WO2022016068A1 - Solution de dexaméthasone pour le traitement d'infections par le coronavirus du syndrome respiratoire aigu sévère (sars-cov-2) - Google Patents

Solution de dexaméthasone pour le traitement d'infections par le coronavirus du syndrome respiratoire aigu sévère (sars-cov-2) Download PDF

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Publication number
WO2022016068A1
WO2022016068A1 PCT/US2021/042002 US2021042002W WO2022016068A1 WO 2022016068 A1 WO2022016068 A1 WO 2022016068A1 US 2021042002 W US2021042002 W US 2021042002W WO 2022016068 A1 WO2022016068 A1 WO 2022016068A1
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WO
WIPO (PCT)
Prior art keywords
dexamethasone
cov
sars
metered dose
dose inhaler
Prior art date
Application number
PCT/US2021/042002
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English (en)
Inventor
Christopher SCIARRA
Brian C. Keller
Todd Maibach
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Tbd Pharma Llc
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Publication date
Application filed by Tbd Pharma Llc filed Critical Tbd Pharma Llc
Publication of WO2022016068A1 publication Critical patent/WO2022016068A1/fr

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Classifications

    • 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
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone

Definitions

  • Coronavirus Disease (COVID-19) is deadly. Since the outbreak elicited by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which belongs to a group of b-coronavirus, it has affected young and old worldwide and has infected millions of individuals in over 200 countries, causing hundreds of thousands of deaths. Dexamethasone has been shown to decrease mortality rates in COVID-19 infected people (Horby PW, Landray MJ, Dexamethasone for COVID- 19-Preliminary Report, RECOVERY Collaborative Group. medRxiv preprind doi: http://doi.org/10.1101/2020.06.22.20137273).
  • COVID-19 patients are presented with elevated levels of leukocytes, anomalous respiratory manifestations and high plasma pro-inflammatory cytokines.
  • the elevated inflammatory cytokines suggest that a cytokine storm, also known as cytokine release syndrome (CRS), may play a major role in the pathology of COVID-19.
  • COVID-19 can be regarded as a viral -induced hyperinflammatory condition with multi organ involvement due to a cytokine cascade.
  • a COVID-19 infection significantly elevates blood levels of cytokines including chemokines and interleukins in the human body, including IL-6, IL-7, IL-8, IL-9, IL-10, IL1RA, ILl-b, GCSF, GMCSF, basic FGF2, IP10, MCP1, MIRIa, MIRIb, PTNGg, TNFa, PDGFB and VEGFA.
  • cytokines including chemokines and interleukins in the human body, including IL-6, IL-7, IL-8, IL-9, IL-10, IL1RA, ILl-b, GCSF, GMCSF, basic FGF2, IP10, MCP1, MIRIa, MIRIb, PTNGg, TNFa, PDGFB and VEGFA.
  • the disclosure provides a safe and effective anti inflammatory corticosteroid product that applies the dexamethasone directly to affected lung tissue.
  • Other corticosteroid products have not shown similar efficacy to dexamethasone in COVID-19 patients.
  • SARS-CoV-2 is a deadly disease that has affected people worldwide.
  • Dexamethasone decreases mortality in COVID-19 infected people.
  • the disclosure is directed to applying a dexamethasone solution through a metered dose inhaler (MDI) directly to lung tissue.
  • MDI metered dose inhaler
  • Embodiments of the disclosure deliver dexamethasone solution directly into the lungs and onto lung tissue like no other drug product.
  • the term “about” means ⁇ 10 % of the noted value.
  • “about 50 pg” could include from 45 pg to and including 55 pg.
  • This disclosure provides an improvement on what currently exists. By delivering dexamethasone solution directly into the lungs, the drug can reach lung tissues that are affected by SARS-CoV-2 or other viruses. No other drug that has been shown to decrease the death rate in COVID-19 is available in this dosage form.
  • the dosage can be between about 0.1 pg and about 1000 pg, between about 0.5 pg and about 800 pg, between about 1 pg and about 700 pg, between about 5 pg and about 600 pg, between about 5 pg and about 500 pg, between about 5 pg and about 400 pg, between about 5 pg and about 300 pg, between about 5 pg and about 200 pg, and between about 5 pg and about 100 pg.
  • the dosage can be about 0.1 pg, 0.5 pg, 0.6 pg, 0.7 pg, 0.8 pg, 0.9 pg, 1.0 pg, 2 pg, 3 pg, 4 pg, 5 pg, 10 pg, 20 pg, 25 pg, 50 pg, 60 pg, 80 pg, 100 pg, 120 pg, 160 pg, 200 pg, 250 pg, 300 pg, 350 pg, 400 pg, 450 pg, 500 pg, 550 pg, 600 pg, 650 pg, 700 pg, 750 pg, 800 pg, 850 pg, 900 pg, 950 pg, or 1000 pg, or any ranges between the specified values.
  • the dosage can be administered once daily. In certain embodiments, the dosage can be administered twice daily. In certain embodiments, the dosage can be administered three, four, five, or six times daily.
  • the present disclosure is directed to a method of treating
  • COVID-19 comprising administering to a subject in need thereof an effective amount of dexamethasone solution through a metered dose inhaler (MDI).
  • MDI metered dose inhaler
  • the present disclosure is directed to a method of treating a viral infection, comprising administering to a subject in need thereof an effective amount of dexamethasone solution through a metered dose inhaler (MDI).
  • MDI metered dose inhaler
  • the viral infection can be influenza (including H7N9 and H1N1), SARS-CoV-1, SARS-CoV-2, MERS, or bacterial pneumonia.
  • the subject can be within a particular patient population.
  • the subject can be pediatric, adult, or elderly.
  • the subject can be pediatric (e.g., ages 0-17 years).
  • the subject can be adult (e.g., ages 18-64 years).
  • the subject can be elderly (e.g., ages 65 years and above).
  • the subject can be a severely ill COVID-19 patient.
  • the patient can have lung involvement.
  • a vehicle such as ethyl alcohol
  • a propellant such as an HF A propellant
  • the vehicle can be a polar solvent.
  • the vehicle can be ethyl alcohol, propylene glycol, glycerin, or isopropyl alcohol.
  • the vehicle can be ethyl alcohol.
  • the propellant can be an HFA (hydrofluoroalkane) propellant.
  • the HFA propellant can be 1,1,1,2-tetrafluoroethane (134a), 1,1,1,2,3,3,3-heptafluoropropane (P227), or 1,1-difluoroethane (152a).
  • #1 can be incorporated into #2 and #2 and #3 can be incorporated into #4.
  • the present disclosure is directed to an MDI apparatus comprising dexamethasone, ethyl alcohol as a vehicle, an HFA propellant, and a Metered Dose Inhaler canister.
  • the dexamethasone and the ethyl alcohol are incorporated together and the HFA propellant and the Metered Dose Inhaler canister are incorporated together.
  • COVID-19 sets off an inflammatory cascade also knows as the cytokine storm. Proinflammatory substrates are released into the blood steam and cause multiorgan involvement including the lungs that leads to acute respiratory distress syndrome (ARDS).
  • ARDS acute respiratory distress syndrome
  • the anti-inflammatory mechanism and most of the metabolic actions of dexamethasone commences with binding to specific receptors within the cytoplasm of targeted cells.
  • the receptor- steroid complex then migrates into the nucleus, where it binds to DNA and alters genetic synthesis of proteins. Any number of cellular functions are thereby modified, including the production of enzymes that regulate myriad metabolic processes and those that regulate synthesis of inflammatory autacoids and immune-related cytokines. This mechanism is time consuming and accounts for a delayed onset of effect (6-8 hours) when glucocorticoids are administered systemically.
  • dexamethasone When dexamethasone is administered through the lung by an MDI delivery to the needed site of action, the pharmacological results can be immediate.
  • the anti inflammatory effects of dexamethasone are largely due to a reduction in the synthesis and/or release of a variety of inflammatory mediators, which includes cytokines and interleukins. Cytokines have important effects in the activity of many cells. However, they are of particular importance because of their significance in regulating the immune system. The function of cytokines in the development of inflammatory disease as a result to viral infection is one issue with COVID-19. Interleukin are a subset of cytokines.
  • Interleukin (IL)- l b, IL-8, tumor necrosis factor alpha (TNF-a), IL-6, and IL-12 are the most remarkable secretions included in these inflammatory reactions. The sum of these actions results the dynamic changes responsible for the cardinal signs of inflammation. Dexamethasone inhibits certain aspects of this cascade of reactions. How to Make Embodiments of the Disclosure:
  • the subject can inhale one puff, two puffs, three puffs, four puffs, five puffs, or six puffs.
  • the spray can be one actuation, two actuations, three actuations, four actuations, five actuations, or six actuations.
  • the spray can be one actuation into an inhaler spacer, two actuations into an inhaler spacer, three actuations into an inhaler spacer, four actuations into an inhaler spacer, five actuations into an inhaler spacer, or six actuations into an inhaler spacer, and the subject can breathe in the contents in the spacer changer.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Otolaryngology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne l'utilisation de dexaméthasone dans un inhalateur doseur pour traiter les symptômes pulmonaires et la tempête de cytokines provoquée par les infections par le SARS-CoV-2 chez l'homme.
PCT/US2021/042002 2020-07-16 2021-07-16 Solution de dexaméthasone pour le traitement d'infections par le coronavirus du syndrome respiratoire aigu sévère (sars-cov-2) WO2022016068A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202063052637P 2020-07-16 2020-07-16
US63/052,637 2020-07-16

Publications (1)

Publication Number Publication Date
WO2022016068A1 true WO2022016068A1 (fr) 2022-01-20

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PCT/US2021/042002 WO2022016068A1 (fr) 2020-07-16 2021-07-16 Solution de dexaméthasone pour le traitement d'infections par le coronavirus du syndrome respiratoire aigu sévère (sars-cov-2)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150232855A1 (en) * 2006-08-10 2015-08-20 Roy C. Levitt Localized Therapy of Lower Airways Inflammatory Disorders With Proinflammatory Cytokine Inhibitors
US20170071850A1 (en) * 2009-05-29 2017-03-16 Pearl Therapeutics, Inc. Compositions for respiratory delivery of active agents and associated methods and systems
US20170189630A1 (en) * 2014-05-09 2017-07-06 Norton (Waterford) Limited Aerosol device

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150232855A1 (en) * 2006-08-10 2015-08-20 Roy C. Levitt Localized Therapy of Lower Airways Inflammatory Disorders With Proinflammatory Cytokine Inhibitors
US20170071850A1 (en) * 2009-05-29 2017-03-16 Pearl Therapeutics, Inc. Compositions for respiratory delivery of active agents and associated methods and systems
US20170189630A1 (en) * 2014-05-09 2017-07-06 Norton (Waterford) Limited Aerosol device

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HORBY PETER, LIM WEI SHEN, EMBERSON JONATHAN, MAFHAM MARION, BELL JENNIFER, LINSELL LOUISE, STAPLIN NATALIE, BRIGHTLING CHRISTOPHE: "Effect of Dexamethasone in Hospitalized Patients with COVID-19 – Preliminary Report", MEDRXIV, 22 June 2020 (2020-06-22), XP055899488, Retrieved from the Internet <URL:https://www.medrxiv.org/content/10.1101/2020.06.22.20137273v1.full.pdf> DOI: 10.1101/2020.06.22.20137273 *

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