WO2021207489A1

WO2021207489A1 - Methods and pharmaceutical compositions to treat pulmonary inflammation in infected patients

Info

Publication number: WO2021207489A1
Application number: PCT/US2021/026372
Authority: WO
Inventors: Joseph V. PERGOLIZZI
Original assignee: Rtu Pharmaceuticals, Llc
Priority date: 2020-04-08
Filing date: 2021-04-08
Publication date: 2021-10-14

Abstract

Disclosed in certain embodiments is a method of treating pulmonary inflammation in a patient experiencing comprising administering a non-steroidal anti-inflammatory agent formulation to a patient in need thereof.

Description

Methods and Pharmaceutical Compositions to Treat Pulmonary Inflammation in Infected Patients

Background of the Invention

[0001] Bacteria and vital infections are serious diseases that are often accompanied by pulmonary inflammation.

[0002] Infections such as Covid-19 typically gain entry into the lung from the nose or month. After entry into the lungs, the virus causes injury top the respiratory system such as pulmonary inflammation and associated fluid retention. This can cause chest tightness and increased pain while breathing.

[0003] This inflammation and fluid retention fluid can affect a oxygen levels, and pneumonia can be mild, moderate, severe or even life-threatening, depending on how impaired gas transfer becomes and how difficult it is to breathe.

[0004] If the transfer of oxygen into the blood stream is reduced, a person will often need supplemental oxygen and very close monitoring in a hospital setting.

[0005] In very serious cases, a patient may need to be placed on ventilator support in an intensive care unit. A ventilator can result in increased complications such as an additional secondary infection.

[0006] A person with pre-existing lung diseases, such as asthma, generally has less respiratory reserve than a person with no lung issues. Because of this, these individuals may be more vulnerable and may have more difficulty if their lungs are impacted by an acute infection. [0007] There have been reports that the use of non-steroidal anti-inflammatory agents (NSAIDS) such as ibuprofen increases the risk of developing severe and fatal Covid-19. Fang, Lei, George Karakiulakis, and Michael Roth. "Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?." The Lancet. Respiratory Medicine 8.4 (2020): e21. [0008] The present disclosure is directed to compositions and methods for the treatment of patients who have pulmonary inflammation associated with a bacterial or viral infection, e.g., Covid-19.

Objects and Summary

[0009] In certain embodiments, the disclosure is directed to a method of treating pulmonary inflammation in a patient comprising administering a non-steroidal anti-inflammatory to a patient in need thereof. In certain embodiments, the pulmonary inflammation is caused by a bacterial or viral infection, e.g., Covid-19.

[00010] In other embodiments, the disclosure is directed to a pharmaceutical composition comprising an effective amount of a non-steroidal anti-inflammatory to treat pulmonary inflammation, e.g., in a patient experiencing a bacterial or viral infection, e.g., Covid-19.

Detailed Description

[00011] In certain embodiments, the present invention is directed to a method of treating pulmonary inflammation in a patient comprising administering a non-steroidal anti inflammatory agent to patient with an infection (e.g., Covid-19) without exacerbating or significantly exacerbating the condition, the infection or the symptoms of the infection (e.g., Covid-19).

[00012] In certain embodiments, the present invention is directed to a method of treating pulmonary inflammation (including hyperinflammation) in a patient comprising administering a non-steroidal anti-inflammatory agent to a patient in need thereof as well as pharmaceutical compositions as disclosed herein. The terms “treatment of’ and “treating” include the administration of an active agent(s) with the intent to lessen the severity and/or manage the symptoms of a condition.

[00013] In certain embodiments, the pulmonary inflammation is caused by a bacterial or viral or fungal infection (such as coccidioides fungus which may cause Valley Fever). In other embodiments, the pulmonary inflammation is caused by a systemic autoimmune disease such as systemic lupus erithematosus, rheumatoid arthritis, systemic sclerosis, polymyositis/dermatomyositis, Sjogren's syndrome, mixed connective tissue disease, Wegener's granulomatosis, Churg-Strauss syndrome, Goodpasture's syndrome, and ankylosing spondylitis.

[00014] In certain embodiments, the non-steroidal antiinflammatory is selected from the group consisting of naproxen, aceclofenac, acemetacin, aloxiprin, aspirin, benorilate, bromfenac, celecoxib, deracoxib, diclofenac, diflunisal, ethenzamide, etodolac, etofenamate, etoricoxib, fenbufen, fenoprofen, flufenamic acid, flurbiprofen, lonazolac, lomoxicam, ibuprofen, indomethacin, isoxicam, kebuzone, ketoprofen, ketorolac, licofelone, loxoprofen, lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam, metamizol, mofebutazone, nabumetone, niflumic acid, nimesulide, oxaprozin, oxyphenbutazone, parecoxib, phenidone, phenylbutazone, piroxicam, propyphenazone, rofecoxib, salicylamide, sulfinpyrazone, sulindac, suprofen, tiaprofenic acid, tenoxicam, tolmetin, valdecoxib and pharmaceutically acceptable salts thereof.

[00015] In certain embodiments, the active agent is ketorolac or a pharmaceutically acceptable salt thereof, e.g., ketorolac tromethamine.

[00016] In certain embodiments, the non-steroidal anti-inflammatory agent reduces cytokines, e.g., pulmonary cytokines. The cytokines can be selected from, e.g., one or more of IFNy, IL- lRa, IL-2Ra, IL-6, IL-10, IL-18, HGF, MCP-3, MIG, M-CSF, G-CSF, MIG-la, and IP-10. In one embodiment, the cytokines are selected from one or more of IP-10, IL-IRa, and MCP-3. Cytokines also encompass chemokines which are a family of small cytokines, or signaling proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines. Cytokine proteins are classified as chemokines according to behavior and structural characteristics. [00017] In certain embodiments, the administration is by oral, parenteral, nasal, inhalational, topical, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratrachael, otic, intraocular, or intrathecal route.

[00018] In certain embodiments, the administration is by parenteral route, e.g., subcutaneously, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intraorbitally, intra cardiacally, intradermally, intraperitoneally, transtracheally, subcuticularly, intraarticularly, subcapsularly, subarachnoidly, intraspinally, intrasternally, or through infusion. In certain embodiments, the administration is by continuous infusion. [00019] In certain embodiments, the administration is by intratracheal instillation or intratracheal inhalation with an endotracheal tube. In certain embodiments, the administration is with a metered dose inhaler, nebulizer, soft mist inhaler, a high efficiency nebulizer, jet nebulizer or ultrasonic nebulizer.

[00020] In certain embodiments, the administration is with an oral solid dosage form or an oral solution or suspension.

[00021] In certain embodiments, the pulmonary inflammation is caused by systemic inflammatory response syndrome, cytokine release syndrome, macrophage activation syndrome, hemophagocytic lymphohistiocytosis, serine racemase (SR) activity or a combination thereof.

[00022] In certain embodiments, the pulmonary inflammation is caused by pneumonia, tuberculosis, bronchitis, emphysema, cystic fibrosis, allergy or asthma.

[00023] In certain embodiments, the viral infection is coronavirus, e.g., Covid-19. In certain embodiments, the viral infection is SARS, MERS, swine flu (including G4 EA H1N1) and Zika virus.

[00024] In certain embodiments, the pulmonary inflammation is associated with acute respiratory distress syndrome (ARDS). In certain embodiments, the ARDS may be caused by a bacterial or viral infection. In other embodiments, the ARDS is not caused by a bacterial or viral infection. In alternative embodiments, the ARDS is due to trauma, inhalation of toxic substance, blood transfusion, or drowning.

[00025] In certain embodiments, the pulmonary inflammation is associated with chronic obstructive pulmonary disease (COPD). In certain embodiments, the COPD is caused by a bacterial or viral infection. In other embodiments, the COPD is not caused by a bacterial or viral infection. In alternative embodiments, the COPD is due to tobacco smoke, air pollution or genetic conditions.

[00026] In certain embodiments, the formulation is free of alcohol or substantially free of alcohol. In certain embodiments, the formulation has less than about 1% alcohol (e.g., ethanol), less than about 0.5% alcohol or less than about 0.1% alcohol.

[00027] In certain embodiments, the NSAID is ketorolac and is formulated as a pharmaceutical composition for parenteral administration comprising: an aqueous solution comprising ketorolac tromethamine in an amount from about 0.1 mg/mL to about 50 mg/mL; 0.1 mg/mL to about 30 mg/mL; or 0.1 mg/mL to aboOut 10 mg/mL; and a pharmaceutically acceptable excipient selected from the group consisting of anhydrous or hydrous forms of sodium chloride, dextrose, sucrose, xylitol, fructose, glycerol, sorbitol, mannitol, potassium chloride, mannose, calcium chloride, magnesium chloride; wherein the composition is substantially free of alcohol, has a pH from about 4.5 to about 8.5 and maintains at least 90% of the amount of ketorolac or a pharmaceutically acceptable salt thereof after storage for 6 months at 25 degrees C; and wherein the composition is contained in a pharmaceutically acceptable container selected from the group consisting of intravenous bags and intravenous bottles.

[00028] In certain embodiments, the composition maintains at least 90% of the amount of ketorolac or a pharmaceutically acceptable salt thereof after storage for 1 year or for 2 years. [00029] In certain embodiments, the composition maintains at least 95% of the amount of ketorolac or a pharmaceutically acceptable salt thereof after storage for 6 months, for one year or 2 years.

[00030] In certain embodiments, the agent is ketorolac or a salt thereof and the administration is parenteral and comprises a continuous intravenous parenteral infusion and an optional bolus dose (e.g., intravenous or intramuscular), before, during or after the infusion.

[00031] In certain embodiments, the bolus dose is from about 10 mg to about 50 mg, from about 20 mg to about 40 mg, or about 30 mg and continuous infusion is from about 0.5 mg to about 5 mg per hour, from about 1 mg to about 4 mg per hour, or from about 2 mg to about 3 mg per hour.

[00032] In certain embodiments, the NSAID is diclofenac and is formulated as a pharmaceutical composition for parenteral administration comprising about 20 mg to about 50 mg diclofenac per ml, about 30 mg to about 45 mg per ml or about 37.5 mg per ml. The administration may be, e.g., by bolus intravenous administration of about 20 mg to about 50 mg diclofenac, about 30 mg to about 45 mg diclofenac or about 37.5 mg diclofenac over a time period, e.g., of about 5 seconds to about 30 minutes, about 10 seconds to about 10 minutes, about 15 seconds to about 5 minutes, less than about 5 minutes, less than about 4 minutes, less than about 3 minutes, less than about 2 minutes, less than about 1 minute or about 15 seconds. The administered dose may be repeated as needed, e.g., every 4 hours, every 6 hours, every 8 hours, every 12 hours or every 24 hours. In certain embodiments, the dose of diclofenac does not exceed about 150 mg per day.

[00033] In certain embodiments, the NSAID is ibuprofen and is formulated as a pharmaceutical composition for parenteral administration comprising about 200 mg to about 1,600 mg diclofenac per ml, about 400 mg to about 1,200 mg per ml or about 800 mg per ml. The administration may be, e.g., intravenous administration of about 50 mg to about 1,000 mg diclofenac, about 400 mg to about 800 mg diclofenac or about 100 mg to about 200 mg diclofenac over a time period, e.g., of about 1 minutes to about 60 minutes, about 5 minutes to about 45 minutes, about 10 minutes to about 40 minutes, less than about 60 minutes, less than about 50 minutes, less than about 45 minutes, less than about 40 minutes, or about 30 minutes. The administered dose may be repeated as needed, e.g., every 4 hours, every 6 hours, every 8 hours, every 12 hours or every 24 hours. In certain embodiments, the dose of ibuprofen does not exceed about 3,200 mg per day.

[00034] In certain embodiments, the NS AID is indomethacin and is administered orally from about 25 mg to about 250 mg per day, or about 50 mg to about 200 mg per day or aboyut 75 mg to 150 mg per day. The daily dos can be administed in divided doses, e.g., every 4 hours, every 6 hours, every 8 hours or every 12 hours. The dosage of individual units can be, e.g., 20 mg; 25 mg; 40 mg; 50 mg; 75 mg or 100 mg.

[00035] In certain embodiments, the formulations for pulmonary administration (e.g., nebulization) comprise one or more excipients selected from an isotonicity agent (e.g., sodium chloride), mineral acids and bases (e.g., to maintain or adjust pH), nitrogen headspace sparging, benzalkonium chloride, calcium chloride, sodium citrate, disodium edtate, and polysorbate 80. [00036] In certain embodiments, the methods further comprise administering chloroquine or hydroxychloroquine to the patient.

[00037] In certain embodiments, the methods further comprise administering an antibiotic to the patient, e.g., aminoglycosides, penicillins, cephalosporins, carbapenems, fluoroquinolones, sulfonamides, macrolides, and tetracyclines. Further examples of antibiotics that may be included in the preparation include: gentamicin, tobramycin, penicillin, amoxicillin, ampicillin, cephalexin, ciprofloxacin, levofloxacin, ofloxacin, co-trimoxazole, trimethoprim, erythromycin, clarithromycin, azithromycin, tetracycline, and doxycycline. [00038] In certain embodiments, the methods further comprise administering an antiviral to the patient, e.g., amantadine.

[00039] In certain embodiments, the non-steroidal anti-inflammatory agent is administered with a continuous positive airway pressure (CPAP), BIPAP or ventilator machine. In certain embodiments, the non-steroidal anti-inflammatory agent is administered without a continuous positive airway pressure (CPAP), BIPAP or ventilator machine. In certain embodiments, the non-steroidal anti-inflammatory agent is administered to prevent the need to use a continuous positive airway pressure (CPAP), BIPAP or ventilator machine. In certain embodiments, the non-steroidal anti-inflammatory agent is administered after use with a continuous positive airway pressure (CPAP), BIPAP or ventilator machine which is later discontinued after administration of the NSAID.

[00040] In certain embodiments, a bronchodilator can also be administered. Suitable brochodilators include short-acting beta2 agonists, long-acting beta2 agonists, muscarinic agents, methylxanthines, short-acting anticholinergic agents, and combinations thereof.

[00041] Suitable short-acting beta2 agonists include albuterol, epinephrine, pirbuterol, levalbuterol, metaproteronol, pirbuterol, pharmaceutically acceptable salts thereof and combinations thereof.

[00042] Suitable long-acting beta2 agonists include salmeterol, formoterol and isomers (e.g. arformoterol), clenbuterol, tulobuterol, vilanterol, indacaterol, carmoterol, isoproterenol, procaterol, bambuterol, milveterol, olodaterol, pharmaceutically acceptable salts thereof and combinations thereof.

[00043] Suitable muscarinic agents include tiotroprium, trospium, glycopyrrolate, aclidinium, ipratropium, oxitropium pharmaceutically acceptable salts thereof and combinations thereof.

[00044] Suitable methylxanthines include aminophylline, ephedrine, theophylline, oxtriphylline, pharmaceutically acceptable salts thereof and combinations thereof [00045] In one embodiment, the compositions are formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical compositions. Pharmaceutically acceptable carriers, which are useful, include, but are not limited to, glycerol, water, saline, ethanol and other pharmaceutically acceptable salt solutions such as phosphates and salts of organic acids. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In certain embodiments, there can be the inclusion of isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition.

[00046] Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, inhalational, intravenous, subcutaneous, transdermal enteral, or any other suitable mode of administration. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like.

[00047] The pharmacologically acceptable salts of any of the active agents utilized in the methods and compositions of the present disclosure can be, for example, an inorganic salt such as a hydrochloride, a sulfate, a phosphate or a hydrobromide; or an organic salt such as an oxalate, a malonate, a citrate, a fumarate, a lactate, a malate, a succinate, a tartrate, an acetate, a trifluoroacetate, a maleate, a gluconate, a benzoate, a salicylate, a xinafoate, a pamoate, an ascorbate, an adipate, a methanesulfonate, a p-toluenesulfonate or a cinnamate. These salts may be present in the form of a hydrate, a solvate or a crystalline polymorph. The drug can also be in a complex with a cyclodextrin.

[00048] In certain embodiments, ketorolac is formulated to be administered by any route according to 20190105301, hereby incorporated by reference.

[00049] In certain embodiments with an additional active agent, the active agents are administered simultaneously or sequentially. In certain embodiments, at least two active agents are administered sequentially.

[00050] In certain embodiments with an additional active agent, the active agents are administered by the same route of administration. In certain embodiments, the active agents are administered by at least two different routes of administration.

[00051] In certain embodiments with an additional active agent, the active agents are administered in the same pharmaceutical composition or the active agents are administered in at least two different pharmaceutical compositions.

[00052] In certain embodiments, the methods of the present invention are initiated when the infected patient has a SP02 measurement of less than about 90, less than about 80, less than about 75, less than about 60, less than about 50, less than about 40, less than about 30, less than about 20 or less than about 10. In other embodiments, the methods of the present invention raise the SP02 level at least about 5%, at least about 10%, at least about 20%. At least about 35%, at least about 50%, at least about 65%, at least about 75%, at least about 85%, at least about 95%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, at least about 350%, at least about 400% or at least about 500%.

[00053] In certain embodiments, the methods of the present invention are initiated when the infected patient has an arterial blood gas measurement of less than about 80 mm hg, less than about 75 mm hg, less than about 60 mm hg, less than about 50 mm hg, less than about 40 mm hg, less than about 30 mm hg, less than about 20 mm hg or less than about 10 mm hg. In other embodiments, the methods of the present invention raise the arterial blood gas level at least about 5%, at least about 10%, at least about 20%. At least about 35%, at least about 50%, at least about 65%, at least about 75%, at least about 85%, at least about 95%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, at least about 350%, at least about 400% or at least about 500%.

[00054] The methods of the present invention can be initiated on a patient who is symptomatic of hypoxemia or who is asymptomatic of hypoxemia. In certain embodiments, the methods of the present invention are initiated on a patient who is experiencing one or more symptoms of hypoxemia selected from shortness of breath, chest pain, confusion, headache, rapid heartbeat and cyanosis. In certain embodiments, the methods of the present invention are initiated on a patient who is not experiencing any hypoxemia symptoms such as shortness of breath, chest pain, confusion, headache, rapid heartbeat and cyanosis but the patient has a SP02 measurement (e.g., less than 90% etc.) or arterial blood gas measurement (e.g. less than 80 mm hg etc.) that is as disclosed above.

[00055] The arterial blood gas measurement can be performed by measuring oxygen in blood draw from an artery rather than a vein as blood in the arteries are oxygenated. Typically, the wrist arteries are used as they are more easily felt than other arteries of the body.

[00056] SP02 is measured with a pulse oximeter (pulse ox) which is a noninvasive device that estimates the amount of oxygen in blood by sending infrared light into capillaries, e.g., in the finger, toe, or earlobe. The device then measures how much light is reflected off the gases and indicated the percentage of blood that is saturated (SP02).

[00057] In certain embodiments, the NSAID is administered solely to treat the pulmonary inflammation caused by an infection and is no used to treat other conditions that are alleviated by NS AID therapy such a one or more of bodyache, headache, backache and fever. In other embodiments, the NSAID therapy of the present invention is initiated at the onset of pulmonary inflammation caused by an infection (e.g., Covid-19). In other embodiments, the NSAID therapy of the present invention is initiated at the diagnosis of an infection (e.g., Covid-19) but before the onset of pulmonary inflammation as prophylactic treatment. In other embodiments, the NSAID therapy of the present invention is initiated prior to diagnosis and/or onset of pulmonary inflammation caused by an infection (e.g., Covid-19) and the treatment is continued after diagnosis and/or onset of pulmonary inflammation caused by an infection (e.g., Covid- 19)

[00058] The following examples set forth certain embodiments of the invention and are not meant to limit the invention in any way.

Examples (Prophetic)

[00059] A patient diagnosed with Covid-19 is experiencing pulmonary inflammation. The patient is administered ketorolac by intravenous bolus with about 10 mg to about 50 mg followed by continuous infusion is from about 0.5 mg to about 5 mg per hour for about 24 hours or as needed.

[00060] A patient diagnosed with Covid-19 is experiencing pulmonary inflammation. The patient is administered 37.5 mg diclofenac by intravenous bolus over a time period of about 15 seconds. The administered dose is repeated every 6 hours not to exceed 150 mg per day. [00061] A patient diagnosed with Covid-19 is experiencing pulmonary inflammation. The patient is administered 40 mg to 800 mg ibuprofen by intravenously over a time period of about 30 minutes. The administered dose is repeated every 4 to 6 hours not to exceed 3,200 mg per day. [00062] A patient diagnosed with Covid-19 is experiencing pulmonary inflammation. The patient is administered 50 mg oral indomethacin every 8 hours.

Claims

What is claimed is:

1. A method of treating pulmonary inflammation in a patient comprising administering a non-steroidal anti-inflammatory agent formulation to a patient with an arterial blood gas measurement of less than about 80 mm hg.

2. The method of claim 1, wherein the pulmonary inflammation associated with a bacterial infection, viral infection, fungus infection or systemic autoimmune disease.

3. The method of any of claims 1 or 2, wherein the non-steroidal antiinflammatory is selected from the group consisting of naproxen, aceclofenac, acemetacin, aloxiprin, aspirin, benorilate, bromfenac, celecoxib, deracoxib, diclofenac, diflunisal, ethenzamide, etodolac, etofenamate, etoricoxib, fenbufen, fenoprofen, flufenamic acid, flurbiprofen, lonazolac, lomoxicam, ibuprofen, indomethacin, isoxicam, kebuzone, ketoprofen, ketorolac, licofelone, loxoprofen, lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam, metamizol, mofebutazone, nabumetone, niflumic acid, nimesulide, oxaprozin, oxyphenbutazone, parecoxib, phenidone, phenylbutazone, piroxicam, propyphenazone, rofecoxib, salicylamide, sulfinpyrazone, sulindac, suprofen, tiaprofenic acid, tenoxicam, tolmetin, valdecoxib and pharmaceutically acceptable salts thereof.

4. The method of claim 3, wherein the active agent is ketorolac or a pharmaceutically acceptable salt thereof.

5. The method of claim 4, wherein the active agent is ketorolac tromethamine.

6. The method of any of claims 1-5, wherein the non-steroidal anti-inflammatory agent reduces cytokines and/or chemokines.

7. The method of claim 6, wherein the non-steroidal anti-inflammatory agent reduces pulmonary cytokines.

8. The method of any of claims 1-7, wherein the administration is by oral, parenteral, nasal, inhalational, topical, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratrachael, otic, intraocular, or intrathecal route

9. The method of claim 8, wherein the administration is by parenteral route.

10. The method of claim 9, wherein the parenteral route is selected from the group consisting of subcutaneously, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intraorbitally, intra cardiacally, intradermally, intraperitoneally, transtracheally, subcuticularly, intraarticularly, subcapsularly, subarachnoidly, intraspinally, intrasternally, or through infusion.

11. The method of claim 10, wherein the administration is by continuous infusion.

12. The method claim 8, wherein the administration is by intratracheal instillation or intratracheal inhalation with an endotracheal tube.

13. The method of claim 8, wherein the administration is with a metered dose inhaler, nebulizer, soft mist inhaler, a high efficiency nebulizer, or ultrasonic nebulizer.

14. The method of any of claims 1-4, wherein the administration is with an oral solid dosage form or an oral solution or suspension.

15. The method of any preceding claim, wherein the patient is infected with a bacterial infection.

16. The method of any preceding claim, wherein the patient is infected with a viral infection.

17. The method of claim 20, wherein the viral infection is coronavirus.

18. The method of claim 21, wherein the coronavirus is Covid-19.

19. The method of claim 20, wherein the viral infection is SARS, MERS, swine flu and

Zika virus.

20. The method of any preceding claim, wherein the formulation is free of alcohol or substantially free of alcohol.

21. The method of any preceding claim, wherein the NSAID is ketorolac and is formulated as a pharmaceutical composition for parenteral administration comprising: an aqueous solution comprising ketorolac tromethamine in an amount from about 0.1 mg/mL to about 10 mg/mL; and a pharmaceutically acceptable excipient selected from the group consisting of anhydrous or hydrous forms of sodium chloride, dextrose, sucrose, xylitol, fructose, glycerol, sorbitol, mannitol, potassium chloride, mannose, calcium chloride, magnesium chloride; wherein the composition is substantially free of alcohol, has a pH from about 4.5 to about 8.5 and maintains at least 90% of the amount of ketorolac or a pharmaceutically acceptable salt thereof after storage for 6 months at 25 degrees C; and wherein the composition is contained in a pharmaceutically acceptable container selected from the group consisting of intravenous bags and intravenous bottles.

22. The method of claim 21, wherein the composition maintains at least 90% of the amount of ketorolac or a pharmaceutically acceptable salt thereof after storage for 1 year or for

2 years.

23. The method of claim 21, wherein the composition maintains at least 95% of the amount of ketorolac or a pharmaceutically acceptable salt thereof after storage for 6 months, for one year or 2 years.

24. The method of any preceding claim wherein the agent is ketorolac or a salt thereof and the administration is parenteral and comprises a continuous intravenous parenteral infusion and an optional bolus dose (e.g., intravenous or intramuscular), before, during or after the infusion.

25. The method of claim 24, wherein the bolus dose is from about 10 mg to about 50 mg, from about 20 mg to about 40 mg, or about 30 mg and continuous infusion is from about 0.5 mg to about 5 mg per hour, from about 1 mg to about 4 mg per hour, or from about 2 mg to about 3 mg per hour.

26. The method of any preceding claim formulations for nebulization with one or more excipients selected from an isotonicity agent (e.g., sodium chloride), mineral acids and bases (e.g., to maintain or adjust pH), nitrogen headspace sparging, benzalkonium chloride, calcium chloride, sodium citrate, disodium edtate, and polysorbate 80.

27. The method of any preceding claims, further comprising administering chloroquine or hydroxychloroquine to the patient.

28. The method of any preceding claims, further comprising administering chloroquine or hydroxychloroquine to the patient.

29. The method of any preceding claims, further comprising administering an antibiotic to the patient.

30. The method of claim 28, wherein the antibiotic is azithromycin.

31. The method of any of preceding claims comprising administering an antiviral to the patient.

32. The method of claim 30, wherein the antiviral is amantadine.

33. The method of claim 6 or 7, wherein the cytokines are selected from one or more of IFNy, IL-lRa, IL-2Ra, IL-6, IL-10, IL-18, HGF, MCP-3, MIG, M-CSF, G-CSF, MIG- la, and IP- 10.

34. The method of claim 6 or 7, wherein the cytokines are selected from one or more of IP- 10, IL-lRa, and MCP-3.

35. The method of any of claims 1-33, wherein the pulmonary inflammation is associated with acute respiratory distress syndrome (ARDS).

36. The method of claim 34, wherein the ARDS is caused by a bacterial or viral infection.

37. The method of claim 34, wherein the ARDS is not caused by a bacterial or viral infection.

38. The method of claim 34, wherein the ARDS is due to trauma, inhalation of toxic substance, blood transfusion, or drowning.

39. The method of any of claims 1-33, wherein the pulmonary inflammation is associated with chronic obstructive pulmonary disease (COPD).

40. The method of claim 38, wherein the COPD is caused by a bacterial or viral infection.

41. The method of claim 38, wherein the COPD is not caused by a bacterial or viral infection.

42. The method of claim 38, wherein the COPD is due to tobacco smoke, air pollution or genetic conditions.

43. The method of any preceding claims, wherein the pulmonary inflammation is caused by systemic inflammatory response syndrome, cytokine release syndrome, macrophage activation syndrome, hemophagocytic lymphohistiocytosis or a combination thereof.

44. The method of claim 1-33, wherein the pulmonary inflammation is caused by pneumonia, tuberculosis, bronchitis, emphysema, cystic fibrosis, allergy or asthma.

45. A pharmaceutical composition or formulation as disclosed herein and/or as used in the methods disclosed herein.