fluid viscosities. Furthermore, the reservoir support can be integrated into any component, including the cylinder. Furthermore, any vents for reservoir pressure balancing can be moved away from the reservoir body itself and into the connector that forms the interface between the reservoir and the hollow cylinder, thus facilitating construction and avoiding the need for an essentially "open" reservoir body.

[0082] As mentioned, the lockable means for storing potential energy may be adapted to store energy in its locked state and release the stored energy when unlocked. The means may be mechanically coupled to the hollow cylinder such that unlocking the means causes the cylinder to move longitudinally in a propulsive manner toward the downstream end of the pump unit. During this movement, the internal volume of the cylinder, i.e., the volume of the pumping chamber, decreases. Conversely, when the means for storing potential energy is in the locked state, the hollow cylinder is in its most upstream position where the volume of the pumping chamber is greatest. The locked state can also be considered a priming state. When the state of the energy storing means is changed from the unlocked state to the locked state, which may be referred to as priming the device, the hollow cylinder undergoes a repulsive longitudinal movement, i.e., moving from its most downstream position toward its most upstream position. A pumping cycle typically consists of two subsequent opposing movements of the cylinder, starting from its most downstream position to its most upstream (or primed) position and then returning to its most downstream position, driven by the means for storing potential energy, which then releases its energy.

[0083] In one preferred embodiment of the described inhalation device, the pump unit is a high-pressure pump unit adapted to operate or eject fluid at a pressure of at least about 50 bar. In other preferred embodiments, the operating pressure of the pump unit is at least about 10 bar, or at least about 100 bar, or from about 2 bar to about 1000 bar, or from about 50 bar to about 250 bar, respectively. As used herein, the operating pressure is the pressure at which the pump unit ejects fluid, particularly a pharmaceutically active liquid such as an inhalable aqueous liquid formulation of a pharmaceutically active liquid, from its pump chamber downstream, i.e., toward the nozzle. In this context, the expression "adapted to operate" means that the components of the pump unit are selected with respect to materials, dimensions, surface quality, and finish to allow operation at the specified pressure.

[0084] Furthermore, such a high-pressure pump unit means that the means for storing potential energy is capable of storing and releasing sufficient amounts of energy to drive the longitudinal propulsive movement of the cylinder with such force that the respective pressures are obtained.

[0085] The potential energy storage means may be designed as a tension or pressure spring. Alternatively, a metal or plastic body, or a gaseous medium or magnetic material, can also be used as the energy storage means. Potential energy is supplied to the means by compression or tension. One end of the means is supported in a housing or housing at a suitable position. This end is therefore essentially immobile. The other end is connected to a hollow cylinder containing a pump chamber. This end is therefore essentially movable. The means can be locked after being charged with a sufficient amount of energy and can store energy until unlocking occurs. Once unlocked, the means can release potential energy (e.g., spring energy) into the cylinder containing the pump chamber, which is then driven to perform a movement (in this case, longitudinal). Because energy release typically occurs suddenly, a high pressure can build up in the pump chamber before a significant amount of liquid is released, causing a pressure drop. Indeed, during a significant portion of the release phase, there is an equilibrium between the pressure delivered by the potential energy storage means and the amount of liquid already released. Thus, the amount of liquid remains essentially constant during this phase, which is a significant advantage over devices that use manual force from the user for expulsion, such as those disclosed in U.S. Patent Application Publication Nos. 2005 / 0039738, 2009 / 0216183, 2004 / 0068222, or 2012 / 0298694, the contents of each of which are incorporated herein by reference in their entirety, because manual force is dependent on the individual user or patient and is highly likely to vary significantly during the expulsion phase, resulting in non-uniform droplet formation, size, and quantity. In contrast to the prior art, the measures according to the present invention ensure that the inhalation device produces highly reproducible results.

[0086] The means for storing potential energy may also be provided in the form of a highly pressurized gas container. By proper placement and repeatable intermittent actuation (opening), a portion of the energy stored in the gas container can be released into the cylinder. This process can be repeated until the remaining energy is insufficient to re-establish the desired pressure in the pump chamber. After this, the gas container must be refilled or replaced.

[0087] In one preferred embodiment, the means for storing potential energy is a spring having a load of at least 10 N in a deflected state. In a particularly preferred embodiment, the means for storing potential energy is a steel compression spring having a load of about 1 N to about 500 N in a deflected state. In other preferred embodiments, the steel compression spring has a load of about 2 N to about 200 N, or about 10 N to about 100 N in a deflected state.

[0088] Inhalation devices that can be used in the methods of the present invention are preferably adapted to deliver nebulized medically active aerosol in a discontinuous manner, i.e., in the form of individual units, with one unit delivered per pump cycle. In this manner, the device differs from commonly known nebulizers, such as jet nebulizers, ultrasonic nebulizers, vibrating mesh nebulizers, or electrohydrodynamic nebulizers, which generate and deliver a continuous nebulized aerosol over a period typically ranging from a few seconds to a few minutes, thereby requiring multiple successive breathing maneuvers for the aerosol to be inhaled by the patient or user. Instead, inhalation devices suitable for administering medically active liquids according to the present invention are preferably adapted to generate and release individual aerosol units, each unit corresponding to the amount (i.e., volume) of fluid (i.e., medically active liquid) pumped by the pump unit into the nozzle in one pumping cycle, where it is immediately aerosolized and delivered to the user or patient. Conversely, the amount of medically active liquid pumped by the pump unit in one pumping cycle determines the amount of pharmacologically active agent the patient receives per dose. It is therefore very important that the pump unit operates accurately, reliably and reproducibly in order to achieve the desired therapeutic effect. The inventors have found that an inhalation device incorporating such a pump unit is particularly advantageous in that it exhibits high accuracy and reproducibility.

[0089] In one preferred embodiment, a single dose of medication (i.e., the atomized aerosol of a medically active liquid) is contained in one unit, i.e., the amount delivered from the pump unit to the nozzle to generate the aerosol in one pumping cycle, in which case the user or patient primes and actuates the device only once and inhales the emitted aerosol in one breathing maneuver per dose (i.e., per dosing event).

[0090] In another preferred embodiment, a single dose of medication consists of two units of aerosol, thus requiring two pumping cycles. Typically, the user or patient primes the device, activates it to release and inhale a unit of aerosol, and then repeats the process. Alternatively, three or more aerosol units may constitute a single dose.

[0091] The volume of fluid (e.g., medically active liquid) pumped by the pump unit in one pumping cycle is preferably in the range of about 2 to about 150 μl. In particular, the volume may be in the range of about 0.1 to about 1000 μl, or about 1 to about 250 μl, respectively. These volume ranges are approximately the same as the volume of the liquid phase contained in one unit of aerosol generated by an inhalation device, with slight variations possibly due to minute losses of liquid within the device.

[0092] In another preferred embodiment, the pump unit of the inhalation device includes an inlet valve, also called a check valve or inlet check valve, located within the hollow cylinder. According to this embodiment, the interior space of the hollow cylinder, i.e., the pump chamber, is fluidly connected to the fluid reservoir via the inlet check valve. The inlet valve allows liquid to flow into the pump chamber but prevents liquid from flowing back into or into the fluid reservoir. The inlet valve may be located at or near the upstream end of the cylinder, making substantially the entire internal volume of the hollow cylinder available to function as the pump chamber. Alternatively, it may be located more centrally along the main (longitudinal) axis of the hollow cylinder, defining an upstream segment and a downstream segment of the cylinder, with the upstream segment being upstream of the inlet valve and the downstream segment being downstream of the valve. In this case, the pump chamber is located in the downstream segment.

[0093] As mentioned above, one of the advantages is that a relatively large inlet valve can be accommodated in this position, i.e., at the upstream end of the pump chamber. This is particularly beneficial because it allows for a large fluid conduit within the valve, thereby enabling a high fluid velocity to be transferred to the rapid filling of the pump chamber during priming of the inhalation device. Furthermore, it becomes possible to use liquids with higher viscosities than typical liquid formulations for inhalation therapy, such as highly concentrated solutions of soluble active ingredients.

[0094] According to a further preferred embodiment, the inlet valve may be adapted to open only when the pressure difference between the upstream and downstream sides of the valve, i.e., the fluid reservoir side and the pump chamber side, exceeds a predetermined threshold value. The inlet valve remains closed as long as the pressure difference remains below the threshold value. When used in this context, the term "pressure difference" means that only the relative pressure difference between the two sides is relevant for determining whether the valve blocks or opens, regardless of the absolute pressure value. For example, if the pressure on the upstream (reservoir) side is already positive (e.g., 1.01 bar due to thermal expansion) but the pressure on the downstream (pump chamber) side is ambient pressure (1.0 bar, without device activation), the pressure difference (here, 0.01 bar) is below the threshold value (e.g., 20 mbar), and the valve remains closed even when a positive pressure is applied in the opening direction. This means that the check valve remains closed until the threshold pressure is met, thus safely closing the passage between the reservoir and the pump chamber, for example, when the inhalation device is not in use. Examples of threshold pressure differences are in the range of 1 to 1000 mbar, more preferably between about 10 and about 500 mbar, or between about 1 and about 20 mbar.

[0095] When the inhalation device is actuated, when the potential energy storing means changes its state from locked to unlocked, energy can be released causing the cylinder to perform its propulsive longitudinal motion, building up significant pressure in the pump chamber, which creates a high pressure in the pump chamber and a significant pressure differential (due to the substantially lower pressure in the fluid reservoir) that exceeds the pressure differential threshold, causing the check valve to open and allowing the pressure chamber to fill with liquid from the reservoir.

[0096] A valve type that can be designed to operate at such a threshold pressure difference is, for example, a spring-preloaded ball valve. The spring presses the ball into its seat, and the ball valve opens only when the pressure acting on the spring force exceeds the spring force. Other valve types that can operate at such a threshold pressure difference, depending on their construction, are duckbill valves or flap valves.

[0097] The advantage of such a valve operating at a threshold pressure differential is that the reservoir can remain closed until the inhalation device is actively used, thus reducing undesirable splashing of reservoir liquid during device transport or evaporation during long-term storage of the device.

[0098] In a further preferred embodiment, the suction device usable in accordance with the present invention further comprises an outlet valve inside or at the end of the riser pipe to prevent backflow of liquid or air from the riser pipe into the hollow cylinder. The use of such an outlet valve proves advantageous in many cases. Typically, the downstream end of the riser pipe is located near the nozzle, which is in fluid communication with the outside air. After the amount of liquid delivered from the pump unit through the nozzle, driven by the longitudinal propulsive movement of the cylinder, is released in aerosolized form, the pump chamber must be recharged. To this end, the pump chamber slides back along the riser pipe to its previous upstream position (i.e., performs a repulsive longitudinal movement) so that the internal volume of the pump chamber increases. This generates a negative pressure (sometimes referred to as "underpressure") inside the pump chamber, drawing liquid into the pump chamber from a fluid reservoir located upstream of the pump chamber. However, such negative pressure can also propagate downstream through the riser pipe to the outside of the nozzle, potentially leading to air being sucked into the device through the nozzle or nozzle opening, respectively. This problem can be avoided by providing an outlet valve, also called an outlet check valve, which opens towards the nozzle opening and blocks in the opposite direction.

[0099] Optionally, the outlet valve is of the type that shuts off below (and opens above) a threshold pressure difference, as described in the context of the inlet valve above. If a spring-loaded ball valve is used, the force of the spring must be directed toward the pump chamber so that the outlet valve opens when the difference between the internal pressure of the pump chamber and the ambient pressure exceeds the threshold pressure difference value. The advantages of such a valve correspond to each of the advantages described above.

[0100] As mentioned above, the outlet valve may be located in the riser pipe. Alternatively, the suction device may not be integrated into the riser pipe, but may instead include an outlet valve located at or near one end of the riser pipe, particularly at or near its downstream end, for example, at or near a separate connector between the riser pipe and the nozzle. This embodiment may be advantageous in certain cases, for example, when a riser pipe with a particularly small diameter is required, which makes integrating a valve difficult. By accommodating the outlet valve downstream of the riser pipe, a valve with a relatively large diameter can be used, thus simplifying the valve design requirements.

[0101] In a further alternative embodiment, there is no outlet valve. This embodiment may be feasible because the fluid channel of the impingement nozzle can have a relatively small cross section, resulting in little or very slow backflow at given pressure conditions during priming of the device. If the amount of backflow is deemed acceptable given the particular product application, the inhaler design may be simplified by avoiding the outlet valve.

[0102] In either case, the inhalation device can be designed with or without an outlet valve, and all other options and preferences discussed with respect to other device features are applicable to both of these alternative embodiments.

[0103] In a further preferred embodiment, the inhalation device according to the invention comprises fluid reservoirs rigidly attached to the hollow cylinder so as to be movable together with the hollow cylinder within the housing. This means that during each ejection phase of a pumping cycle, the fluid reservoirs move together with the hollow cylinder from an initial ("upstream") position, where the pump chamber has its maximum internal volume, towards an end ("downstream") position, where the volume of the pump chamber is smallest, and during the next "priming" step, the fluid reservoirs return together with the hollow cylinder to their initial ("upstream") position.

[0104] As used herein, the phrase "firmly attached" includes both permanent and non-permanent (i.e., releasable) forms of attachment. Furthermore, it includes direct and indirect (i.e., via one or more connections) types of attachment. At the same time, as noted above, "firmly attached" means that the respective parts are fixed to one another in a manner that substantially prevents their movement relative to one another. In other words, two parts that are firmly attached to one another can only move together and may be immovable or immovable relative to one another.

[0105] One advantage of this embodiment, in which the fluid reservoir is rigidly attached to the hollow cylinder, is that it provides the smallest possible dead volume between the reservoir and the pump chamber.

[0106] According to another embodiment, the fluid reservoir is fluidly connected to the hollow cylinder by a flexible tubular element and rigidly attached to the housing. According to this embodiment, the reservoir is not rigidly attached to the hollow cylinder and does not move with it as the cylinder moves longitudinally. Instead, it is rigidly, but optionally detachably, attached directly or indirectly to the housing or a portion of the housing. One advantage of this embodiment is that the energy suddenly released upon unlocking the potential energy storage means acts only on the hollow cylinder, not the fluid reservoir. This can be particularly advantageous when the initial (fully filled) fluid reservoir has a relatively large mass at the start of use, reducing overuse. A higher acceleration of the hollow cylinder translates into a higher pressure in the pump chamber.

[0107] For the avoidance of doubt, all other options and preferences described above and below with respect to other device features are applicable to both of these alternatives, i.e., whether or not the fluid reservoir is rigidly attached to the hollow cylinder.

[0108] In one embodiment, the fluid reservoir is designed to be collapsible, such as by having flexible or elastic walls. The advantage of such a design is that upon repeated use of the device, including the gradual emptying of the reservoir, the flexible or elastic walls buckle or fold, reducing the internal volume of the reservoir, so that the negative pressure required to extract a certain amount of liquid does not need to increase substantially over the period of use. In particular, the reservoir may be designed as a collapsible bag. The advantage of a collapsible bag is that the pressure in the reservoir is largely independent of the filling level and the effects of thermal expansion are largely negligible. Furthermore, the structure of such a reservoir type is fairly simple and already well established.

[0109] A similar effect can be achieved by a rigid container with a movable bottom (or wall), whereby the internal volume of the reservoir can also be continuously reduced.

[0110] Soft mist inhalers, such as the particular soft mist inhalers described in detail above, allow for the administration of discrete doses of a medically active liquid comprising remdesivir or a pharmaceutically acceptable salt thereof over a short period of time, as the generation of an aerosol of the medically active liquid administered by inhalation is typically completed within a time period of up to 3 seconds or up to 5 seconds (also referred to herein as the "spray duration" or "event duration"), typically within a time period selected within the range of about 0.5 to about 5 seconds, or about 0.5 or about 1 to about 3 seconds.

[0111] In a third aspect, the present invention provides use of remdesivir or a pharmaceutically acceptable salt thereof for preparing or manufacturing a medically active liquid for preventing or treating a viral infection or viral disease, disorder, or condition in a subject, wherein the medically active liquid is administered to the subject in a nebulized form by inhalation using an inhalation device. In some embodiments, the viral disease, disorder, or condition is a respiratory disease, disorder, or condition.

[0112] In a fourth aspect, the present invention provides use of an inhalation device for preventing or treating a viral infection or viral disease, disorder, or condition in a subject, wherein a medically active liquid is administered in nebulized form using the inhalation device, and the medically active liquid comprises remdesivir or a pharmaceutically acceptable salt thereof. In some embodiments, the viral disease, disorder, or condition is a respiratory disease, disorder, or condition.

[0113] In a fifth aspect, the present invention provides a use of a medically active liquid comprising remdesivir for preventing or treating a viral infection or viral disease, disorder, or condition in a subject, wherein the medically active liquid is administered to the subject in a nebulized form by inhalation using an inhalation device.

[0114] In a sixth aspect, the present invention provides kits, particularly kits for treating or preventing a viral infection or viral disease, disorder or condition in a subject, the kit comprising: - a medically active liquid comprising remdesivir or a pharmaceutically acceptable salt thereof, the medically active liquid being adapted to be administered to a subject in a nebulized form by inhalation; and - an inhalation device, preferably a handheld inhalation device such as a soft mist inhaler;

[0115] According to this aspect of the invention, the medically active liquid comprising remdesivir or a pharmaceutically acceptable salt thereof may also be provided in the form of a fluid reservoir, as described above, containing a medically active liquid.

[0116] In a seventh aspect, the present invention provides use of a medically active liquid comprising remdesivir or a pharmaceutically acceptable salt thereof in the manufacture of a kit for preventing or treating a viral infection or viral disease, disorder, or condition in a subject, the kit comprising: - a medically active liquid comprising remdesivir or a pharmaceutically acceptable salt thereof for the prevention or treatment of a viral infection or viral disease, disorder, or condition in a subject, the medically active liquid being adapted to be administered to the subject in a nebulized form by inhalation; and - an inhalation device, preferably a handheld inhalation device such as a soft mist inhaler;

[0117] It is noted that all embodiments, features and combinations thereof disclosed above in relation to the medically active liquid for the method of the first aspect and the use according to the second aspect of the invention apply equally to all further aspects of the invention. Detailed Description of the Drawings

[0118] One preferred embodiment of an inhalation device useful in the method according to the invention is shown diagrammatically, not to scale, in Figure 1. Figure 1 shows the situation before first use.

[0119] The inhalation device comprises a housing (1), preferably shaped and sized to be held in one hand and operated with one finger, e.g., the thumb or index finger (not shown). A fluid reservoir (2) for storing the medically active liquid (F) to be administered in accordance with the present invention is disposed within the housing (1). The illustrated reservoir (2) is designed to be collapsible, such that its soft or elastic walls deform so that the negative pressure required to draw liquid from the reservoir remains substantially constant over time as the reservoir is emptied through repeated use of the device. A similar effect can be achieved in an alternative embodiment (not shown) using a rigid container with a movable bottom, thereby also allowing the internal volume of the reservoir to be continuously reduced.

[0120] Furthermore, the illustrated inhalation device comprises a pump unit having a hollow cylinder (9) within the housing (1), which forms a pump chamber (3) for generating the desired pressure required to expel the liquid (F) (i.e., the medically active liquid) and nebulize it. The pump unit may also comprise further components not shown in the figures, such as a push button, a locking device, etc.

[0121] As a potential energy storage means (7), a spring is provided which is connected to one end (upward or downstream) of the cylinder (9) and supported by the housing (1) (bottom of the figure).

[0122] The illustrated suction device further includes riser pipes (5) having internal ends (5A) facing or upstream of at least one reservoir that can be accommodated within the cylinder (9). In other words, the riser pipes (5) can be at least partially pushed into the hollow cylinder (9), resulting in a reduction in the internal volume of the pump chamber (3). The term "internal volume" refers to the volume extending from the reservoir-facing inlet of the cylinder (9) to the location where the internal ends (5A) of the respective riser pipes (5) are located. In the illustrated situation, the riser pipes (5) are almost completely accommodated within the cylinder (9). As a result, the internal volume of the pump chamber (3) located between the inlet valve (4) and the internal ends (5A) of the riser pipes (5) is minimal.

[0123] Preferably, the portion (or segment) of the hollow cylinder (9) that serves as or houses the pump chamber (3) and that houses the riser pipe (5) presents a circular inner cross-section whose diameter matches relatively closely (e.g., except for a small gap) the diameter of the circular outer cross-section of the corresponding segment of the riser pipe (5). Of course, other (e.g., non-circular) cross-sectional shapes are also possible.

[0124] According to the embodiment shown, the inlet valve (4) is arranged between the reservoir (2) and the inlet of the pump chamber (3) formed by the cylinder (9).

[0125] The inhalation device further comprises a nozzle (6) fluid-tightly connected to the external (or downstream) end (5B) of the riser pipe (5). The nozzle (6) is an impingement type nozzle for producing an atomized aerosol by the collision of at least two liquid jets. Preferably, the cross section of the liquid-containing channel is relatively small, typically in the micron range.

[0126] Also shown is an optional outlet valve (8) inside the riser pipe (5) to prevent backflow of liquid or air from the outside into the external end (5B) of the riser pipe (5). The outlet valve (8) is located at the internal end (5A) of the riser pipe (5). Liquid (F) is allowed to pass through the outlet valve (8) in the direction of the nozzle (6), but the outlet valve (8) blocks any undesired backflow in the opposite direction.

[0127] As can be seen in FIG. 1, the riser pipe (5) is designed to be immobile relative to the housing (1) and fixed to it, as indicated by its connection with the housing (1) in the region of its outer end (5B). The riser pipe (5) is also rigidly attached to the nozzle (6), which in turn is likewise attached to the housing (1). In contrast, the hollow cylinder (9) comprising the pump chamber (3) is designed to be movable relative to the housing (1) and the nozzle (6). The advantages of this design have been explained; see the respective sections above.

[0128] Referring to Figure 2, an apparatus similar to that of Figure 1 is shown. However, the embodiment shown in Figure 2 lacks the (optional) outlet valve (8). All other components are present and functionally equivalent. In this embodiment, the pump chamber (3) extends from downstream of the valve (4) to the nozzle (6), where the resistance to the fluid increases significantly. In an alternative embodiment, where the inner diameter of the riser pipe (5) is particularly small, the pump chamber (3) extends only from downstream of the valve (4) to the upstream inner end (5A) of the riser pipe (5).

[0129] Figure 3 shows the embodiment of Figure 1 with the pump chamber being filled. The hollow cylinder (9) has been moved to its most upstream position, thereby loading the potential energy storage means (7). The outlet valve (8) is closed by the negative pressure in the pump chamber (3), and the inlet valve (4) is open to the fluid reservoir (2). While the gradual collapse of the reservoir (2) wall allows the internal pressure in the reservoir (2) to remain approximately constant, the pressure in the pump chamber (3) decreases due to the longitudinal propulsive movement of the hollow cylinder (9), thus increasing the volume of the pump chamber (3). As a result, the pump chamber (3) is filled with medically active liquid (F) from the reservoir (2).

[0130] Figure 4 shows the situation after the first actuation of the suction device of Figure 1. The potential energy storage means (7) is disengaged from the loaded position as shown in Figure 3. This pushes the cylinder (9) downstream, sliding it on the riser pipe (5). The inner end (5A) of the riser pipe (5) approaches the inlet check valve (4), which is now closed. As a result, pressure in the pump chamber (3) rises, keeping the inlet valve (4) closed but opening the outlet valve (8). Liquid (F) flows from the riser pipe (5) through its outer end (5B) toward the nozzle (6).

[0131] Figure 5 shows the inhalation device of Figure 1 in the situation at the end of the aerosol release phase. The potential energy storage means (7) is in its most relaxed end position (the spring is fully extended). Also, almost the entire hollow cylinder (9) is forced onto the riser pipe (5) so that the internal volume of the pump chamber (3) reaches its minimum. Most of the liquid (F) previously contained in the pump chamber (3) has entered the main part of the riser pipe (5) through the outlet valve (8). Some liquid (F) is forced towards and through the nozzle (6) from which the spraying occurs, so that the nebulized aerosol is released towards the user or patient.

[0132] Figure 6 shows the suction device of Figure 1 in the situation after refilling the pump chamber. The hollow cylinder (9) is moved (repulsively) in the upstream direction, thus increasing the volume of the pump chamber (3) that it contains. The potential energy storage means (7) is loaded (the spring is compressed). While the cylinder (9) moves away from the nozzle (6), a negative pressure is created in the pump chamber (3), closing the outlet valve (8) and opening the inlet check valve 4. As a result, further liquid (F) is drawn from the reservoir (2) into the pump chamber (3). The pump chamber (3) of the suction device is refilled and ready for the next discharge of liquid (F) by releasing the spring.

[0133] Figure 7 shows the mean particle size distribution versus total spray duration for various combinations of water and ethylene glycol mixtures prepared to mimic the viscosity of a high molecular weight compound such as remdesivir at concentrations of 5%, 10%, 15%, 20%, and 25% (wt%) as described in Example 1. Particle size distributions are determined with 95% confidence intervals based on the T-distribution. As used herein, the term "T-distribution," also known as "Student's t-distribution," refers to a member of a family of continuous probability distributions that arise when estimating the mean of a normally distributed population when the sample size is small and the population standard deviation is unknown.

[0134] Figure 8 shows the mean particle size distribution over spray duration for various concentrations of remdesivir (3.56, 5.08, 7.63, and 10.17 mg / ml) in 100% ethanol or 70:30 ethanol:water (% w / w), as described in Example 2. Particle size distribution is determined with a 95% confidence interval based on the T-distribution. [Explanation of symbols]

[0135] 1. Housing 2 fluid reservoir, reservoir 3. Pump Room 4 inlet valve 5 Riser Pipe 5A internal end 5B External end 6 nozzles 7. Means of storing potential energy 8 Outlet Valve 9 Hollow cylinder, cylinder F Liquids, fluids, medically active liquids

[0136] The following examples serve to illustrate the present invention but should not be understood as limiting the scope of the invention. (Example) material and method

[0137] For Example 1, a solution of water and ethylene glycol was prepared by combining the two solvents at room temperature. For Example 2, a solution of remdesivir in ethanol (100%) was prepared by dissolving remdesivir in ethanol at room temperature. For Example 2, a solution of remdesivir in ethanol:water (70:30% w / w) was prepared by dissolving remdesivir in ethanol at room temperature and adding water to the solution. Each solution was dispensed using a soft mist inhaler embodiment as disclosed herein, with an operating pressure of at least 200 bar and a nebulization duration of 1 to 5 seconds (Example 1) or 1 to 3 seconds (Example 2). The particle size distribution of the dispensed solution was measured using a Malvern Spraytec® device. Example 1

[0138] Solutions of water and ethylene glycol were prepared to mimic the viscosity of high molecular weight compounds such as remdesivir at concentrations of 5%, 10%, 15%, 20%, and 25% (wt% of compound in solution). The wt% ethylene glycol and water values ​​for each solution are summarized in Table 1. [Table 1]

[0139] The solutions were dispensed at room temperature using a soft mist inhaler embodiment as disclosed herein. The dispensing parameters and particle size distribution results are summarized in Table 2 and Figure 7. The term "event duration" refers to the overall spray duration in seconds (s) when the solution is dispensed. The term "Stdev" means standard deviation. [Table 2] Example 2

[0140] Solutions of remdesivir in ethanol (100%) and ethanol:water (70:30% w / w) were prepared at concentrations of approximately 3.56 mg / mL ("REM3.56"), 5.08 mg / mL ("REM5.08"), 7.63 mg / mL ("REM7.63"), and 10.17 mg / mL ("REM10.17"). The solutions were dispensed at room temperature using a soft mist inhaler embodiment as disclosed herein. Dispensing parameters and particle size distribution results are summarized in Table 3 and Figure 8. The addition of water increases particle size. [Table 3] List of Items

[0141] In particular, the present disclosure relates to the following specific embodiments E1 to E26:

[0142] E1. A method of treating or preventing a viral infection or viral disease, disorder or condition in a subject, comprising administering to said subject by inhalation a medically active liquid in aerosol form; -the method, wherein the medically active liquid comprises remdesivir or a pharmaceutically acceptable salt thereof, and wherein the medically active liquid is administered in nebulized form using an inhalation device.

[0143] E2 The method of embodiment 1, wherein the viral infection or viral disease, disorder or condition is a coronavirus infection or coronavirus disease, disorder or condition.

[0144] E3 The method of embodiment 2, wherein the coronavirus infection is a SARS-CoV or SARS-CoV-2 infection, or the coronavirus disease, disorder, or condition results from a SARS-CoV or SARS-CoV-2 infection.

[0145] E4 The method of embodiment 2, wherein the coronavirus infection is Middle East Respiratory Syndrome coronavirus infection or the coronavirus disease, disorder or condition is caused by Middle East Respiratory Syndrome coronavirus infection.

[0146] E5 The method of any one of embodiments 1 to 4, wherein the viral infection or viral disease, disorder or condition is responsive to inhibition of viral replication.

[0147] E6 The method of any one of embodiments 1 to 5, wherein the viral disease, disorder or condition is a disease, disorder or condition of the immune system; an inflammatory disease, disorder or condition; an autoimmune disease, disorder or condition; a disease, disorder or condition of the cardiovascular system; a cancer; a tumor or other malignancy; a disease, disorder or condition of the renal system; a disease, disorder or condition of the gastrointestinal tract; a disease, disorder or condition of the respiratory system; a disease, disorder or condition of the endocrine system; and / or a disease, disorder or condition of the central nervous system (CNS).

[0148] E7 The method of any one of embodiments 1 to 6, wherein the viral disease, disorder or condition is an inflammatory disease, disorder or condition.

[0149] E8 The method of any one of embodiments 1 to 7, wherein the viral disease, disorder or condition is Severe Acute Respiratory Syndrome (SARS).

[0150] E9 The method of any one of embodiments 1 to 8, wherein the viral infection or viral disease, disorder or condition is a respiratory or pulmonary infection or disease, disorder or condition.

[0151] E10 The method of embodiment 9, wherein the lung infection is a lower respiratory tract infection.

[0152] E11 The method of embodiment 10, wherein the lower respiratory tract infection is pneumonia.

[0153] E12. The method of any one of embodiments 1 to 11, wherein the subject is a human or an animal.

[0154] E13. The method of any one of embodiments 1 to 12, wherein the subject is diagnosed with a viral infection or viral disease, disorder or condition.

[0155] E14 The method of embodiment 13, wherein the subject has been diagnosed with COVID-19.

[0156] E15 The method of any one of embodiments 1 to 14, wherein remdesivir or a pharmaceutically acceptable salt thereof is administered to the subject's lungs.

[0157] E16 The method of any one of embodiments 1 to 15, wherein the inhalation device used to administer the medically active liquid comprising remdesivir or a pharmaceutically acceptable salt thereof is a handheld device.

[0158] E17 The method of any one of embodiments 1 to 16, wherein the inhalation device used to administer the medically active liquid comprising remdesivir or a pharmaceutically acceptable salt thereof is a soft mist inhaler.

[0159] E18 The method of any one of embodiments 1 to 17, wherein the inhalation device used to administer the medically active liquid comprising remdesivir or a pharmaceutically acceptable salt thereof is a soft mist inhaler having at least one impingement nozzle.

[0160] E19 The inhalation device used to administer the medically active liquid containing remdesivir or a pharmaceutically acceptable salt thereof is a handheld inhalation device for delivering a nebulized medically active aerosol for inhalation therapy, (a) a housing having a user-facing side; (b) an impingement nozzle for producing an atomized aerosol by the collision of at least two liquid jets, the impingement nozzle being rigidly attached to the user-facing side of the housing so that the nozzle is immovable relative to the housing; (c) a fluid reservoir disposed within the housing; and (d) a pump unit disposed within the housing, an upstream end fluidly connected to a fluid reservoir; a downstream end fluidly connected to the nozzle; the pump unit is adapted to pump fluid from the fluid reservoir to the nozzle; The pump unit is (i) a riser pipe having an upstream end, - adapted to act as a piston in a pump unit, a riser pipe fixedly secured to the user-facing side of the housing so as to be immovable relative to the housing; and (ii) a hollow cylinder located upstream of the riser pipe, the upstream end of the riser pipe being inserted into the cylinder such that the cylinder is longitudinally movable on the riser pipe; 19. The method of any one of claims 1 to 18, further comprising (iii) lockable means for storing potential energy when locked and releasing the stored energy when unlocked, the means being disposed outside of the cylinder and mechanically coupled to the cylinder, wherein unlocking of the means causes longitudinal propulsive movement of the cylinder toward the downstream end of the pump unit.

[0161] E20 The method of any one of embodiments 1 to 19, wherein the medically active liquid comprises remdesivir at a concentration of about 10 μg / μL to about 30 μg / μL.

[0162] E21 The method of embodiment 20, wherein the medically active liquid comprises remdesivir at a concentration of about 15 μg / μL.

[0163] E22 The method of any one of embodiments 1 to 21, wherein the administered medically active liquid comprises about 150 μg to about 230 μg of remdesivir.

[0164] E23 The method of embodiment 22, wherein the administered medically active liquid comprises about 225 μg of remdesivir.

[0165] E24. The method of any one of embodiments 1 to 23, wherein the medically active liquid has a mean particle size distribution of Dv50 from about 2.0 μm to about 4.0 μm.

[0166] E25 The method of any one of embodiments 1 to 24, wherein the medically active liquid comprises alcohol.

[0167] E26 The method of embodiment 25, wherein the alcohol is ethanol.

Claims

1. 1. A medically active liquid comprising remdesivir or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a viral infection or viral disease, disorder, or condition in a subject, wherein the liquid is administered to the subject in nebulized form by inhalation using an inhalation device; the medically active liquid comprises alcohol; the medically active liquid comprises remdesivir at a concentration of 10 μg / μL to 30 μg / μL; the inhalation device used to administer the medically active liquid comprising remdesivir or a pharmaceutically acceptable salt thereof is a soft mist inhaler having at least one impingement nozzle; the viral infection or viral disease, disorder or condition is a respiratory or pulmonary infection or disease, disorder or condition; Medically active liquid.

2. 2. The medically active liquid for use according to claim 1, wherein the viral infection or viral disease, disorder or condition is a coronavirus infection or coronavirus disease, disorder or condition.

3. 3. The medically active liquid for use according to claim 2, wherein said coronavirus infection is a SARS-CoV or SARS-CoV-2 infection, or said coronavirus disease, disorder or condition is caused by a SARS-CoV or SARS-CoV-2 infection.

4. 3. The medically active liquid for use according to claim 2, wherein said coronavirus infection is Middle East Respiratory Syndrome coronavirus infection or said coronavirus disease, disorder or condition is caused by Middle East Respiratory Syndrome coronavirus infection.

5. 5. The medically active liquid for use according to any one of claims 1 to 4, wherein the viral infection or viral disease, disorder or condition is responsive to the inhibition of viral replication.

6. 6. The medically active liquid for use according to any one of claims 1 to 5, wherein said viral disease, disorder or condition is an inflammatory disease, disorder or condition.

7. 7. The medically active liquid for use according to any one of claims 1 to 6, wherein said viral disease, disorder or condition is Severe Acute Respiratory Syndrome (SARS).

8. 2. The medically active liquid for use according to claim 1, wherein the lung infection is a lower respiratory tract infection.

9. 9. The medically active liquid for use according to claim 8, wherein the lower respiratory tract infection is pneumonia.

10. 10. The medically active liquid for use according to any one of claims 1 to 9, wherein the subject is a human or an animal.

11. 11. The medically active liquid for use according to any one of claims 1 to 10, wherein the subject has been diagnosed with a viral infection or a viral disease, disorder or condition.

12. 12. The medically active liquid for use according to claim 11, wherein the subject has been diagnosed with COVID-19.

13. 13. The medically active liquid for use according to any one of claims 1 to 12, wherein the remdesivir or a pharmaceutically acceptable salt thereof is administered to the lungs of the subject.

14. 14. The medically active liquid for use according to any one of claims 1 to 13, wherein the inhalation device used to administer the medically active liquid comprising remdesivir or a pharmaceutically acceptable salt thereof is a handheld device.

15. the inhalation device used to administer the medically active liquid comprising remdesivir or a pharmaceutically acceptable salt thereof is a handheld inhalation device for delivering a nebulized medically active aerosol for inhalation therapy; (a) a housing having a user-facing side; (b) an impingement nozzle for generating the atomized aerosol by the collision of at least two liquid jets, the impingement nozzle being rigidly attached to the user-facing side of the housing such that the nozzle is immovable relative to the housing; (c) a fluid reservoir disposed within the housing; and (d) a pump unit disposed within the housing, an upstream end fluidly connected to said fluid reservoir; a pump unit having a downstream end fluidly connected to said nozzle, the pump unit is adapted to pump fluid from the fluid reservoir to the nozzle; The pump unit comprises: (i) a riser pipe having an upstream end, - adapted to act as a piston of said pump unit, a riser pipe fixedly secured to the user-facing side of the housing so as to be immovable relative to the housing; and (ii) a hollow cylinder located upstream of the riser pipe, the upstream end of the riser pipe being inserted into the cylinder such that the cylinder is longitudinally movable on the riser pipe; (iii) lockable means for storing potential energy when locked and releasing the stored energy when unlocked, said means being located outside of said cylinder and mechanically coupled to said cylinder, wherein unlocking of said means causes longitudinal propulsive movement of said cylinder towards the downstream end of said pump unit.

15. A medically active liquid for use according to any one of claims 1 to 14, further comprising:

16. 10. The medically active liquid for use according to claim 1, wherein the medically active liquid comprises remdesivir at a concentration of 15 μg / μL.

17. 17. The medically active liquid for use according to any one of claims 1 to 16, wherein the administered medically active liquid comprises 150 μg to 230 μg of remdesivir.

18. 18. The medically active liquid for use according to claim 17, wherein the administered medically active liquid comprises 225 μg of remdesivir.

19. A medically active liquid for use according to any one of claims 1 to 18, wherein the medically active liquid has a mean particle size distribution of Dv50 between 2.0 μm and 4.0 μm.

20. 2. The medically active liquid for use according to claim 1, wherein said alcohol is ethanol.

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