WO2022016068A1

WO2022016068A1 - Dexamethasone solution for the treatment of severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infections

Info

Publication number: WO2022016068A1
Application number: PCT/US2021/042002
Authority: WO
Inventors: Christopher SCIARRA; Brian C. Keller; Todd Maibach
Original assignee: Tbd Pharma LLC
Current assignee: Tbd Pharma LLC
Priority date: 2020-07-16
Filing date: 2021-07-16
Publication date: 2022-01-20
Anticipated expiration: 2023-01-16

Abstract

The use of dexamethasone in a metered dose inhaler for treating pulmonary symptoms and the cytokine storm caused by SARS-CoV-2 infections in humans.

Description

DEXAMETHASONE SOLUTION FOR THE TREATMENT OF SEVERE ACUTE RESPIRATORY SYNDROME CORONA VIRUS 2 (SARS-COV-2) INFECTIONS

BACKGROUND

[0001] 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).

[0002] About 50.5% of COVID-19 patients have chronic health conditions, including cerebrovascular and cardiovascular diseases. Among coexisting diseases, individuals with hypertension and diabetes mellitus are the most vulnerable.

[0003] The precise mechanism by which SARS-CoV-2 ensues COVID-19 still remains to be elucidated. However, a few findings that could contribute to the pathogenicity have been suggested. Globally, the increasing fatalities in recent outbreak of SARS-CoV-2 can be attributed to severity of symptoms in COVID-19 patients.

[0004] 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. In many respects 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. PET ATT, ED DESCRIPTION

[0005] In certain embodiments, 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.

[0006] Of the various cytokines, the presence of raised circulating levels of IL-6 appears to be key and is closely connected to disease severity and respiratory failure, not only in COVID-19, but also in avian-origin H7N9 influenza infections and the common seasonal H1N1 influenza A.

[0007] As stated, SARS-CoV-2 is a deadly disease that has affected people worldwide. Dexamethasone decreases mortality in COVID-19 infected people.

[0008] In certain embodiments, the disclosure is directed to applying a dexamethasone solution through a metered dose inhaler (MDI) directly to lung tissue. By following embodiments of the disclosure, inflammation can be quickly abated, the potential of elevated blood levels of cytokines arrested, the cytokine cascade can begin to shut down, and the chance for survival can increase rapidly and can decrease the potential for death. By delivering the drug directly to the site of action, lung health can be improved.

[0009] The disclosure differs from what currently exists. Embodiments of the disclosure deliver dexamethasone solution directly into the lungs and onto lung tissue like no other drug product.

[0010] As used herein, the term “about” means ±10 % of the noted value. By way of example only, “about 50 pg” could include from 45 pg to and including 55 pg.

[0011] Various examples and embodiments of the subject matter disclosed are possible and will be apparent to a person of ordinary skill in the art, given the benefit of this disclosure. In this disclosure reference to “some embodiments,” “certain embodiments,” “certain exemplary embodiments” and similar phrases each means that those embodiments are non-limiting examples of the inventive subject matter, and there may be alternative embodiments which are not excluded. [0012] The articles “a,” “an,” and “the” are used herein to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0013] The word “comprising” is used in a manner consistent with its open-ended meaning, that is, to mean that a given product or process can optionally also have additional features or elements beyond those expressly described. It is understood that wherever embodiments are described with the language “comprising,” otherwise analogous embodiments described in terms of “consisting of’ and/or “consisting essentially of’ are also contemplated and within the scope of this disclosure.

[0014] 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.

[0015] In certain embodiments, 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. In certain embodiments, 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.

[0016] In certain embodiments, 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.

[0017] In certain embodiments, 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).

[0018] In certain embodiments, 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). [0019] In certain embodiments, the viral infection can be influenza (including H7N9 and H1N1), SARS-CoV-1, SARS-CoV-2, MERS, or bacterial pneumonia.

[0020] In certain embodiments, the subject can be within a particular patient population. In certain embodiments, the subject can be pediatric, adult, or elderly. In certain embodiments, the subject can be pediatric (e.g., ages 0-17 years). In certain embodiments, the subject can be adult (e.g., ages 18-64 years). In certain embodiments, the subject can be elderly (e.g., ages 65 years and above).

[0021] In certain embodiments, the subject can be a severely ill COVID-19 patient. In certain embodiments, the patient can have lung involvement.

Embodiments of the Disclosure Include:

1. Dexamethasone

2. A vehicle (such as ethyl alcohol)

3. A propellant (such as an HF A propellant)

4. A Metered Dose Inhaler canister

[0022] In certain embodiments, the vehicle can be a polar solvent. In certain embodiments, the vehicle can be ethyl alcohol, propylene glycol, glycerin, or isopropyl alcohol. In certain embodiments, the vehicle can be ethyl alcohol.

[0023] In certain embodiments, the propellant can be an HFA (hydrofluoroalkane) propellant. In certain embodiments, 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).

Relationship Between the Components:

[0024] #1 can be incorporated into #2 and #2 and #3 can be incorporated into #4.

[0025] In certain embodiments, 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.

[0026] In certain embodiments of the apparatus, the dexamethasone and the ethyl alcohol are incorporated together and the HFA propellant and the Metered Dose Inhaler canister are incorporated together. How Embodiments of the Disclosure Work:

[0027] Without wishing to be bound by theory, Applicant believes that embodiments of the disclosure are successful in treating COVID-19 for at least the following reasons. 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).

[0028] 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.

[0029] 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:

[0030] Add ethyl alcohol to dexamethasone and stir until dissolved. Add dexamethasone solution to a canister suitable for use as a container for attaching a metered dose inhaler. Charge the canister with an HFA propellant suitable for inhalation and seal the canister.

How to Use Embodiments of the Disclosure:

[0031] Inhale two puffs every 12 hours or spray two actuations into an inhaler spacer and breathe in the contents in the spacer chamber. In certain embodiments, the subject can inhale one puff, two puffs, three puffs, four puffs, five puffs, or six puffs. In certain embodiments, the spray can be one actuation, two actuations, three actuations, four actuations, five actuations, or six actuations. In certain embodiments, 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.

Claims

What is claimed is:

1. A method of treating COVID-19 in a subject, comprising administering to a subject in need thereof a pharmaceutically effective amount of dexamethasone solution through a metered dose inhaler (MDI).

2. The method according to claim 1, wherein the dexamethasone solution comprises dexamethasone and a vehicle.

3. The method according to any one of claims 1 or 2, wherein the vehicle comprises ethyl alcohol.

4. The method according to any one of claims 1-3, wherein the metered dose inhaler comprises an HFA propellant and a Metered Dose Inhaler canister.

5. The method according to any one of claims 1-4, comprising a dexamethasone dosage strength of from about 0.1 pg to about 1000 pg.

6. An MDI apparatus comprising dexamethasone, a vehicle, an HFA propellant, and a Metered Dose Inhaler canister.

7. The MDI apparatus according to claim 6, wherein the vehicle comprises ethyl alcohol.

8. The MDI apparatus according to claims 6 or 7, comprising a dexamethasone dosage strength of from about 0.1 pg to about 1000 pg.

9. A method of treating a viral infection in a subject, comprising administering to a subject in need thereof a pharmaceutically effective amount of dexamethasone solution through a metered dose inhaler (MDI).

10. The method according to claim 9, wherein the dexamethasone solution comprises dexamethasone and a vehicle.

11. The method according to any one of claims 9 or 10, wherein the vehicle comprises ethyl alcohol.

12. The method according to any one of claims 9-11, wherein the metered dose inhaler comprises an HFA propellant and a Metered Dose Inhaler canister.

13. The method according to any one of claims 9-12, comprising a dexamethasone dosage strength of from about 0.1 pg to about 1000 pg.

14. The method according to any one of claims 9-13, wherein the viral infection is from influenza (including H7N9 and H1N1), SARS-CoV-1, SARS-CoV-2, MERS, or bacterial pneumonia.

15. The method according to any one of claims 9-14, wherein the influenza comprises H7N9 or HINT