WO2021245656A1 - Compositions de nicotine pour inhalation et leurs utilisations antivirales - Google Patents

Compositions de nicotine pour inhalation et leurs utilisations antivirales Download PDF

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Publication number
WO2021245656A1
WO2021245656A1 PCT/IL2021/050639 IL2021050639W WO2021245656A1 WO 2021245656 A1 WO2021245656 A1 WO 2021245656A1 IL 2021050639 W IL2021050639 W IL 2021050639W WO 2021245656 A1 WO2021245656 A1 WO 2021245656A1
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Prior art keywords
composition
porous medium
nebulizer
liquid
nicotine
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Application number
PCT/IL2021/050639
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English (en)
Inventor
Miron Hazani
Original Assignee
Nicogen Ltd.
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Publication date
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Publication of WO2021245656A1 publication Critical patent/WO2021245656A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
    • A61M11/001—Particle size control
    • A61M11/002—Particle size control by flow deviation causing inertial separation of transported particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
    • A61M11/02—Sprayers or atomisers specially adapted for therapeutic purposes operated by air or other gas pressure applied to the liquid or other product to be sprayed or atomised
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0001—Details of inhalators; Constructional features thereof
    • A61M15/0003—Details of inhalators; Constructional features thereof with means for dispensing more than one drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0001—Details of inhalators; Constructional features thereof
    • A61M15/0021—Mouthpieces therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0085—Inhalators using ultrasonics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
    • A61M11/005—Sprayers or atomisers specially adapted for therapeutic purposes using ultrasonics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/04—Liquids
    • A61M2202/0468—Liquids non-physiological
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/20—Pathogenic agents
    • A61M2202/206—Viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/02—General characteristics of the apparatus characterised by a particular materials
    • A61M2205/0272—Electro-active or magneto-active materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/07—General characteristics of the apparatus having air pumping means
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/10—General characteristics of the apparatus with powered movement mechanisms
    • A61M2205/103—General characteristics of the apparatus with powered movement mechanisms rotating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/12—General characteristics of the apparatus with interchangeable cassettes forming partially or totally the fluid circuit
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/12—General characteristics of the apparatus with interchangeable cassettes forming partially or totally the fluid circuit
    • A61M2205/123—General characteristics of the apparatus with interchangeable cassettes forming partially or totally the fluid circuit with incorporated reservoirs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/33—Controlling, regulating or measuring
    • A61M2205/3331—Pressure; Flow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/35—Communication
    • A61M2205/3576—Communication with non implanted data transmission devices, e.g. using external transmitter or receiver
    • A61M2205/3592—Communication with non implanted data transmission devices, e.g. using external transmitter or receiver using telemetric means, e.g. radio or optical transmission
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/50—General characteristics of the apparatus with microprocessors or computers
    • A61M2205/502—User interfaces, e.g. screens or keyboards
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/82—Internal energy supply devices
    • A61M2205/8206—Internal energy supply devices battery-operated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/82—Internal energy supply devices
    • A61M2205/8218—Gas operated
    • A61M2205/8225—Gas operated using incorporated gas cartridges for the driving gas

Definitions

  • the present disclosure generally relates to the field of nicotine compositions for pulmonary administration, and uses thereof in treating viral infections, in particular coronaviruses.
  • the nicotine compositions contain a bronchodilator and are administered in the form of an aerosol generated by a nebulizer.
  • COVID-19 coronavirus disease 2019 (COVID-19). Since then, COVID- 19 disease spread worldwide in more than 150 countries with millions of sick and hundreds of thousands deceased.
  • Current experimental drugs designed to treat COVID- 19 are administered in dosage forms suitable for enteral administration, such as oral, and for intravenous, intramuscular and subcutaneous administrations.
  • Myara et al. (Miyara et al., (2020) Low incidence of daily active tobacco smoking in patients with symptomatic COVID-19. Qeios ID: WPP19W.3; preprint v3. Retrieved from: https://doi.Org/10.32388/WPP19W.3 on May 17, 2020) suggests that daily smokers have a very much lower probability of developing symptomatic or severe SARS-CoV-2 infection as compared to the general population.
  • Changeux et al. (Comptes Rendus. Biologies, Tome 343 (2020) no. 1, pp. 33-39.) hypothesizes that under controlled settings, nicotinic agents could provide an efficient treatment for an acute infection such as COVID-19.
  • a bronchodilator is a substance that dilates the bronchi and bronchioles, decreasing resistance in the respiratory airway and increasing airflow to the lungs.
  • Bronchodilators may be medications administered for the treatment of breathing difficulties, usually in the form of inhalers. They are most useful in obstructive lung diseases, of which asthma and chronic obstructive pulmonary disease are the most common conditions.
  • Salbutamol also known as albuterol is a bronchodilator that opens up the medium and large airways in the lungs. It is a short-acting b2 adrenergic receptor agonist which works by causing relaxation of airway smooth muscle. It is used to treat asthma, including asthma attacks, exercise-induced bronchoconstriction, and chronic obstructive pulmonary disease (COPD). Salbutamol is usually used with an inhaler or nebulizer, but it is also available in a pill, liquid, and intravenous solution.
  • WO 2016/059630 to the inventor of the present invention discloses a nebulizer comprising a porous medium configured to produce aerosols, a displaceable wetting mechanism configured to spread a liquid over the porous medium thereby to wet the porous medium and a gas channel configured to introduce pressure gradient to the porous medium.
  • compositions for treatment or prevention of diseases caused by a coronavirus are useful for treating COVID-19 disease.
  • the compositions of the present invention comprise nicotine and a bronchodilator, and are for pulmonary administration.
  • the present composition may be provided in a dosage form suitable for aerosolization. More specifically, the dosage form may be a nebulizer cartridge containing the composition, which is adapted for aerosolization from a nebulizer. Alternatively, the composition may be for filling a nebulizer.
  • the nicotine is provided in its protonated form, e.g. in an aqueous solution having pH lower than 6.
  • the bronchodilator is salbutamol.
  • the dosage form and administration of the current invention are more effective than currently known and experimented therapies, which include mainly oral administration by ingestion or through injection.
  • the current invention further provides methods of treatment of diseases caused by a coronavirus, according to some embodiments. Said methods include administering, via inhalation, to a subject in need thereof a nicotine-bronchodilator composition in the form of an aerosol.
  • the administration disclosed herein is carried out using a nebulizer.
  • the administration disclosed herein is carried out using a nebulizer, as disclosed herein, which is specifically designed to provided aerosol having droplet at a diameter, which is effective in reaching the lungs and treating diseases caused by a coronavirus, such as COVID-19 disease.
  • a nebulizer for use in the methods of the invention does not include a heating element.
  • an “aerosol”, as used herein, is a suspension of fine solid particles or liquid droplets in air or another gas.
  • a method for treating or preventing a disease caused by a coronavirus comprising administering, via inhalation, to a subject in need thereof a pulmonary composition comprising nicotine and a bronchodilator.
  • the coronavirus is a human coronavirus.
  • the human coronavirus is selected from MERS-CoV, SARS- CoV and SARS-CoV-2.
  • the disease is COVID-19.
  • the nicotine is in a protonated form.
  • the composition has pH lower than 7.
  • the composition has pH lower than 6.
  • the composition comprises an aqueous solution of nicotine and the bronchodilator.
  • the nicotine is at a concentration in the range of 0.5% to 5%, w/w. According to some embodiments, the concentration of the nicotine in the composition is in the range of 0.2 to 50 gr/L. According to some embodiments, the bronchodilator is at a concentration in the range of 0.03% to 0.5%, w/w. According to some embodiments, the concentration of the bronchodilator in the composition is in the range of 0.2 to 5 gr/L.
  • the bronchodilator is salbutamol.
  • the composition comprises an aqueous solution of nicotine in a protonated form, and salbutamol, wherein the nicotine is at a concentration in the range of 0.5% to 5%, w/w, wherein the salbutamol is at a concentration in the range of 0.03% to 0.5%, w/w, and wherein the aqueous solution has pH lower than 6.
  • the composition further comprises at least one additive selected from the group consisting of a propellant, an anti-coughing agent and a flavorant.
  • the method comprises the steps of:
  • the nebulizer comprises a porous medium configured to produce aerosols, a displaceable wetting mechanism configured to spread a liquid over the porous medium thereby to wet the porous medium and a gas channel configured to introduce pressure gradient to the porous medium.
  • the displaceable wetting mechanism comprises a rotatable elongated member configured to move across the surface of the porous medium, thereby to homogeneously or semi-homogeneously spread the liquid over the surface.
  • the nebulizer comprises a porous medium configured to produce aerosols, a liquid absorbing material configured to absorb a liquid, a wetting mechanism configured to press the liquid absorbing material against the porous medium, thereby to wet the porous medium with the liquid absorbed in the liquid absorbing material and a gas channel configured to introduce pressure gradient to the porous medium.
  • the nebulizer comprises: a porous medium having a first side of the porous medium and a second side of the porous medium, configured to produce aerosols: a liquid absorbing material having a first side of the liquid absorbing material and a second side of the liquid absorbing material, configured to absorb a liquid; a wetting mechanism configured to press the liquid absorbing material against the porous medium, thereby to wet the porous medium with the liquid absorbed in the liquid absorbing material; an opening configured to deliver aerosols to a subject; and a gas channel configured to introduce gas pressure gradient, such that different gas pressure levels between the first side of the porous medium and a second side of to the porous medium is formed, thereby producing the aerosol; wherein the wetting mechanism is attached to the first side of the liquid absorbing material; wherein the first side of the porous medium is facing the liquid absorbing material and the opening, and the second side of the porous medium is facing the gas channel.
  • the nebulizer is an ultrasonic nebulizer, comprising a piezoelectric transducer.
  • step (b) comprises applying electric power to the piezoelectric transducer, thereby creating vibrations at an ultrasonic frequency in a transducer plate associated with the piezoelectric transducer, wherein the vibrations result in generating an aerosol from the composition in the liquid container.
  • the droplets of the aerosol delivered by the nebulizer are having a mass median aerodynamic diameter (MMAD) of no more than 5 microns.
  • MMAD mass median aerodynamic diameter
  • a pulmonary composition provided in a dosage form suitable for aerosolization using a nebulizer, for use in treatment or prevention of a disease caused by a coronavirus, wherein the composition comprises nicotine and a bronchodilator.
  • the nicotine is in a protonated form.
  • the composition has pH lower than 7.
  • the composition has pH lower than 6.
  • the composition comprises an aqueous solution of nicotine and the bronchodilator.
  • the composition comprises an aqueous solution of protonated nicotine, wherein the aqueous solution has pH lower than 6.
  • the nicotine is at a concentration in the range of 0.5% to 5%, w/w.
  • the bronchodilator is salbutamol.
  • the bronchodilator is at a concentration in the range of 0.03% to 0.5%, w/w.
  • the concentration of the nicotine in the composition is in the range of 0.2 to 50 gr/L.
  • the composition comprises an aqueous solution of nicotine in a protonated form and salbutamol, wherein the nicotine is at a concentration in the range of 0.5% to 5%, w/w, wherein the salbutamol is at a concentration in the range of 0.03% to 0.5%, w/w, wherein the aqueous solution has pH lower than 6.
  • the composition further comprises at least one additive selected from the group consisting of a propellant, an anti-coughing agent and a flavorant.
  • the coronavirus is a human coronavirus.
  • the human coronavirus is selected from MERS-CoV, SARS- CoV and SARS-CoV-2.
  • the disease is COVID-19.
  • a nebulizer cartridge comprising a liquid container, wherein the liquid container contains the composition according to the present invention.
  • the nebulizer comprises a porous medium configured to produce aerosols, a displaceable wetting mechanism configured to spread a liquid over the porous medium thereby to wet the porous medium and a gas channel configured to introduce pressure gradient to the porous medium.
  • the displaceable wetting mechanism comprises a rotatable elongated member.
  • the rotatable elongated member is configured to move across the surface of the porous medium, thereby to homogeneously or semi-homogeneously spread the liquid over the surface.
  • the rotatable elongated member is axially movable.
  • the displaceable wetting mechanism further comprises an actuator configured to displace or induce the displacement of the rotatable elongated member.
  • the rotatable elongated member comprises a first magnet
  • the actuator comprises a second magnet, magnetically associated with said first magnet, such that by moving the second magnet displacement of the rotatable elongated member is induced.
  • the method of the present invention comprises the steps of the steps of:
  • a nebulizer comprising a porous medium configured to produce aerosols, a displaceable wetting mechanism configured to spread the liquid composition over the porous medium thereby to wet the porous medium and a gas channel, wherein said porous medium is having two sides, wherein a first side is facing the displaceable wetting mechanism; (ii) providing a liquid composition comprising at least one anti-infective agent;
  • the nebulizer comprises a porous medium configured to produce aerosols, a liquid absorbing material configured to absorb a liquid, a wetting mechanism configured to press the liquid absorbing material against the porous medium or a first surface of the porous medium, thereby to wet the porous medium with the liquid absorbed in the liquid absorbing material and a gas channel configured to introduce pressure gradient to the porous medium.
  • the liquid absorbing material is selected from the group consisting of a sponge, a tissue, a foam material, a fabric, and combinations thereof.
  • the nebulizer is an ultrasonic nebulizer, further comprising a piezoelectric transducer.
  • the ultrasonic nebulizer comprises a transducer plate, wherein upon application of electric power to the piezoelectric transducer, vibrations are created at an ultrasonic frequency in a transducer plate wherein the vibrations result in generating an aerosol from the composition in the liquid container.
  • an aerosol composition comprising 50-99% w/w solvent or diluent, 0.5-5% w/w nicotine and 0.03-0.5% salbutamol, wherein the aerosol comprises droplets having a mass median aerodynamic diameter (MMAD) of no more than 5 microns.
  • MMAD mass median aerodynamic diameter
  • the aerosol composition comprises the same ingredients and amounts thereof as in the pulmonary composition disclosed herein.
  • the aerosol composition is for use in the treatment or prevention of a disease caused by a coronavirus.
  • the aerosol comprises an aqueous solution of nicotine in a protonated form, and salbutamol, wherein the nicotine is at a concentration in the range of 0.5% to 5%, w/w, wherein the salbutamol is at a concentration in the range of 0.03% to 0.5%, w/w, and wherein the aqueous solution has pH lower than 6.
  • an aerosol upon aerosolization of the composition of the present invention, an aerosol is created, said aerosol has a pH in the range of 4 to about 6.
  • Certain embodiments of the present disclosure may include some, all, or none of the above advantages.
  • One or more technical advantages may be readily apparent to those skilled in the art from the figures, descriptions and claims included herein.
  • specific advantages have been enumerated above, various embodiments may include all, some or none of the enumerated advantages.
  • Fig. 1 schematically illustrates a nebulizer with a porous medium, according to some embodiments
  • Fig. 2 schematically illustrates a nebulizer with porous medium and medication containers, according to some embodiments
  • Fig. 3 schematically illustrates a nebulizer with a sponge pressed against a porous medium, according to some embodiments
  • Fig. 4 schematically illustrates generation of aerosol within a nebulizer, according to some embodiments
  • Fig. 5 schematically illustrates a nebulizer system, according to some embodiments
  • Fig. 6a schematically illustrates a nebulizer with a rotatable wetting mechanism and a bottom actuator at side cross section, according to some embodiments
  • Fig. 6b schematically illustrates a nebulizer with a rotatable wetting mechanism and a bottom actuator at top cross section, according to some embodiments
  • Fig. 6c schematically illustrates a nebulizer with a rotatable wetting mechanism and a peripheral actuator at side cross section, according to some embodiments
  • Fig. 6d schematically illustrates a nebulizer with a rotatable wetting mechanism and a peripheral actuator at top cross section, according to some embodiments
  • Fig. 6e schematically illustrates a nebulizer with a rotatable wetting mechanism and a flexible medication deploying end at side cross section, according to some embodiments
  • Fig. 6f schematically illustrates a nebulizer with a rotatable wetting mechanism and a flexible medication deploying end at top cross section, according to some embodiments
  • Fig. 6g schematically illustrates a nebulizer with a rotatable wetting mechanism having protruding ends at side cross sections, according to some embodiments
  • Fig. 6h schematically illustrates a nebulizer with a rotatable wetting mechanism having protruding ends at top cross section, according to some embodiments
  • Fig. 6i schematically illustrates a nebulizer with a rotatable wetting mechanism and a spacer at side cross sections, according to some embodiments
  • Fig. 6j schematically illustrates a nebulizer with a rotatable wetting mechanism and a spacer at top cross sections, according to some embodiments
  • Fig. 7 schematically illustrates nebulizer with a rotatable wetting mechanism and a liquid deploying structure, according to some embodiments
  • Fig. 8 schematically illustrates nebulizer with a rotatable wetting mechanism and a liquid absorbing material, according to some embodiments
  • Fig. 9 schematically illustrates a side cross section of a nebulizer assembly including an aerosolizing cartridge comprising a rotatable wetting mechanism, according to some embodiments
  • Fig. 10 schematically illustrates a nebulizer system assembly with a rotatable wetting mechanism, according to some embodiments.
  • Fig. 11 illustrates a schematic diagram of a prior art nebulizer 10, according to some embodiments.
  • compositions for treating or preventing a disease caused by a coronavirus are specifically effective in the treatment of COVID-19 disease caused by a human coronavirus, which is a rapidly spreading pandemic nowadays with millions of sick and hundreds of thousands diseased globally.
  • the delivery is preferably conducted by a nebulizer. More preferably, the delivery is preferably conducted by a nebulizer as disclosed herein, which is configured to provide aerosols having droplet profile, which is specifically suitable for treatment of COVID-19 by pulmonary medicament delivery.
  • the treatment provided by the current invention is effective, even with compositions for inhalation comprising nicotine and bronchodilator(s), which are not considered anti-viral.
  • domain A of coronavirus S glycoproteins mediates attachment to oligosaccharide receptors, such as for HCoV-OC43 and BCoV, which interact with 9-O-Ac-Sia, or MERS-CoV, which binds to a2,3-linked (and to a lesser extent to a2,6-linked) sialic acids, with sulfated sialyl-Lewis X being the preferred binder.
  • oligosaccharide receptors such as for HCoV-OC43 and BCoV, which interact with 9-O-Ac-Sia, or MERS-CoV, which binds to a2,3-linked (and to a lesser extent to a2,6-linked) sialic acids, with sulfated sialyl-Lewis X being the preferred binder.
  • key saccharide-binding residues locate to the viral membrane distal side of the BCoV b-sandwich.
  • the receptor-interacting site is conserved in all coronavirus S glycoproteins known to attach to 9-O-Ac-sialoglycans and shares architectural similarity with the ligand binding pockets of coronavirus HEs and influenza virus C/D HEF glycoproteins, thus highlighting common structural principles of recognition.
  • First stage of interaction involves electrostatic binding to a negatively charged group.
  • nicotine at neutral and acidic conditions, is positively charged and may serve as a competitor for the binding, and as a result prevent binding of coronavirus.
  • salbutamol bronchodilatory site of action is the upper airways where the smooth muscles and receptors are located, which may contribute to the therapeutic activity of nicotine detailed herein.
  • a pulmonary composition provided in a dosage form suitable for aerosolization using a nebulizer, for use in treatment of a disease is caused by a coronavirus, wherein the composition comprises nicotine and a bronchodilator.
  • compositions for inhalation are provided.
  • compositions of the present invention are provided in a dosage form suitable for aerosolization using a nebulizer, for use in treatment of a disease caused by a coronavirus, according to some embodiments.
  • the compositions of the present invention comprise nicotine and a bronchodilator, according to some embodiments.
  • compositions for inhalation are not limited to a specific treatment.
  • a liquid composition comprising nicotine and a bronchodilator.
  • the liquid composition comprises an aqueous solution of nicotine in a protonated form, and salbutamol, wherein the nicotine is at a concentration in the range of 0.5% to 5%, w/w, wherein the salbutamol is at a concentration in the range of 0.03% to 0.5%, w/w, and wherein the aqueous solution has pH lower than 6.
  • the liquid composition is a pulmonary composition.
  • the composition is provided in a dosage form suitable for aerosolization ⁇
  • the composition is provided in a dosage form suitable for aerosolization using a nebulizer. Further embodiment may refer to any of the present compositions - either the compositions for use or the compositions provided per se.
  • dosage forms which are “suitable for aerosolization using a nebulizer” means dosage form, which comprise compositions which are suitable or approve for aerosolization and inhalation, and are in a form intended for aerosolization ⁇
  • dosage forms, which are typically intended for aerosolization include, but not limited to, inhaler cartridges comprising inhaled compositions, nebulizer cartridges comprising inhaled compositions, and filling compositions for such devices.
  • the composition is a liquid or semi-liquid composition.
  • the composition of the current invention is in the form of a liquid mixture.
  • the composition of the current invention is in the form of an aqueous mixture.
  • the liquid mixture is selected from liquid solution, liquid suspension and liquid emulsion.
  • the aqueous mixture is selected from aqueous solution, aqueous suspension and aqueous emulsion.
  • the aqueous mixture comprises at least 40%, 50%, 60%, 70%, 80% or at least 90% water.
  • the composition of the current invention is in the form of an aqueous solution.
  • the composition is a liquid or semi-liquid composition, wherein the liquid medium comprises a non-aqueous solvent.
  • the non-aqueous solvent is a polyol.
  • the polyol is selected from glycerol, propylene glycol, or both.
  • the non-aqueous solvent comprises glycerol.
  • the non-aqueous solvent is glycerol.
  • the non-aqueous solvent comprises propylene glycol.
  • the non-aqueous solvent is propylene glycol.
  • the non-aqueous solvent comprises glycerol or propylene glycol.
  • the non-aqueous solvent comprises glycerol and propylene glycol.
  • the non-aqueous solvent comprises a polyol combination of propylene glycol and vegetable glycerin.
  • the polyol combination comprises 20 to 50% propylene glycol and 50 to 80% vegetable glycerin.
  • the polyol combination comprises 25 to 35% propylene glycol and 65 to 75% vegetable glycerin.
  • the composition is a solution.
  • solution refers to a homogeneous liquid dosage form that contains one or more chemical substances dissolved in a solvent or in a mixture of mutually miscible solvents.
  • the composition is a clear solution.
  • the term “clear solution” refers to essentially transparent solutions devoid of particles above 100 nm.
  • the term “clear solution” refers to essentially transparent solutions devoid of particles above 50 nm.
  • the term “clear solution” refers to essentially transparent solutions devoid of particles above 40 nm.
  • compositions that does not include, contain or comprise a particular compound or particles e.g. said composition comprises less than 0.1 %, less than 0.01 %, or less than 0.001 % of the such compounds or particles.
  • the concentration of the nicotine in the composition is in the range of 0.1 to 50 gr/L. According to some embodiments, the concentration of the nicotine in the composition is in the range of 0.2 to 20 gr/L. According to some embodiments, the concentration of the nicotine in the composition is in the range of 0.5 to 10 gr/L. According to some embodiments, the concentration of the nicotine in the composition is in the range of 0.5 to 5 gr/L. According to some embodiments, the concentration of the nicotine in the composition is in the range of 1 to 5 gr/L.
  • the composition comprises a solution of nicotine, wherein the nicotine is at a concentration in the range of 0.01% to 10%, w/w. According to some embodiments, the composition comprises a solution of nicotine, wherein the nicotine is at a concentration in the range of 0.08% to 10%, w/w. According to some embodiments, the composition comprises a solution of nicotine, wherein the nicotine is at a concentration in the range of 0.15% to 10%, w/w. According to some embodiments, the composition comprises a solution of nicotine, wherein the nicotine is at a concentration in the range of 1% to 5%, w/w. According to some embodiments, the present pulmonary composition comprises at least one bronchodilator. According to some embodiments, the composition comprises at least two bronchodilator s.
  • bronchodilator refers to a substance that dilates the bronchi and bronchioles, decreasing resistance in the respiratory airway and increasing airflow to the lungs. Bronchodilators are typically used in the treatment of lung disorders, including COPD and asthma. According to some embodiments, the bronchodilator is long-acting. According to some embodiments, the bronchodilator is short-acting.
  • Non limiting examples of bronchodilators include albuterol (Proventil HFA®, ProAir®, Ventolin HF A®), levalbuterol (Xopenex®), ipratropium (Atrovent®), indacaterol (Arcapta®), umeciidinium (Incruse®), tiotropium (Spiriva®), olodaterol (Stiverdi®), formoterol (Foradil®), aclidinium (Tudorza®), and salmeterol (Serevent®).
  • the bronchodilator is selected from the group consisting of: albuterol (salbutamol), levalbuterol, ipratropium, indacaterol, umeciidinium, tiotropium, olodaterol, formoterol, aclidinium, and salmeterol.
  • albuterol saccharide
  • levalbuterol levalbuterol
  • ipratropium indacaterol
  • umeciidinium tiotropium
  • olodaterol formoterol
  • salmeterol salmeterol.
  • the bronchodilator is a non-volatile compound.
  • the bronchodilator has boiling point above 300°C, above 250°C or above 200°C. Each possibility represents a separate embodiment of the invention.
  • the bronchodilator is selected from the group consisting of albuterol, salbuterol, terbutaline, metoproperanol, isoproterenol, epinephrine, and isoetharine.
  • the bronchodilator comprises salbutamol. According to some embodiments, the bronchodilator is salbutamol.
  • the bronchodilator is selected from a long acting beta agonist (LABA), a long acting muscarinic antagonist (LAMA) and a combination thereof.
  • the bronchodilator is a long acting beta agonist (LABA).
  • the bronchodilator is a long acting muscarinic antagonist (LAMA).
  • the bronchodilator is a combination of a long acting beta agonist (LABA) and a long acting muscarinic antagonist (LAMA).
  • the pharmaceutical composition comprises from 0.1 wt% to 1 wt% of a LAMA. According to some embodiments, the pharmaceutical composition comprises from 0.1 wt% to 1 wt% of a LABA.
  • the bronchodilator is at a concentration in the range of 0.03% to 0.5%, w/w. According to some embodiments, the concentration of the bronchodilator in the composition is in the range of 0.3 to 5 gr/L. According to some embodiments, the concentration of the bronchodilator in the composition is in the range of 0.5 to 5 gr/L. According to some embodiments, the salbutamol is at a concentration in the range of 0.03% to 0.5%, w/w. According to some embodiments, the concentration of the salbutamol in the composition is in the range of 0.3 to 5 gr/L. According to some embodiments, the concentration of the salbutamol in the composition is in the range of 0.5 to 5 gr/L.
  • the composition comprises pharmaceutically active ingredients consisting essentially of and the nicotine and the bronchodilator.
  • the pharmaceutical composition comprises nicotine and the bronchodilator as the sole active ingredients.
  • the composition comprises pharmaceutically active ingredients consisting essentially of and the nicotine and the salbutamol.
  • the pharmaceutical composition comprises nicotine and the bronchodilator as the sole active ingredients.
  • the composition for inhalation of the current invention is a pharmaceutical composition.
  • the pharmaceutical composition further comprises at least one anti-infective agent. According to some embodiments, the pharmaceutical composition further comprises an anti-infective agent. According to some embodiments, the pharmaceutical composition further comprises at least two anti- infective agents.
  • the pharmaceutical composition of the present invention further comprises an additional active agent.
  • the additional active agent is an anti-infective agent.
  • the additional active agent is selected from the group consisting of antibiotics, anti-inflammatory agents, mucolytics, antiviral agents, antibacterial agents, antifungal agents, antiprotozoan agents and a combination thereof. Each possibility represents a separate embodiment.
  • the additional active agent is selected from antibiotics, anti-inflammatory agents, mucolytics and antiviral agents. Each possibility represents a separate embodiment.
  • the additional active ingredient is an anti-viral agent.
  • active agent refers to an agent that has biological activity, pharmacologic effects and/or therapeutic utility.
  • pharmaceutical composition refers to a composition comprising at least one active agent, optionally formulated together with one or more pharmaceutically acceptable carriers. Formulation of the pharmaceutical composition may be adjusted according to their intended use and administration route. In particular, the pharmaceutical composition may be formulated using a method known in the art so as to provide rapid, continuous or delayed release of the active ingredient after administration to mammals. According to one embodiment, the pharmaceutical composition is formulated for administration via inhalation.
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U. S. Pharmacopeia or other generally recognized pharmacopeia for use in animals and, more particularly, in humans.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, preservatives, antioxidants, coatings, isotonic and absorption delaying agents, surfactants, fillers, disintegrants, binders, diluents, lubricants, glidants, pH adjusting agents, buffering agents, enhancers, wetting agents, solubilizing agents, surfactants, antioxidants the like, that are compatible with pharmaceutical administration.
  • the use of such media and agents for pharmaceutically active substances is well known in the art.
  • the pharmaceutical composition comprises a pharmaceutically acceptable carrier or excipient.
  • pharmaceutically acceptable carriers include, for example, lactose, glucose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water and methylcellulose.
  • Other pharmaceutical carriers can be sterile liquids, such as water, alcohols (e.g., ethanol) and lipid carriers such as oils (including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like), phospholipids (e.g. lecithin), polyethylene glycols, glycerine, propylene glycol or other synthetic solvents.
  • alcohols e.g., ethanol
  • lipid carriers such as oils (including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like), phospholipids (e.g. lecithin), polyethylene glycols, glycerine, propylene glycol or other synthetic solvents.
  • oils including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like
  • phospholipids e.g. lecithin
  • polyethylene glycols e.glycerine,
  • Pharmaceutical acceptable diluents include, but are not limited to, sterile water, phosphate saline, buffered saline, aqueous dextrose and glycerol solutions, and the like. Each possibility is a separate embodiment of the invention.
  • nicotine refers to a well known compound which is a chiral alkaloid that is naturally produced in the nightshade family of plants (most predominantly in tobacco and Duboisia hopwoodii) and is widely used recreationally as a stimulant and anxiolytic.
  • the term “nicotine” unless stated otherwise, refers to either the basic (i.e. bearing neutral charge; non-protonated) or acidic (i.e. bearing positive charge; protonated) form.
  • nicotine is an alkaloid and a tertiary amine and comprises both a pyridine and pyrrolidine ring. It is a weak base with a pKa value of about 7.9.
  • nicotine can be protonated, As known in the art.
  • the nicotine in the composition is in a protonated form.
  • the composition has pH lower than 7. According to some embodiments, the composition has pH lower than 6. According to some embodiments, the composition comprises an aqueous solution of protonated nicotine, wherein the aqueous solution has pH lower than 6.
  • the pH of the composition of the present invention is in the range of 4 to about 6.
  • the composition for inhalation further comprises at least one buffer.
  • buffer refers to compounds which reduce the change of pH upon addition of small amounts of acid or base, or upon dilution.
  • buffering agent refers to a weak acid or weak base in a buffer solution.
  • the buffer is an acetate buffer.
  • the composition comprises an aqueous solution of nicotine in a protonated form, and salbutamol, wherein the nicotine is at a concentration in the range of 0.5% to 5%, w/w, wherein the salbutamol is at a concentration in the range of 0.03% to 0.5%, w/w, and wherein the aqueous solution has pH lower than 6.
  • the composition of the current invention further comprises at least one additive selected from the group consisting of a propellant, an anti-coughing agent and a flavorant.
  • the composition further comprises at least one additive.
  • the at least one additive is selected from the group consisting of a propellant, an anti-coughing agent, a flavorant, and combinations thereof.
  • the composition comprises the at least one additive at a concentration of 0.1-1% w/w. According to some embodiments, the composition comprises the at least one additive at a concentration of 0.1-0.5% w/w. According to some embodiments, the composition comprises the at least one additive at a concentration of 0.1-0.3% w/w.
  • the additive is approved for use in inhaling solutions.
  • the flavorant is a sweetener.
  • the sweetener is selected from the group of artificial sweeteners including saccharine, aspartame, dextrose, mannitol and fructose.
  • the additive is selected from menthol, eucalyptol, tyloxapol and a combination thereof. According to some embodiments, the additive is selected from menthol, eucalyptol, tyloxapol and a combination thereof, and is present at a concentration of 0.1-0.5% w/w based on the total weight of the composition.
  • the term "% w/w” refers to % weight/weight as well known in the art. According to any one of the embodiments of the present invention the term “% w/w may be substituted by the term “% w/v”. the term “% w/v” refers to percent weight/volume as well known in the art. According to some embodiments, the composition further comprises at least one preservative.
  • the preservative is selected from the group consisting of benzyl alcohol, propylparaben, methylparaben, benzalkonium chloride, phenylethyl alcohol, chlorobutanol, potassium sorbate, phenol, m-cresol, o- cresol, p- cresol, chlorocresol and combinations thereof.
  • anti-coughing agent refers to an active agent used for the suppression, alleviation or prevention of coughing and irritations and other inconveniencies in the large breathing passages that can, or may, generate coughing.
  • Anti-coughing agent include, but are not limited to antitussives, which are used for which suppress coughing, and expectorants, which alleviate coughing, while enhancing the production of mucus and phlegm. Anti-coughing agents may ease the administration of inhaled aerosols.
  • the at least one anti-coughing agent is selected from expectorants, antitussives or both.
  • the at least one anti-coughing agent is selected from the group consisting of menthol, dextromethorphan, dextromethorphan hydrobromide, hydrocodone, caramiphen dextrorphan, 3-methoxymorphinan or morphinan- 3-ol, carbetapentane, codeine, acetylcysteine and combinations thereof.
  • a suitable propellant is any fluorocarbon, e.g. a 1-4 hydrogen containing fluorocarbon (such as CHF2CHF2, CF3CH2F, CH2F2CH3 and CF3CHFCF3), a perfluorocarbon, e.g. a 1-4 carbon perfluorocarbon, (such as CF3CF3, CF3CF2CF3); or any mixture of the foregoing, having a sufficient vapor pressure to render them effective as propellants.
  • Some typical suitable propellants include conventional chlorofluorocarbon (CFC) propellants such as mixtures of propellants 11, 12 and 114.
  • Non-CFC propellants such as 1,1,1,2-tetrafluoroethane (Propellant 134a), 1,1,1,2,3,3,3-heptafluoropropane (Propellant 227) or mixtures thereof are preferred.
  • the composition is for use that comprises administering a dose ranging from 2 to 1000 mg/day of the composition. According to some embodiments, the composition is for use that comprises administering a dose ranging from 2 to 200 mg/day of the nicotine.
  • the composition is co-administered with an additional active agent.
  • the additional active agent is an anti- viral agent. Any additional active agent used to treat a coronavirus infection may be used, in any treatment regimen, that includes the compositions of the present invention.
  • the additional active agent may be administered before, simultaneously with, or after the compositions of the present invention.
  • the additional active agent is administered by a parenteral route, e.g. intravenous.
  • the pulmonary compositions of the present invention are suitable for administration by inhalation as an aerosol created upon aerosolization of the composition by a nebulizer, according to some embodiments.
  • a nebulizer configured to create aerosols having droplets having a specific diameter.
  • droplets having the diameter profile as provided by the nebulizer disclosed herein are highly effective in treating COVID-19 with a nicotine-based composition.
  • a method for treating or preventing a disease caused by a coronavirus comprising administering, via inhalation, to a subject in need thereof a composition in the form of an aerosol, wherein the composition comprises nicotine and a bronchodilator.
  • the composition is the pulmonary composition disclosed herein.
  • treating refers to taking steps to obtain beneficial or desired results, including clinical results.
  • beneficial or desired clinical results include, but are not limited to, ameliorating abrogating, substantially inhibiting, slowing or reversing the progression of a disease, condition or disorder, substantially ameliorating or alleviating clinical or esthetical symptoms of a condition, substantially preventing the appearance of clinical or esthetical symptoms of a disease, condition, or disorder, and protecting from harmful or annoying symptoms. Treating further refers to accomplishing one or more of the following: (a) reducing the severity of the disorder;
  • the term “preventing” or “prevention” refers to preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
  • the method can thus be used as a preventive treatment in subjects that are suspected to develop a disease caused by a coronavirus, such as subjects that were exposed to infected patients, or subjects who show initial signs of infection (e.g. symptoms in the upper respiratory system).
  • the present invention is further beneficial for reducing the global spread of various coronaviruses which upon infecting the lungs, can cause severe and potentially life-threatening diseases.
  • composition of the current invention is a composition for inhalation.
  • composition for inhalation pulmonary composition
  • nicotine-based composition as used herein, are interchangeable and refer to a composition adapted to be delivered to a subject through the respiratory tract.
  • the compositions for inhalation of the current invention may be delivered to the lungs of the subject via a dedicated device, such as an inhaler or a nebulizer.
  • compositions for inhalation as disclosed herein are administered to the lungs, for example orally (by inhalation through the trachea) or nasally (by inhalation through the nose).
  • pulmonary administration is intended to encompass any suitable delivery method by which the composition is delivered to the lungs via the respiratory tract.
  • compositions for inhalation as disclosed herein are administered to the lungs through the throat of a subject. According to some embodiments, the compositions for inhalation as disclosed herein are administered to the lungs through the pharynx of a subject. According to some embodiments, the compositions for inhalation as disclosed herein are administered to the lungs through the nose of a subject.
  • compositions for inhalation are intended to the lungs and are administered through the pharynx and trachea to the lungs.
  • compositions for the respiratory system may also be delivered nasally (i.e. through the nose).
  • Nasal administration is less common, but is being developed by means of Orally Inhaled and Nasal Drug Product (OINDP).
  • OINDPs are defined by the International Pharmaceutical Aerosol Consortium on Regulation & Science (IPAC-RS) as providing therapeutic benefit by delivery of a pharmaceutical substance to the lungs or nasal cavity.
  • OINDP is generally characterized by: (a) delivery of the drug at a specific range of particle sizes, which may be the drug particle alone, or bound to a carrier, or dissolved or suspended in a liquid droplet; and (b) targeted deposition to specific membranes.
  • the coronavirus is a human coronavirus.
  • the human coronavirus is a betacoronavirus.
  • the human coronavirus is selected from MERS-CoV, SARS-CoV and SARS-CoV-2. According to some embodiments, the human coronavirus is MERS-CoV. According to some embodiments, the human coronavirus is SARS-CoV. According to some embodiments, the human coronavirus is SARS- CoV-2.
  • the disease is COVID-19.
  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), formerly known as the 2019 novel coronavirus (2019-nCoV), is a positive-sense single-stranded RNA virus. It is contagious among humans and is the cause of coronavirus disease 2019 (COVID-19). There is no vaccine, but several antiviral drugs are already in clinical trials. SARS-CoV-2 has strong genetic similarity to known bat coronaviruses, making a zoonotic origin in bats likely, although an intermediate reservoir such as a pangolin is thought to be involved. From a taxonomic perspective SARS-CoV-2 is classified as a strain of the species severe acute respiratory syndrome-related coronavirus.
  • SARS- CoV-2 is the cause of the ongoing 2019-20 coronavirus outbreak, a Public Health Emergency of International Concern that originated in Wuhan, China. Because of this connection, the virus is sometimes referred to informally, among other nicknames, as the “Wuhan coronavirus”.
  • the coronavirus is a human coronavirus selected from the group consisting of Human coronavirus 229E (HCoV-229E), Human coronavirus OC43 (HCoV-OC43), Severe acute respiratory syndrome coronavirus (SARS-CoV), Human coronavirus NL63 (HCoV-NL63, New Haven coronavirus), Human coronavirus HKU1, Middle East respiratory syndrome-related coronavirus (MERS- CoV), and Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
  • the human coronavirus is selected from MERS-CoV, SARS- CoV and SARS-CoV-2.
  • the composition for inhalation of the present invention is for use in treatment of a disease caused by a human coronavirus is selected from MERS-CoV, SARS-CoV and SARS-CoV-2.
  • the disease is COVID-19.
  • the composition for inhalation of the present invention is for use in treating COVID-19.
  • treating the disease comprises alleviating at least one of the symptoms of the disease.
  • treating the disease comprises at least one of reducing temperature, improving oxygenation, improvement in respiratory parameters such as rate, reduction in viral load and obtaining negative test for the virus e.g. for SARS-CoV-2.
  • the coronavirus treated by the present method is a human coronavirus.
  • the disease is affecting the human respiratory system.
  • the human coronavirus is selected from MERS-CoV, SARS-CoV and SARS-CoV-2.
  • the disease is COVID-19.
  • the method comprises administering a dosage ranging from 2 to 1000 mg/day of the composition to the subject in need thereof. According to some embodiments, the method comprises administering a dosage ranging from 2 to 100 mg/day of the nicotine to the subject in need thereof.
  • the administration of the present composition is to the respiratory system of the subject. According to some embodiments, the administration is to the lungs of the subject. According to some embodiments, the method comprises pulmonary administration of the composition.
  • the method further comprises co-administering the composition of the present invention with an additional active agent.
  • the additional active agent may be any other active pharmaceutical agent, which is effective in treating a disease caused by a coronavirus, and may be delivered by inhalation or by any other administration route.
  • the additional active agent is an antiviral agent.
  • the additional active agent may be administered before, simultaneously with, or after the compositions of the present invention.
  • the additional active agent is administered in a route other than pulmonary, i.e. orally through ingestion or intravenously.
  • the pharmaceutical composition is provided in a dosage form suitable for aerosolization using a nebulizer.
  • the precise dose to be employed of the presently disclosed composition depends on the progression of the disease, and should be decided according to the judgment of the practitioner and each patient's circumstances.
  • the administration schedule can be taken once-daily, twice- daily, thrice-daily, once- weekly, twice-weekly, thrice-weekly, once-monthly, twice- monthly, thrice-monthly, or any other administration schedule known to those of skill in the art.
  • the pharmaceutical composition is administered twice a week.
  • the administration may be continuous, i.e., every day, or intermittently.
  • intermittent administration can be administration in one to six days per week or it may mean administration in cycles (e.g. daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week) or it may mean administration on alternate days.
  • the use comprises co-administration of the pharmaceutical composition of the present invention with an additional active agent.
  • the additional active agent may be any other active pharmaceutical agent, which is effective in treating any infective disease, including diseases caused by a coronavirus, and may be delivered by inhalation or by any other administration route.
  • the additional active agent is an antiviral agent.
  • the additional active agent is administered in a route other than pulmonary, i.e. orally through ingestion or intravenously.
  • coadministration encompasses administration of a first and second agent in an essentially simultaneous manner.
  • the agents can be administered in a sequential manner in either order.
  • the agents may be administered sufficiently close in time to have the desired effect (e.g., complex formation).
  • sequential manner refers to an administration of two compounds at different times, and optionally in different modes of administration.
  • the agents can be administered in a sequential manner in either order.
  • substantially simultaneous manner refers to administration of two compounds with only a short time interval between them. According to some embodiments, the time interval is in the range of from 0.5 to 60 minutes.
  • the method comprises the steps of:
  • the method comprises the steps of:
  • the nebulizer is as disclosed herein.
  • a person skilled in the art would appreciate based on the below how to implement any one of the nebulizers disclosed herein for generating the present aerosols from the present pulmonary compositions.
  • the method comprises the steps of:
  • a nebulizer comprising a porous medium configured to produce aerosols, a displaceable wetting mechanism configured to spread liquids over the porous medium thereby to wet the porous medium and a gas channel, wherein said porous medium is having two sides, wherein a first side is facing the displaceable wetting mechanism; (ii) providing a liquid composition comprising nicotine and a bronchodilator;
  • the droplets of the aerosol delivered by the method of the present invention are having a mass median aerodynamic diameter (MMAD) of no more than 5 microns.
  • the droplets of the aerosol delivered by the nebulizer are having a mass median aerodynamic diameter (MMAD) of no more than 5 microns.
  • nebulizers are also configured to carry out the method of the present invention.
  • the nebulizers are configured for delivery of compositions using a porous medium and a displaceable spreading mechanism or liquid absorbing material.
  • the aerosol may be generated by wetting the porous medium. Wetting may include applying the displaceable spreading mechanism thereby spreading liquid on the surface of the porous medium. Alternatively, wetting may include wetting the liquid absorbing material, then pressing it against the porous medium, or a surface thereof, resulting in a relatively uniform wetting of the porous medium.
  • the nebulizers are configured to provide the aerosol by implementing pressure differentials, rather than heating/vaporization.
  • the dosage form described herein is suitable for aerosolization using the type of nebulizers, which do not include a heating unit.
  • the nebulizer is devoid from a heating unit.
  • the method of the current invention is devoid from heating the composition.
  • nebulizers elaborated herein below provides aerosols having small droplet size, which was surprisingly found to be specifically beneficial for treatment and prevention of COVID-19.
  • nebulizer may function as an inhaler under some circumstances.
  • inhaler as used herein may be interchangeable.
  • the nebulizer provides an aerosol containing a therapeutically effective amount of the composition for inhalation of the present invention.
  • therapeutically effective amount refers to a pharmaceutically acceptable amount of the composition for inhalation which prevents or ameliorates at least partially, the symptoms signs of a particular disease, for example, COVID-19.
  • the nebulizer is mobile. According to some embodiments, the nebulizer is handheld. According to some embodiments, the nebulizer is powered by a mobile power source.
  • a nebulizer housing configured to host at least one cartridge having a liquid absorbing material.
  • the housing may further include any one or more of a porous medium, an opening, a nozzle connected to the opening, one or more container for containing the composition for inhalation, and a combination thereof.
  • the nebulizer housing is mobile. According to some embodiments, the housing is handheld. According to some embodiments, the nebulizer is powered by a mobile power source. According to some embodiments, the cartridge is disposable. According to some embodiments, the cartridge is recyclable. According to some embodiments, the liquid absorbing material is disposable. According to some embodiments, the cartridge is reusable.
  • the nebulizer is configured to communicate wirelessly with servers, databases, personal devices (computers, mobile phones) among others.
  • the nebulizer is assembled by introducing a cartridge into the housing.
  • Nebulizers comprising a wetting mechanism comprising a liquid absorbing material
  • the nebulizer referred herein above comprises a porous medium that is configured to produce aerosols, a liquid absorbing material configured to absorb a liquid, a wetting mechanism configured to press the liquid absorbing material against the porous medium or a first surface of the porous medium, thereby to wet the porous medium with the liquid absorbed in the liquid absorbing material and a gas channel configured to introduce pressure gradient to the porous medium.
  • applying pressure gradient entails introducing pressurized air to one side of the porous medium.
  • applying pressure gradient entails introducing vacuum or sub-atmospheric pressure near one side of the porous medium.
  • applying pressure gradient upon the porous medium entails having different pressure levels between two sides or surfaces of the porous medium.
  • Nebulizer 100 further comprises a sponge 102, a wetting mechanism 106, a gas channel 110 and an outlet 112.
  • Wetting mechanism 106 comprises a rod and a solid plate connected to sponge 102.
  • the liquid absorbing material is a sponge, a tissue, a foam material, a fabric or any other material capable of fully or partially retrievably absorbing liquids.
  • the liquid absorbing material is configured to enable small diameter droplets to pass through the structure thereof and to obstruct large diameter droplets from passing through the material thereof.
  • the liquid absorbing material is configured to filter the passage of droplets depending on their diameter, such that large diameter droplets are obstructed by the liquid absorbing material.
  • the terms ‘sponge’ and ‘liquid absorbing material’ as used herein refer to any material that is capable of incorporating, taking in, drawing in or soaking liquids, and upon applying physical pressure thereto, release a portion or the entire amount/volume of the absorbed liquid. The physical pressure may be achieved for example by pressing the material against a solid structure.
  • the liquid absorbing material is having two sides, wherein a first side is facing the wetting mechanism and a second side is facing the porous medium.
  • the wetting mechanism is a movable solid medium facing the first side of the liquid absorbing material.
  • the wetting mechanism is in close proximity to the first side of the liquid absorbing material.
  • the wetting mechanism is attached to the first side of the liquid absorbing material.
  • the porous medium is having two sides, wherein a first side is facing the liquid absorbing material and a second side is facing the gas channel. According to some embodiments, the first side of the porous medium is facing the liquid absorbing material and the gas channel. According to some embodiments, the liquid absorbing material and the porous medium are in close proximity. According to some embodiments, the first side of the liquid absorbing material and the first side of the porous medium are in close proximity.
  • a pressure gradient at the porous medium reflects the presence of value difference between the pressure at the first side of the porous material and the pressure at the second side of the porous material, such that pressure values vary inside the volume of the porous medium. These values range from the pressure value at the first side to the pressure value at the second side of the porous medium.
  • the gas channel is a gas delivery channel configured to introduce pressure gradient to the porous medium.
  • the gas channel is a gas delivery channel configured to introduce pressurized gas to the porous medium.
  • the gas channel is a gas suction channel configured to introduce sub-pressurized gas to the porous medium.
  • the term 'channel' as used herein is interchangeable with any one or more of the terms port, passage, opening, orifice, pipe and the like.
  • a pressurized gas container is configured to deliver pressurized gas through the gas channel to the porous medium and create an ultra- atmospheric pressure on one side of the porous medium, thereby induce a pressure gradient at the porous medium.
  • pressurized gas' as used herein is interchangeable with the term 'compressed gas' and refers to gas under pressure above atmospheric pressure.
  • a vacuum container or sub-atmospheric pressure container is configured to suck gas through the gas channel and create a sub- atmospheric pressure on one side of the porous medium, thereby induce a pressure gradient within the porous medium.
  • the gas channel is connected to a gas source.
  • the gas source is a mobile gas source, such as, a gas container.
  • the gas source is a gas pump, configured to introduce pressure gradient in the porous medium by pumping gas to or from the gas delivery channel.
  • the gas source is a pressurized gas container, configured to contain pressurized gas and to induce a pressure gradient in the porous medium by releasing pressurized gas to the pressurized-gas delivery channel.
  • the nebulizer further comprises an opening configured to deliver the aerosols to a respiratory system of a subject.
  • the opening is connected to a nozzle.
  • the opening is mechanically connected to a nozzle.
  • the nozzle is detachable.
  • the liquid absorbing material comprises the composition for inhalation of the current invention. According to some embodiments, the liquid absorbing material comprises the nicotine-based composition of the current invention as disclosed herein above.
  • the nebulizer further comprises a first container, configured to contain liquids to be delivered to the liquid absorbing material.
  • the liquids comprise the composition for inhalation of the current invention.
  • the nebulizer further comprises a second container configured to contain a composition comprising the additional active agent, as disclosed herein above.
  • the wetting mechanism is a mechanic mechanism configured to apply pressure onto the liquid absorbing medium.
  • the wetting mechanism is a pneumatic mechanism configured to apply pressure onto the liquid absorbing medium.
  • the wetting mechanism is coupled with an actuator.
  • the wetting mechanism comprises a metering pump adapted to delivering a pre-determined volume of liquid at desired pressure(s) directly to the surface of the porous medium.
  • the nebulizer is provided as part of a nebulizer system comprising a housing, an opening in the housing configured to deliver an aerosols to a subject, a receptacle configured to receive a cartridge (the cartridge comprises a liquid absorbing material, and a porous medium, having at least one porous surface, configured to produce aerosols and a wetting mechanism configured to press the liquid absorbing material against the porous medium or against a surface of the porous medium), an actuator configured to control the wetting mechanism and a gas channel, to introduce a pressure gradient to the porous medium.
  • a nebulizer system comprising a housing, an opening in the housing configured to deliver an aerosols to a subject, a receptacle configured to receive a cartridge (the cartridge comprises a liquid absorbing material, and a porous medium, having at least one porous surface, configured to produce aerosols and a wetting mechanism configured to press the liquid absorbing material against the porous medium or against a surface of the porous medium), an actuator
  • the liquid absorbing material is presoaked with the composition for inhalation.
  • the presoaked liquid absorbing material is hermetically or semi hermetically sealed.
  • the seal is configured to be disrupted or otherwise removed upon usage.
  • the seal is configured to be automatically disrupted or otherwise removed, for example, by an actuator in the nebulizer system.
  • the seal is configured to be manually removed or disrupted by a user prior to use thereof.
  • the nebulizer system further comprises control mechanism configured to control the release of the liquid from the container containing same, into the liquid absorbing material.
  • the control mechanism is configured to control the release of the liquid in a slow and/or gradual release manner.
  • the nebulizer system further comprises deployment mechanism configured to deploy the medication or liquid from the container containing same and into the liquid absorbing material.
  • some mechanisms of the nebulizer system are configured to provide homogeneous or semi homogeneous wetting of the porous medium.
  • the mechanisms are other than the liquid absorbing material and the wetting mechanism. Examples for such mechanisms include, but are not limited to, spray mechanism, wiping mechanisms and the like.
  • Nebulizer 200 further comprises a liquid container 214 and a medication container 216.
  • Liquid container 214 and medication container 216 are configured to enable deployment of their possibly contained contents to sponge 202 to be pressed against porous medium 204.
  • FIG. 3 schematically illustrates a nebulizer 300 comprising a porous medium 304 and a sponge 302, according to some embodiments.
  • a liquid container 314 and a medication container 316 have had their content deployed to sponge 302, and sponge 302 is pressed against porous medium 304 by a wetting mechanism 306.
  • a pressurized gas 318 is delivered to porous medium 304 via a gas channel 310.
  • FIG. 4 schematically illustrates generation of aerosol within a nebulizer, according to some embodiments.
  • a nebulizer 400 is introduced comprising a porous medium 404, a sponge 402 and a nozzle 412, according to some embodiments.
  • Sponge 402 is released from its previous press and wetting position (press and wetting of porous medium 404).
  • a pressurized gas 418 delivered to porous medium 404 via a gas channel 410 introduces a pressure gradient to porous medium 404.
  • the pressure gradient results in the production of an aerosol having large droplets 422 and small droplets 420. Large droplets 422 are impacted by sponge 402 which obstructs their path towards nozzle 412.
  • Small droplets 420 are lighter than large droplets 422, and are mostly drifted away from impacting sponge 402, thus they are not obstructed and may flow towards nozzle 412.
  • Large droplets 422 are impacted and obstructed by sponge 402, advantageously resulting in a delivery of aerosol characterized with small diameter/size droplets.
  • control over droplet size (e.g., MMAD) and modality of generated aerosol is achieved by controlling physical properties of the porous medium.
  • the physical properties of the porous medium are adjusted based on the desired droplet size.
  • the physical properties of the porous medium may include, but are not limited to, physical dimensions of the porous medium as a whole, pore count, pore density, pore distribution, pore shape, homogeneity of the aforementioned pore features, hydrophobicity of the porous material, and electromagnetic affinity among other properties. Each possibility is a separate embodiment of the invention.
  • modality refers to the modality of size distributions and includes, but is not limited to, uni-modal, bi-modal and tri-modal size distributions.
  • control over droplet size and modality of generated aerosol is achieved by controlling the physical properties of the liquid absorbing material.
  • control over droplet size and modality of generated aerosol is achieved by controlling the pressure gradient on the porous medium.
  • control over droplet size and modality of generated aerosol is achieved by controlling the properties of the medication and/or liquid and/or composition.
  • the properties of the medication and/or liquid and/or composition which may be adjusted to achieve the desired aerosol include, but are not limited to, viscosity, surface tension, pH, electrolyte concentration, solid content and polarity.
  • control over droplet size and modality of generated aerosol is achieved by introducing an impactor.
  • the liquid absorbing material is configured to act as an impactor.
  • the liquid absorbing material is the impactor.
  • control over droplet size of generated aerosol is achieved by introducing a filter.
  • the liquid absorbing material is configured to act as a filter.
  • the liquid absorbing material is the filter.
  • the impactor is an independent structure, different from the liquid absorbing material.
  • the filter is an independent structure, different from the liquid absorbing material.
  • Nebulizer system 500 comprises a gas pump 528 an actuator 530 a first deployment controller 524, a second deployment controller 526, a wetting mechanism 506, a sponge 502, a porous medium 504, a gas channel 510, a liquid container 514, a medication container 516 and a nozzle 512.
  • pump 528 is configured to deliver compressed gas to porous medium 504 via gas channel 510.
  • Actuator 530 is configured to control the movement and function of wetting mechanism 506 for pressing sponge 502 against porous medium 504.
  • First deployment controller 524 is configured to control the deployment of contained liquid in liquid container 514 to sponge 502, and second deployment controller 526 is configured to control the deployment of medication in medication container 516 to sponge 502.
  • the actuator is configured to control the pressure applied onto the liquid absorbing material. According to some embodiments, the actuator is configured to control the movement of the wetting mechanism. According to some embodiments, the actuator operates through mechanic, electro mechanic, electromagnetic, electro thermal, hydraulic, pneumatic or electronic mechanism. Each possibility is a separate embodiment of the invention.
  • a method for treating a disease caused by a coronavirus comprising the steps of providing a liquid absorbing material, a porous medium having two sides in which the first side is facing the liquid absorbing material and further providing a composition as described herein is the form of a liquid, wetting the liquid absorbing material with the composition, pressing liquid absorbing material against the porous medium, introducing pressure gradient to the porous medium and producing aerosol at the first side of the porous medium, the produced aerosol comprises droplets of the composition.
  • the composition is provided in a container.
  • the method further comprises controlling the release of the liquid from the container into the liquid absorbing material.
  • the method further comprises releasing the liquid in a slow and/or gradual release manner.
  • the method further comprises deploying the medication or liquid from the container and into the liquid absorbing material.
  • the method further comprises providing a first container with a liquid and a second container with medication, and mixing the medication with the liquid to form the composition disclosed herein, prior to aero soli z ati on.
  • 'wetting' refers to homogenous or pseudo homogenous wetting of one side of the porous medium.
  • the method further comprises wetting the porous medium homogenously.
  • the method further comprises providing the composition for inhalation disclosed herein and mixing the composition for inhalation with the liquid, prior to wetting the liquid absorbing agent.
  • the liquid absorbing material already includes the composition for inhalation, such that upon wetting the liquid absorbing material, the composition for inhalation is reconstituted, or otherwise diluted, thereby resulting with the required pharmaceutically acceptable form suitable for inhalation following the conversion thereof into aerosols.
  • the liquid absorbing material comprises the nicotine- bronchodilator composition for inhalation at least partially absorbed therein.
  • partially absorbed therein refers to the percentage of liquid absorbed in the pores of the porous material, wherein 0% refers to a porous material where all of its pores are vacant of liquid.
  • the term “partially absorbed therein” may refer to a porous material wherein at least 0.005% of the pores contain liquid, or wherein the overall contents of the vacant space within the porous material occupied with liquid is 0.005%.
  • partially absorbed therein refers to at least 0.001% liquid contents within the porous material.
  • partially absorbed therein refers to at least 0.05% liquid contents within the porous material.
  • partially absorbed therein refers to at least 0.01% liquid contents within the porous material. According to some embodiments, partially absorbed therein refers to at least 0.5% liquid contents within the porous material. According to some embodiments, partially absorbed therein refers to at least 0.1% liquid contents within the porous material. According to some embodiments, partially absorbed therein refers to at least 1% liquid contents within the porous material. According to some embodiments, partially absorbed therein refers to at least 5% liquid contents within the porous material. According to some embodiments, partially absorbed therein refers to at least 10% liquid contents within the porous material. According to some embodiments, partially absorbed therein refers to at least 20% liquid contents within the porous material.
  • partially absorbed therein refers to at least 30% liquid contents within the porous material. According to some embodiments, partially absorbed therein refers to at least 40% liquid contents within the porous material. According to some embodiments, partially absorbed therein refers to at least 50% liquid contents within the porous material.
  • the term “partially absorbed therein” may refer to the content of liquid within the volume of pores located on the surface and in the immediate vicinity of the surface (sub surface) of a porous medium.
  • the volume of the sub-surface may extend from the surface to a depth of about 50 micron from the surface.
  • partially absorbed therein refers to a porous material wherein at least 0.5% of the surface and sub-surface pores contain liquid. According to some embodiments, partially absorbed therein refers to at least 1% liquid contents within the surface and sub-surface pores. According to some embodiments, partially absorbed therein refers to at least 10% liquid contents within the surface and sub surface pores. According to some embodiments, partially absorbed therein refers to at least 20% liquid contents within the surface and sub-surface pores. According to some embodiments, partially absorbed therein refers to at least 30% liquid contents within the surface and sub-surface pores. According to some embodiments, partially absorbed therein refers to at least 40% liquid contents within the surface and sub- surface pores.
  • partially absorbed therein refers to at least 50% liquid contents within the surface and sub-surface pores. According to some embodiments, partially absorbed therein refers to at least 60% liquid contents within the surface and sub- surface pores.
  • the pressing of the liquid absorbing material upon the porous medium is iterated a plurality of times. According to some embodiments, the pressing is executed while applying a non-constant pressing force/pressure across iterations.
  • a first pressing of the liquid absorbing material against the porous medium is carried out utilizing a first pressing force (pressure)
  • a second pressing of the liquid absorbing material against the porous medium is executed utilizing a second pressing force, and so on.
  • the first pressing force is lower than the second pressing force, advantageously resulting in a more unified wetting of the porous surface of the porous medium.
  • a deployment of the composition for inhalation into the liquid absorbing material is performed, then the liquid absorbing material is pressed against the porous medium, wetting the porous surface of the porous medium for generating aerosol, and then a deployment of a second liquid into the liquid absorbing material is performed.
  • the second liquid is sterile.
  • the second liquid is saline, water, carrier, cleansing liquid and the like, the deployment of which may be performed for diluting the composition for inhalation content in the liquid absorbing material.
  • the deployment of the second liquid is performed for cleansing the liquid absorbing material and releasing the residues that may accumulate in the liquid absorbing material to achieve better delivery of further composition for inhalation to the subject, or for cleansing the liquid absorbing material, the porous medium or both.
  • the components may be reused.
  • the cleansing may prevent accumulation of medication residue in the nebulizer or some components thereof.
  • Nebulizers comprising a wetting mechanism comprising a rotatable elongated member
  • a nebulizer for producing the aerosol of the present invention from the composition disclosed herein (e.g. via the method disclosed herein).
  • the nebulizer comprises a wetting mechanism comprising a rotatable/displaceable elongated member, configured to be movably placed on the surface of the porous medium, or in close proximity thereto, or placed on the liquid absorbing material.
  • the wetting mechanism includes a rotatable/displaceable elongated member (e.g. a spinning magnet) configured to be placed on the liquid absorbing material, such that liquid is extracted from the liquid absorbing material by the wetting mechanism.
  • the rotatable elongated member is configured to move across the surface of the porous medium, thereby to homogeneously or semi- homogeneously spread the liquid on the surface of the porous medium.
  • the elongated member is axially movable. According to some embodiments, the elongated member is movable to cover the entire surface of the porous medium or substantial portions thereof. According to some embodiments, the wetting mechanism further includes an actuator, configured to displace/move or induce the displacement/movement of the elongated member.
  • substantially portions as used herein commonly refers to at least 30% coverage of the surface of the porous medium. According to some embodiments, the substantial portions include at least 50% coverage of the surface of the porous medium, at least 60% coverage of the surface of the porous medium, at least 70% coverage of the surface of the porous medium, at least 80% coverage of the surface of the porous medium or at least 90% coverage of the surface of the porous medium.
  • the elongated member may include a magnet
  • the actuator may also include a magnet, magnetically associated with the magnet of the elongated member, such that by moving/displacing the magnet/electromagnet of the actuator, a moving/displacing of the elongated member may be induced.
  • one or more of the magnets includes an electromagnet.
  • the actuator may include a motor configured to move/displace the actuating magnet.
  • the elongated member may be coated by a hydrophobic coating.
  • the elongated member may be at least partially coated by a hydrophobic coating.
  • the coating may be smooth, non-corrosive, non-toxic, non-evaporative or a combination thereof.
  • the coating may include polytetrafluoroethylene (e.g. Teflon®).
  • Teflon® polytetrafluoroethylene
  • the term "at least partially" as used herein may include at least 50% coating of the elongated member, at least 60% coating of the elongated member, at least 70% coating of the elongated member, at least 80% coating of the elongated member or at least 90% coating of the elongated member.
  • the elongated member is an elongated tubular member. According to some embodiments, the elongated member may be movable by an actuator, mechanically connected thereto. According to some embodiments, the elongated member may be movable by an air-flow within the nebulizer and/or through the porous material.
  • the elongated member may be a roller. According to some embodiments, the elongated member may be a smearing device. According to some embodiments, the elongated member may be a spreading device. According to some embodiments, the elongated member may be configured to force at least portions of the liquid to at least some of the pores of the porous medium.
  • the nebulizer comprises a porous medium configured to produce aerosols, a displaceable wetting mechanism configured to spread the composition for inhalation over the porous medium thereby to wet the porous medium and a gas channel configured to introduce pressure gradient to the porous medium.
  • the displaceable wetting mechanism may include a rotatable elongated member.
  • the rotatable elongated member is configured to move across the surface of the porous medium, thereby to homogeneously or semi-homogeneously spread the composition for inhalation on the surface.
  • the elongated member is axially movable.
  • the elongated member is movable to cover approximately all the surface of the porous medium.
  • the term “approximately” as used herein may refer to the percentage of surface of the porous medium that may be coated with liquid by the spreading movement of the elongated member. Approximately may refer to more than 50% coverage, more than 60% coverage, at least 70% coverage, at least 80% coverage, at least 90% coverage or at least 95% coverage.
  • the wetting mechanism further includes an actuator, configured to displace or induce the displacement of the elongated member.
  • displacement as used herein may be interchangeable with any one or more of the terms movement, movement across. This term may refer to the motion of the wetting mechanism across, or along, at least one surface of the porous medium.
  • the elongated member comprises a first magnet
  • the actuator comprises a second magnet, magnetically associated with the first magnet of the elongated member, such that by moving/displacing the second magnet of the actuator, a displacing of the elongated member is induced.
  • said first magnet may comprise a plurality of magnets.
  • said second magnet may comprise a plurality of magnets.
  • one or more of the plurality of magnets includes an electromagnet.
  • the actuator comprises a motor configured to displace the elongated member.
  • the elongated member is at least partially covered with polytetrafluoroethylene (PTFE), commercially knowns as Teflon®, or any other appropriate coating materials.
  • PTFE polytetrafluoroethylene
  • the elongated member is an elongated tubular member.
  • the elongated member is movable by an actuator, mechanically connected thereto.
  • the elongated member is movable by the air-flow within the nebulizer and/or through the porous material.
  • the elongated member is a roller.
  • the elongated member is a smearing device.
  • the elongated member is a spreading device.
  • the elongated member is configured to force at least portions of the liquid to at least some of the pores of the porous medium.
  • the nebulizer further comprises a spacer configured to elevate said displaceable wetting mechanism from the surface of said porous medium.
  • said spacer is integrally formed with said displaceable wetting mechanism.
  • said spacer comprises a protrusion in said displaceable wetting mechanism.
  • said spacer is configured to be placed between said displaceable wetting mechanism and the surface of said porous medium.
  • said pacer comprises a ring-shaped configured to facilitate low-friction displacement of said displaceable wetting mechanism.
  • the nebulizer further comprises a liquid deploying mechanism configured to controllably deploy a liquid (such as a liquid comprising the composition for inhalation) on the surface of said porous medium for being spread by said displaceable wetting mechanism.
  • said liquid deploying mechanism comprises a conduit.
  • said conduit has a receiving end, configured to obtain a liquid from a liquid source, and a deploying end, configured to deploy the liquid on the surface of said porous medium.
  • said deploying end of said conduit is flexible and configured to flexibly move by the displacement of said displaceable wetting mechanism, thereby deploy the liquid at more than one location on the surface of said porous medium.
  • the nebulizer further comprises an opening configured to deliver the aerosols to a respiratory system of a subject.
  • Fig. 6a schematically illustrates a side cross section of a nebulizer 900 with a rotatable wetting mechanism, according to some embodiments.
  • Said nebulizer 900 is adapted to aerosolize the composition for inhalation of the present invention and to produce the aerosol of the present invention, according to some embodiments.
  • the wetting mechanism of nebulizer 900 includes a rotatable elongated member, such as movable magnet 940, which is placed on, or in close proximity to a surface of a porous medium, such as porous disc 904, within a nebulizer housing, such as housing 902.
  • Movable magnet 940 is configured to rotate on porous disc 904, thereby homogeneously or semi- homogeneously spread a liquid (such as a liquid comprising the composition for inhalation of the current invention) on porous disc 904 and/or at least partially force the liquid within the pores of porous disc 904.
  • nebulizer 900 further includes a liquid deploying mechanism, such as medication conduit 946, configured to provide liquids and/or composition(s) (such as the composition for inhalation of the current invention) to movable magnet 940 and/or porous disc 904.
  • nebulizer 900 further includes an actuator configured to directly or indirectly move or induce the displacement of movable magnet 940.
  • the actuator includes a motor 944, mechanically or electromechanically connected to an actuator-magnet, such as motor-magnet 942 being associated with movable magnet 940, such that a displacement of motor-magnet 942 induces a displacement of movable magnet 940.
  • Motor 944 is configured to axially rotate motor-magnet 942, thereby induce an axial rotation of movable magnet 940 over/on the surface of porous medium 904.
  • pressurized gas/air is provided to housing 902, for example through pressurized-gas conduit 910, and introduced to one side of porous disc 904 which interrupts the flow of gasses therethrough, thereby a pressure gradient occurs across porous disc 904.
  • the composition for inhalation may be provided through medication conduit 946 and introduced to the surface of porous disc 904, and then movable magnet 940 spreads the composition homogeneously or semi-homogeneously on the surface and at least partially forced through the pores of porous disc 904 by the axial rotation thereof, induced by the rotation of motor magnet 942 and motor 944.
  • the pressure gradient on porous disc 904 generates a mist of multiple droplets as the gas passes through the pores, the mist is then delivered through an outlet, such as mouthpiece 912.
  • the outlet comprises an adapter for nasal delivery.
  • Fig. 6b schematically illustrates a top cross section view of a nebulizer 901 with a rotatable wetting mechanism, according to some embodiments.
  • the rotatable wetting mechanism includes a displaceable/movable elongated member, such as a movable magnet 940, which is placed on, or in close proximity to a surface of a porous medium, such as a porous disc 904 held within a nebulizer housing 902.
  • Movable magnet 940 is configured to be rotatable (arrows 950) and to spread/smear/distribute the composition for inhalation on the surface of porous disc 904, the liquids may be provided onto the surface of porous disc 904, and According to some embodiments, the composition for inhalation may be provided to rotatable magnet 940.
  • Fig. 6c schematically illustrates a side cross section of a nebulizer 900 with a rotatable wetting mechanism and a peripheral actuator, according to some embodiments.
  • the wetting mechanism of nebulizer 900 includes a rotatable elongated member, such as movable magnet 940, which is placed on, or in close proximity to a surface of a porous medium, such as porous disc 904, within a nebulizer housing, such as housing 902.
  • Movable magnet 940 is configured to rotate on porous disc 904, thereby homogeneously or semi- homogeneously spread the composition for inhalation on porous disc 904 and/or at least partially force a liquid into the pores of porous disc 904.
  • nebulizer 900 further includes a liquid deploying mechanism, such as medication conduit 946, configured to provide liquids and/or composition(s) (such as the composition for inhalation) to movable magnet 940 and/or porous disc 904.
  • nebulizer 900 further includes a peripheral actuator configured to directly or indirectly move or induce the displacement of movable magnet 940.
  • the peripheral actuator included is configured to be placed over, or to surround, movable magnet 940 and to fluctuate the magnetic field flux near movable magnet 940, thereby induce a mechanical movement thereof (rotation).
  • the peripheral actuator may be a ring actuator such as controllable electromagnet-ring 960 which may include a plurality of controllable electro-magnets (not shown) which are electrically controlled for inducing a gradient in the electromagnetic field flux in the environment of movable magnet 940, thereby induce an axial rotation of movable magnet 940 over/on the surface of porous medium 904.
  • nebulizer 901 schematically illustrates a top cross section view of a nebulizer 901 with a rotatable wetting mechanism, according to some embodiments.
  • the rotatable wetting mechanism includes a displaceable/movable elongated member, such as a movable magnet 940, which is placed on, or in close proximity to a surface of a porous medium, such as a porous disc 904 held within a nebulizer housing 902.
  • nebulizer 901 may also include a peripheral actuator configured to induce a change in the magnetic field flux in the environment of movable magnet 940 thereby induce a rotatable movement thereof 950.
  • peripheral actuator may be a ring actuator such as controllable electromagnet-ring 960.
  • movable magnet 940 is configured to be rotatable (arrows 950) and to spread/smear/distribute the composition for inhalation on the surface of porous disc 904, the liquids may be provided onto the surface of porous disc 904, and According to some embodiments, the composition for inhalation may be provided to rotatable magnet 940.
  • nebulizer 900 is essentially similar to the nebulizer of Fig. 6a, and further includes a flexible medication deploying end, such as flexible-conduit 948 which is connected to medication conduit 946 and is configured to provide/deploy the composition for inhalation on porous disc 904.
  • flexible-conduit 948 which is connected to medication conduit 946 and is configured to provide/deploy the composition for inhalation on porous disc 904.
  • flexible-conduit 948 is configured to reach near the surface of porous disc 904, and to be flexibly movable by the rotation of movable magnet 940 for deploying the composition for inhalation at close proximity to the surface of porous disc 904 without obstructing the rotation/axial-movement thereof.
  • deploying medication near the surface of porous disc 904 via a flexible member, such as flexible-conduit 948 may provide a homogeneous spreading of the composition for inhalation on the surface of porous disc 904.
  • Fig. 6f schematically illustrates a top cross section view of a nebulizer 901 with a rotatable wetting mechanism, according to some embodiments.
  • the rotatable wetting mechanism includes a displaceable/movable elongated member, such as a movable magnet 940, which is placed on, or in close proximity to a surface of a porous medium, such as a porous disc 904 held within a nebulizer housing 902.
  • Movable magnet 940 is configured to be rotatable (arrows 950) and to spread/smear/distribute the composition for inhalation on the surface of porous disc 904, the composition for inhalation may be provided onto the surface of porous disc 904, and, according to some embodiments, the composition for inhalation may be provided to rotatable by a flexible medication deploying member, such as flexible- conduit 948 shown at a first location, and is flexibly movable (arrow 951) to a second location 949 by the rotation of movable magnet 940.
  • a flexible medication deploying member such as flexible- conduit 948 shown at a first location, and is flexibly movable (arrow 951) to a second location 949 by the rotation of movable magnet 940.
  • nebulizer 900 further includes two spacers mounter/fastened on movable magnet 940, such as a first TeflonTM ball 962 and second TeflonTM ball 964, each being mechanically connected to one end of movable magnet 940 for elevating it from the surface of porous disc 904 and thereby improve the homogeneous spreading of the composition for inhalation and lead to production of controllable aerosol droplet size.
  • the two spacers may be integrally formed with the movable magnet.
  • the two spacers are protrusions at the two ends of the movable magnet.
  • FIG. 6h schematically illustrates a top cross section of a nebulizer 900 with a rotatable wetting mechanism, essentially as described in Fig. 6b, according to some embodiments.
  • first TeflonTM ball 962 and second TeflonTM ball 964 are mechanically connected to one end of movable magnet 940 to prevent direct contact thereof with the surface of porous disc 904.
  • nebulizer 900 further includes a spacer placed/mounted/integrated on the surface of porous disc 904, such as a Teflon-ring 970 which is configured to elevate movable magnet 940 above the surface of porous medium 904 for providing spacing and preventing a direct contact therebetween.
  • movable magnet 940 is tightened to Teflon-ring 970, and is pulled towards porous disc by the magnetic field applied by motor magnet 942.
  • Teflon-ring 970 is configured to facilitate low-friction movement of movable magnet 940 thereon.
  • Fig. 6j schematically illustrates a top cross section of a nebulizer 900 with a rotatable wetting mechanism, essentially as described in Fig. 6b, according to some embodiments.
  • Depicted in Fig. 6j is Teflon-ring 970 placed on the surface of porous disc 904, to prevent direct contact thereof with the movable magnet
  • the spacing/distance/elevation between the surface of the porous medium and the movable magnet is approximately 100 micron (0.1 mhi). According to some embodiments, the spacing/distance/elevation between the surface of the porous medium and the movable magnet is in the range of 50 micron (0.05 mhi) to 150 micron (0.15 mhi). According to some embodiments, the spacing/distance/elevation between the surface of the porous medium and the movable magnet is in the range of 20 micron (0.02 mhi) to 200 micron (0.2 mhi).
  • the term “approximately” may refer to the distance between the surface of the porous medium and the movable magnet, and thus may refer to values within the range of 20% or less from the value indicated.
  • a spacing/distance/elevation of approximately 100 micron (0.1 mhi) includes values within the range of 80-100 micron.
  • the distance between the surface of the porous medium and the movable magnet seems to result with advantageous droplet size distribution, possible due to an improved wetting mechanism.
  • Fig. 7 schematically illustrates nebulizer 1000 with a rotatable wetting mechanism and a liquid deploying structure 1046, according to some embodiments.
  • Liquid deploying mechanism such as liquid conduit 1046 is configured to deploy/provide liquids to the surface of a porous medium 1004 and a rotatable magnet 1040 is placed on the surface of porous medium 1004 and is configured to be movable thereon and to homogeneously or semi-homogeneously spread the liquids provided by liquid conduit 1046 on the surface of porous medium 1004.
  • the wetting mechanism further comprises an actuator having, according to some embodiments, a control-magnet 1042 magnetically /mechanically associated with rotatable magnet 1040 and rotated by a motor 1044.
  • motor 1044 may comprise a brushed or brushless DC motor, for example a steppe moto or the like.
  • motor 1044 may comprise an AC motor, such as an induction motor or the like.
  • Fig. 8 schematically illustrates a nebulizer 1100 with a rotatable wetting mechanism and a liquid absorbing material, such as sponge 1102, according to some embodiments.
  • Liquid absorbing material is placed on a surface of a porous medium 1104 and configured to reversibly contain/absorb liquids, and release the liquids with changed physical conditions such as pressing.
  • a movable elongated spreader/presser, such as rotating rod 1140, is placed on sponge 1102 and is configured to press at least some portions thereof against the surface of porous medium 1104, thereby force the release of absorbed liquids from sponge 1102.
  • rotating rod 1140 is induced/caused by the rotating displacement of an actuator that is mechanically and/or magnetically associated with rotating rod 1140.
  • rotating rod 1140 may be movable/rotatable by inducing magnetic field changes in the environment thereof, and the actuator includes a magnetic-field inducer 1142 rotatable by a motor 1144 and configured to induce the rotation/displacement of rotating rod 1140 on sponge 1102 thereby pressing against various areas thereon and controllably releasing liquid to the surface of porous medium 1104.
  • Nebulizer 1300 includes a housing 1302 with an inlet orifice 1310, an outlet orifice 1312, a liquid conduit 1346 and a pressure-sensor conduit 1348.
  • Nebulizer 1300 further includes a rotatable spreading mechanism, such as spreading elongated magnet 1340 placed on a surface of a porous disc 1304 for spreading liquids thereon, an actuator within housing 1302 is associated with spreading elongated magnet 1340, the actuator includes a motor 1344 mechanically connected to a motor-magnet 1342 and is configured to rotate spreading elongated magnet 1340 for spreading liquids (such as the composition disclosed herein) on the surface and/or through the pores of porous disc 1304.
  • liquid conduit 1346 is configured to provide the composition for inhalation to a central section of spreading elongated magnet 1340.
  • Nebulizer system assembly 1700 includes various functional, control and/or indicatory components.
  • system assembly 1700 includes a nebulizer, a gas pump for providing pressurized gas to the nebulizer, a pressure sensor, control gauges and buttons and others.
  • the composition for inhalation as disclosed herein above is administered via inhalation using an ultrasonic nebulizer.
  • the ultrasonic nebulizer is a piezoelectric nebulizer.
  • Fig. 11 illustrates a schematic diagram of a prior art nebulizer 10, according to some embodiments.
  • Piezoelectric nebulizers are commonly constructed with a piezoelectric transducer submerged within liquid that is to be nebulized.
  • Nebulizer 10 comprises: a liquid reservoir 20 containing liquid 30 (e.g. the ethanol composition) and exhibiting an outlet 40; a piezoelectric transducer 50; and a power source 60.
  • Piezoelectric transducer 50 is submerged within liquid 30 and is in electrical communication with power source 60.
  • liquid reservoir 20 further exhibits an inlet opening arranged to allow for injection of a pulmonary composition there into.
  • power source 60 provides alternating- current (AC) power to piezoelectric transducer 50, thereby causing piezoelectric transducer 50 to vibrate at a predetermined frequency.
  • the vibration of piezoelectric transducer 50 nebulizes liquid 30 into an aerosol which exits via outlet 40.
  • the liquid according to some embodiments, is the composition for inhalation of the present invention.
  • an aerosolization filling composition comprising the composition for inhalation as disclosed herein.
  • the filling is for use in the treatment or prevention of a coronavirus.
  • the present filling may be specified or approved by the relevant authorities to be used for the prevention or treatment of a disease caused by a coronavirus.
  • the aerosolization filling composition is selected from a nebulizer cartridge filling composition and an inhaler cartridge filling composition. Each possibility represents a separate embodiment of the present invention. Optional cartridges are as presented hereinabove.
  • the aerosolization filling composition may be used for filling any one of the devices disclosed herein.
  • an aerosol comprising nicotine and a bronchodilator. It is to be understood that the present aerosol may be formed according to the method of the present invention. For example, the present aerosol may be generated from any one of the present compositions using any one of the nebulizers described herein.
  • any one of the embodiments described herein for the compositions, their constituents and amounts may be applied for the chemical composition of the present aerosol.
  • the person skilled in the art would appreciate that many of the compositional characteristics of the composition for inhalation disclosed herein, similarly apply for the aerosol of the current invention.
  • the person skilled in the art would appreciate that many of the therapeutic characteristics of the composition for inhalation disclosed herein, including types of therapies and diseases, similarly apply for the aerosol of the current invention.
  • the aerosol composition of the current invention is in the form of an aqueous aerosol.
  • the aqueous aerosol comprises at least 40%, 50%, 60%, 70%, 80% or at least 90% water. Each possibility represents a separate embodiment of the invention.
  • the aerosol composition comprises a non-aqueous solvent.
  • the non-aqueous solvent is a polyol.
  • the polyol is selected from glycerol, propylene glycol, or both.
  • the polyol combination comprises 20 to 50% propylene glycol and 50 to 80% vegetable glycerin.
  • the polyol combination comprises 25 to 35% propylene glycol and 65 to 75% vegetable glycerin.
  • the concentration of the nicotine in the aerosol composition is in the range of 0.1 to 50 gr/L. According to some embodiments, the concentration of the nicotine in the aerosol composition is in the range of 0.5 to 5 gr/L.
  • the aerosol composition comprises nicotine is at a concentration in the range of 0.01% to 10% w/w, 0.08% to 10% w/w, 0.15% to 10%, w/w or 1% to 5%, w/w.
  • the bronchodilator in the present aerosol is selected from the group consisting of: albuterol (salbutamol), levalbuterol, ipratropium, indacaterol, umeciidinium, tiotropium, olodaterol, formoterol, aclidinium, and salmeterol.
  • the bronchodilator is salbutamol.
  • the bronchodilator is at a concentration in the range of 0.03% to 0.5%, w/w. According to some embodiments, the concentration of the bronchodilator in the aerosol composition is in the range of 0.3 to 5 gr/L, or 0.5 to 5 gr/L. Each possibility represents a separate embodiment of the invention.
  • the aerosol composition comprises nicotine and the bronchodilator as the sole active ingredients. According to some embodiments, the aerosol composition comprises nicotine and the bronchodilator as the sole active ingredients.
  • the aerosol composition of the present invention further comprises an additional active agent, as described with respect to the pulmonary composition.
  • the aerosol composition comprises a pharmaceutically acceptable carrier or excipient.
  • the nicotine in the aerosol composition is in a protonated form.
  • the aerosol composition has pH lower than 7. According to some embodiments, the aerosol composition has pH lower than 6.
  • the aerosol composition is aqueous and comprises nicotine in a protonated form, and salbutamol, wherein the nicotine is at a concentration in the range of 0.5% to 5%, w/w, wherein the salbutamol is at a concentration in the range of 0.03% to 0.5%, w/w, and wherein the aqueous solution has pH lower than 6.
  • the composition of the current invention further comprises at least one additive selected from the group consisting of a propellant, an anti-coughing agent, a preservative and a flavorant, as detailed with respect to the present pulmonary composition.
  • the aerosol composition is for use that comprises administering a dose ranging from 2 to 1000 mg/day of the composition, including sub ranges thereof.
  • the composition is for use that comprises administering a dose ranging from 2 to 200 mg/day of the nicotine.
  • the aerosol composition is for use in the treatment or prevention of a disease caused by a coronavirus.
  • a disease caused by a coronavirus Specific embodiment regarding the efficacy and various uses and diseases are as detailed in the section dedicated to the composition for inhalation and the method of treatment or prevention.
  • the droplets of the aerosol disclosed herein are having an MMAD value within the range of 0.3 to 7 microns. According to some embodiments, the MMAD is less than 5 microns. According to some embodiments, the MMAD is between 1 and 3 microns.
  • the devices, systems and methods disclosed herein provide a relatively uniform or homogeneous wetting of the porous surface that may result in small diameter aerosol droplets having the MMAD value as specified herein, and confer the ability to yield such small diameter aerosol drops with high efficiency.
  • MMAD median aerodynamic diameter
  • droplets around 10 micron in diameter are suitable for deposition in the oropharynx and the nasal area; droplets around 3-5 micron in diameter are suitable for deposition in the central airways and droplets between 1-3 microns are suitable for delivery to the alveoli (droplets substantially smaller than 1 micron will also target the alveolar region) and may be useful for delivering pharmaceuticals to the systemic circulation).
  • the therapy provided by the present invention is directed to the latter, and indeed it was found that the upon aerosolization of the composition of the present invention with the nebulizer disclosed herein, an aerosol comprising droplet in the range of 1-3 microns is formed.
  • the term “patient”, “subject”, or “individual” are used interchangeably and refer to either a human or a non-human animal. According to some embodiments, the subject is human.
  • the terms “comprising”, “comprise(s)”, “include(s)”, “having”, “has” and “contain(s),” are used herein interchangeably and have the meaning of “consisting at least in part of’. When interpreting each statement in this specification that includes the term “comprising”, features other than that or those prefaced by the term may also be present. Related terms such as “comprise” and “comprises” are to be interpreted in the same manner.
  • compositions or components may include additional ingredients, but only if the additional ingredients do not materially alter the basic and novel characteristics of the claimed compositions or methods.
  • range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
  • the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
  • the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.

Abstract

La présente invention concerne d'une manière générale le domaine des compositions de nicotine pour une administration pulmonaire, et leurs utilisations dans le traitement d'infections virales, en particulier des coronavirus. Spécifiquement, les compositions contiennent un bronchodilatateur et sont administrées sous la forme d'un aérosol généré par un nébuliseur.
PCT/IL2021/050639 2020-05-31 2021-05-30 Compositions de nicotine pour inhalation et leurs utilisations antivirales WO2021245656A1 (fr)

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Citations (3)

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Publication number Priority date Publication date Assignee Title
US20140134251A1 (en) * 2009-03-26 2014-05-15 Pulmatrix, Inc. Pharmaceutical formulations and methods for treating respiratory tract infections
WO2016059630A1 (fr) * 2014-10-13 2016-04-21 Omega Life Science Ltd. Nébuliseurs et leurs utilisations
US20160331034A1 (en) * 2015-05-14 2016-11-17 Lunatech, Llc Vaporization method and apparatus

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140134251A1 (en) * 2009-03-26 2014-05-15 Pulmatrix, Inc. Pharmaceutical formulations and methods for treating respiratory tract infections
WO2016059630A1 (fr) * 2014-10-13 2016-04-21 Omega Life Science Ltd. Nébuliseurs et leurs utilisations
US20160331034A1 (en) * 2015-05-14 2016-11-17 Lunatech, Llc Vaporization method and apparatus

Non-Patent Citations (1)

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Title
FARSALINOS, KONSTANTINOS ET AL.: "Nicotine and SARS-CoV-2: COVID-19 may be a disease of the nicotinic cholinergic system", TOXICOLOGY REPORTS, vol. 7, no. 658, 28 April 2020 (2020-04-28), XP055826960, DOI: 10.1016/j.toxrep.2020.04.012 *

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