CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 63/342,737 filed May 17, 2022. The entirety of this application is hereby incorporated by reference for all purposes.

BACKGROUND

Human fibrotic disorders affect many organ systems, and significant number of deaths are attributable to disorders that are characterized by varying degrees of fibrosis. The most severe form of lung fibrosis is idiopathic pulmonary fibrosis (IPF), a fatal and progressive disorder common in the elderly. IPF is characterized by excessive scar tissue formation and irreversible destruction of the lung parenchyma resulting in gas-exchange abnormalities and ultimately respiratory failure. There is a need for therapies that can prevent or promote the resolution of established lung fibrosis.

Oxidative stress is characterized as an imbalance between reactive oxygen species (ROS) production and antioxidant capacity. Defective antioxidant responses are implicated in the pathogenesis of IPF.

Hecker et al. report the reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Sci. Transl. Med. 2014, 6, 231ra247.

Grzegorzewska et al. report dimethyl fumarate ameliorates pulmonary arterial hypertension and lung fibrosis by targeting multiple pathways. Sci. Rep. 2017, 7, 41605.

Kato et al. report the efficacy of nintedanib in aging models of pulmonary fibrosis. Eur. Respir. J. 2021, 58, 2100759.

Pinto et al. report inhalation of dimethyl fumarate-encapsulated solid lipid nanoparticles attenuate clinical signs of experimental autoimmune encephalomyelitis and pulmonary inflammatory dysfunction in mice. Clin Sci (Lond), 2022, 136 (1): 81-101.

See also US Patent Nos. 11,484,530, 11,083,703, 10,576,055, and 9,422,226.

References cited herein are not an admission of prior art. SUMMARY

This disclosure relates to uses of diroximel fumarate or derivatives thereof by pulmonary administration in the treatment, prevention, or reversal of fibrosis e.g., pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF). In certain embodiments, this disclosure relates to methods of inhibiting the development or progression of lung fibrosis by administering diroximel fumarate or derivatives to a subject in need thereof. In certain embodiments, this disclosure relates to methods of treating established pro-fibrotic phenotypes by administering diroximel fumarate or derivatives to a subject in need thereof. In certain embodiments, the subject is a human.

In certain embodiments, this disclosure relates to methods of treating or preventing lung fibrosis comprising administering to the lungs an effective amount of a diroximel fumarate to a subject in need thereof. In certain embodiments, it is contemplated that diroximel fumarate inhibits the development or progression of fibrosis. In certain embodiments, it is contemplated that diroximel fumarate promotes the reversal of established fibrosis.

In certain embodiments, administration is by inhalation of an aerosol of diroximel fumarate in the pulmonary airway. In certain embodiments, administration is by inhalation diroximel fumarate through the mouth and/or nose.

In certain embodiments, administration is by a metered-dose inhaler. In certain embodiments, administration is by a single or multiple dose dry powder inhaler. In certain embodiments, administration is by a nebulizer.

In certain embodiments, this disclosure relates to pharmaceutical compositions, containers, and kits comprising diroximel fumarate thereof for use in pulmonary administration and optionally comprising another active agent. In certain embodiments, the container is a pressurized or unpressurized container. In certain embodiments, the container is a manual pump spray, inhaler, meter-dosed inhaler, dry powder inhaler, nebulizer, vibrating mesh nebulizer, jet nebulizer, or ultrasonic wave nebulizer.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

Figure 1 shows data indicating that diroximel fumarate (DRF) inhibits the development or progression of fibrosis as treatment inhibits the development of pro-fibrotic phenotypes in human lung fibroblasts. Human lung fibroblasts were treated with DRF (100 pM) followed by treatment +/- TGF-P (2 ng/mL). Whole-cell lysates were assessed for Nrf2 and fibrogenic markers (Fibronectin and a-SMA) expression at 48 hours by Western blot. GAPDH was used as loading control.

Figure 2 shows data indicating diroximel fumarate (DRF) promotes the reversal of established profibrotic phenotypes in IPF lung fibroblasts. Primary fibroblasts were isolated from the lung of a patient with biopsy-proven IPF. IPF fibroblasts were treated with DRF (100 pM). Whole-cell lysates were assessed for Nrf2 and a marker of myofibroblast differentiation (oc-SMA) expression at 24 hours by Western blot.

Figures 3A-3D shows data indicating lung-targeted delivery of DRF inhibits the development of lung fibrosis and improves lung function in an age-relevant pre-clinical model of pulmonary fibrosis.

Figure 3A shows a schematic diagram illustrating age-dependent persistent lung fibrosis and treatment protocol. C57BL/6J aged (19 months) male mice received bleomycin (0.02875 U/mouse) via oropharyngeal instillation. DRF was administered daily by intranasal instillation of DRF (180 pg/50 pL in sterile PBS/mouse) or vehicle from 5-14 days post-injury. All mice were evaluated at 14 days post-injury.

Figure 3B shows data on total lung collagen that was determined by quantitative Sircol™ assay.

Figure 3C shows data on static lung compliance (Cst) as determined by FlexiVent™.

Figure 3D shows a Kaplan-Meier survival curve of aged mice during the treatment period. Data are expressed as a percentage of survival at each time point relative to the total number of mice at the start of treatment. Vehicle (n=7); DRF (n=9).

DETAILED DESCRIPTION

Before the present disclosure is described in greater detail, it is to be understood that this disclosure is not limited to particular embodiments described, and as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described.

All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or in any other order that is logically possible.

An "embodiment" of this disclosure refers to an example and infers that the example is not necessarily limited to the example. Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature.

It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings unless a contrary intention is apparent.

As used in this disclosure and claim(s), the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "include") or "containing" (and any form of containing, such as "contains" and "contain") have the meaning ascribed to them in U.S. Patent law in that they are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

"Consisting essentially of" or "consists of" or the like, have the meaning ascribed to them in U.S. Patent law in that when applied to methods and compositions encompassed by the present disclosure refers to the idea of excluding certain prior art element(s) as an inventive feature of a claim, but which may contain additional composition components or method steps, etc., that do not materially affect the basic and novel character! stic(s) of the compositions or methods, compared to those of the corresponding compositions or methods disclosed herein.

As used herein, the term "about" is synonymous with the term "approximately." Illustratively, the use of the term "about" indicates that a value includes values slightly outside the cited values. Variation may be due to conditions such as experimental error, manufacturing tolerances, variations in equilibrium conditions, and the like. In some embodiments, the term "about" includes the cited value plus or minus 5% or 10%. In all cases, where the term "about" has been used to describe a value, it should be appreciated that this disclosure also supports the exact value.

As used herein “diroximel fumarate” refers to a compound having the chemical name 2- (2,5-dioxopyrrolidin-l-yl)ethyl methyl fumarate, Chemical Abstract Services (CAS) Number, 1577222-14-0, having the following structure:

2-(2 ififle pyrr 1-yl) ethyl methyl film at' ate

"Subject" refers to any animal, preferably a human patient, livestock, rodent, monkey, or domestic pet.

As used herein, the terms "treat" and "treating" are not limited to the case where the subject (e.g., patient) is cured and the disease is eradicated. Rather, embodiments of the present disclosure also contemplate treatment that merely reduces symptoms, and/or delays disease progression.

As used herein, the term "in combination with," when referring to two or more compounds, agents, or additional active pharmaceutical ingredients, means the administration of two or more compounds, agents, or active pharmaceutical ingredients to a subject or human patient prior to, concurrent with, or subsequent to each other such that they are contained/circulating in the patient at the same time, e.g., considering half-lives of the agents.

“Pulmonary fibrosis” refers to thickening or scarring of lung tissue. The normally thin, lacy walls of the air sacs in the lungs are no longer thin and lacy, but get thick, stiff and/or scarred, i.e., fibrotic. “Idiopathic pulmonary fibrosis” refers to someone with pulmonary fibrosis for unknown reasons, e.g., a subject that has pulmonary fibrosis without a diagnosis of cystic fibrosis or caused by exposure to lung toxin, coal miner, or cigarette smoker.

"Bronchiectasis" refers to a condition where the walls of the bronchi are thickened which can result in periodic flare-ups of breathing difficulties, also referred to as exacerbations. Cylindrical (tubular) bronchiectasis is characterized by cylinder-shaped bronchi/bronchioles. Cylindrical bronchiectasis is a morphologic type of bronchiectasis where there is smooth uniform enlargement of bronchi with loss of the normal distal tapering of the airways without focal outpouchings. Bronchial dilatation is typically evaluated in relation to the accompanying pulmonary artery. A broncho to arterial ratio greater than 1 : 1 is typically considered abnormal. Normal bronchi are narrower in diameter the further they are from the lung hilum. Lack of normal bronchial tapering over 2 cm in length, distal from an airway bifurcation, is a sign of bronchiectasis. Varicose bronchiectasis bronchi are irregular, and the airways may be wide or constricted. In cystic bronchiectasis, cysts can occur in the subpleural areas, when they typically represent paraseptal emphysema, bullae, or honeycombing. Bronchiectasis is typically a chronic respiratory condition, characterized by frequent cough and shortness of breath due to a range of conditions that include inherited mucociliary defects, inhalational airway injury, immunodeficiency states and prior respiratory infections. Bronchiectasis is characterized as a thickening and dilation of the walls of the bronchi from inflammation, infection, or other etiologies which result in the inability to clear mucus from the airway. Affected individuals are then more susceptible to repeated lung infections. Bronchiectasis is commonly found in individuals with cystic fibrosis. Cystic fibrosis is typically diagnosed in human patients having mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF patients are typically diagnosed with persistent pulmonary infections, elevated sweat chloride, and pancreatic insufficiency. In certain embodiments, elevated sweat chloride is in a concentration above 30 or 60 millimoles per liter (mEq/L).

As used herein, the term “derivative” refers to a structurally similar compound that retains sufficient functional attributes of the identified analogue. The derivative may be structurally similar because it is lacking one or more atoms, substituted, a salt, in different hydration/oxidation states, or because one or more atoms within the molecule are switched, such as, but not limited to, replacing a oxygen atom with a sulfur atom, replacing an amino group with a hydroxyl group, replacing a nitrogen with a protonated carbon (CH) in an aromatic ring, replacing a bridging amino group (-NH-) with an oxy group (-O-), or vice versa. The derivative may be a prodrug or a metabolite. Derivatives may be prepared by any variety of synthetic methods or appropriate adaptations presented in synthetic or organic chemistry textbooks, such as those provide in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley, 6th Edition (2007) Michael B. Smith or Domino Reactions in Organic Synthesis, Wiley (2006) Lutz F. Tietze hereby incorporated by reference.

The term "prodrug" refers to an agent that is converted into a biologically active form in vivo, i.e., a “metabolite.” The conversion of an ester to a carboxylic acid in vivo is a common metabolite. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A prodrug may be converted into the parent drug metabolite by various mechanisms, including enzymatic processes and metabolic hydrolysis. Typical prodrugs are pharmaceutically acceptable esters. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.

The term "substituted" refers to a molecule wherein at least one hydrogen atom is replaced with a substituent. When substituted, one or more of the groups are "substituents." The molecule may be multiply substituted. In the case of an oxo substituent ("=O"), two hydrogen atoms are replaced. Example substituents within this context may include halogen, hydroxy, alkyl, alkoxy, nitro, cyano, oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -NRaRb, -NRaC(=O)Rb, -NRaC(=O)NRaNRb, -NRaC(=O)ORb, - NRaSO2Rb, -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRb, -OC(=O)NRaRb, -ORa, -SRa, -SORa, - S(=O)2Ra, -OS(=O)2Ra and -S(=O)2ORa. Ra and Rb in this context may be the same or different and independently hydrogen, halogen hydroxyl, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl Methods of Use

This disclosure relates to uses of diroximel fumarate or derivatives thereof in the treatment, prevention, or reversal of fibrosis e.g., pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF). In certain embodiments, this disclosure relates to treating a subject by inhalation to the lung with diroximel fumarate inhibiting pro-fibrotic phenotypes and reversing IPF lung fibroblasts.

In certain embodiments, diroximel fumarate (DRF) inhibits development of lung fibrosis which is applicable to broader pulmonary fibrosis diseases such as chronic lung disease and multiple sclerosis associated interstitial lung disease (MS-ILD). In certain embodiments, multiple sclerosis occurs in adults greater than 20, 40, or 55 years old.

In certain embodiments, this disclosure relates to methods of treating or preventing lung fibrosis comprising administering by inhalation to the lung an effective amount of diroximel fumarate to a subject in need thereof.

In certain embodiments, this disclosure relates to methods of treating or preventing chronic lung disease or interstitial lung disease comprising administering by inhalation to the lung an effective amount of diroximel fumarate to a subject in need thereof.

In certain embodiments, administration is by inhalation of an aerosol of diroximel fumarate in the pulmonary airway. In certain embodiments, administration is by inhalation of diroximel fumarate through the mouth and/or nose.

In certain embodiments, administration is by a metered-dose inhaler. In certain embodiments, administration is by a single or multiple dose dry powder inhaler. In certain embodiments, administration is by a nebulizer. In certain embodiments, is a jet nebulizer driven by compressed air. In certain embodiments, the nebulizer is an ultrasonic nebulizer having a piezoelectric transducer for creating droplets from a liquid reservoir. In certain embodiments, the nebulizer is vibrating mesh nebulizer having perforated membranes actuated by an annular piezo element that vibrates in resonant bending mode.

In certain embodiments, administration is by intratracheal instillation, e.g., using a syringe.

In certain embodiments, administration is by inhalation of diroximel fumarate through a nostril or the mouth.

In certain embodiments, the subject is a human subject 2, 12, 16, or 20 years old or older. In certain embodiments, the subject is a human subject 2, 12, or 15 years old or older or less than 2, 12, or 16 years old. Tn certain embodiments, the subject is a human subject 55 or 65 years old or older. In certain embodiments, the subject is a human subject greater than 55, 60, 65, or 70 years of age. In certain embodiments, the subject is an infant, e.g., from one month to two years of age. In certain embodiments, the subject is a human subject such as a child, e.g., from two to twelve years of age. In certain embodiments, the subject is a human subject such as an adolescent, e.g., from twelve to sixteen years of age. In certain embodiments, the subject is a human subject sixteen years of age or older.

In certain embodiments, diroximel fumarate is administered daily or twice daily for more than one, two, three, four, five, or six weeks, or more than two months.

In certain embodiments, the subject is diagnosed with pulmonary fibrosis, bronchiectasis, or cystic fibrosis.

In certain embodiments, the subject is diagnosed with a bacterial infection or viral infection.

In certain embodiments, diroximel fumarate is administered in combination with another active agent such as a bronchodilator, corticosteroid, antimuscarinic, antibiotic, nintedanib, pirfenidone, or combinations thereof.

In certain embodiments, the bronchodilator is a beta-2 agonist, such as salbutamol, salmeterol, formoterol and vilanterol or an anticholinergic, such as ipratropium, tiotropium, aclidinium, or glycopyrronium, or an antimuscarinic such as atropine or scopolamine, or theophylline.

In certain embodiments, diroximel fumarate is administered in combination with a bronchodilator such as albuterol, formoterol, or levalbuterol or salts thereof.

In certain embodiments, diroximel fumarate is administered in combination with a mucolytic agent such as bromhexine or salts thereof.

In certain embodiments, fumaric acid, diroximel fumarate is administered in combination with is administered in combination with an anti-inflammatory agent such as a corticosteroid, fluticasone, or salts thereof.

In certain embodiments, diroximel fumarate is administered in combination with an antibiotic agent such as macrolides, azithromycin, antipseudomonal, fluoroquinolones, ciprofloxacin, levofloxacin, ceftazidime, piperacillin and tazobactam, imipenem, aminoglycosides, aztreonam, tobramycin, colistin, colistimethate sodium, or salt thereof. Tn certain embodiments, diroximel fumarate is administered in combination with a cystic fibrosis drug such as lumacaftor, elexacaftor, ivacaftor, tezacaftor, cavosonstat, olacaftor, posenacaftor, galicaftor, navocaftor, deutivacaftor, nesolicaftor, or combinations thereof.

In certain embodiments, diroximel fumarate is administered in combination with other pharmaceutically active agents. These compounds include but are not limited to analgesics, antiinflammatory drugs, antipyretics, antidepressants, antiepileptics, antihistamines, antimigraine drugs, antimuscarinics, anxiolytics, sedatives, hypnotics, antipsychotics, bronchodilators, antiasthma drugs, cardiovascular drugs, corticosteroids, dopaminergics, electrolytes, gastro-intestinal drugs, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics, and anti-narcoleptics.

Specific examples of the pharmaceutically active agents that can be adjunctively administered include, but are not limited to, aceclofenac, acetaminophen, atomoxetine, almotriptan, alprazolam, amantadine, amcinonide, aminocyclopropane, amitriptyline, amlodipine, amoxapine, amphetamine, aripiprazole, aspirin, atomoxetine, azasetron, azatadine, beclomethasone, benactyzine, benoxaprofen, bermoprofen, betamethasone, bicifadine, bromocriptine, budesonide, buprenorphine, bupropion, buspirone, butorphanol, butriptyline, caffeine, carbamazepine, carbidopa, carisoprodol, celecoxib, chlordiazepoxide, chlorpromazine, choline salicylate, citalopram, clomipramine, clonazepam, clonidine, clonitazene, clorazepate, clotiazepam, cloxazolam, clozapine, codeine, corticosterone, cortisone, cyclobenzaprine, cyproheptadine, demexiptiline, desipramine, desomorphine, dexamethasone, dexanabinol, dextroamphetamine sulfate, dextromoramide, dextropropoxyphene, dezocine, diazepam, dibenzepin, diclofenac sodium, diflunisal, dihydrocodeine, dihydroergotamine, dihydromorphine, dimetacrine, divalproex, dizatriptan, dolasetron, donepezil, dothiepin, doxepin, duloxetine, ergotamine, escitalopram, estazolam, ethosuximide, etodolac, femoxetine, fenamates, fenoprofen, fentanyl, fludiazepam, fluoxetine, fluphenazine, flurazepam, flurbiprofen, flutazolam, fluvoxamine, frovatriptan, gabapentin, galantamine, gepirone, granisetron, haloperidol, huperzine A, hydrocodone, hydrocortisone, hydromorphone, hydroxyzine, ibuprofen, imipramine, indiplon, indomethacin, indoprofen, iprindole, ipsapirone, ketanserin, ketoprofen, ketorolac, lesopitron, levodopa, lipase, lofepramine, lorazepam, loxapine, maprotiline, mazindol, mefenamic acid, melatonin, melitracen, memantine, meperidine, meprobamate, mesalamine, metapramine, metaxalone, methadone, methadone, methamphetamine, methocarbamol, methyldopa, methylphenidate, methylsalycylate, metoclopramide, mianserin, mifepristone, milnacipran, minaprine, mirtazapine, moclobemide, molindone, morphine, morphine hydrochloride, nabumetone, nadolol, naproxen, naratriptan, nefazodone, neurontin, nomifensine, nortriptyline, olanzapine, olsalazine, ondansetron, opipramol, orphenadrine, oxaflozane, oxaprozin, oxazepam, oxitriptan, oxycodone, oxymorphone, pancrelipase, parecoxib, paroxetine, pemoline, pentazocine, pepsin, perphenazine, phenacetin, phendimetrazine, phenmetrazine, phenylbutazone, phenytoin, phosphatidyl serine, pimozide, pirlindole, piroxicam, pizotifen, pizotyline, pramipexole, prednisolone, prednisone, pregabalin, propranolol, propizepine, propoxyphene, protriptyline, quazepam, quinupramine, reboxetine, reserpine, risperidone, ritanserin, rivastigmine, rizatriptan, rofecoxib, ropinirole, rotigotine, salsalate, sertraline, sibutramine, sildenafd, sulfasalazine, sulindac, sumatriptan, tacrine, temazepam, tetrabenazine, thiazides, thioridazine, thiothixene, tiapride, taziprinone, tizanidine, tofenacin, tolmetin, toloxatone, topiramate, tramadol, trazodone, triazolam, trifluoperazine, trimethobenzamide, trimipramine, tropisetron, valdecoxib, valproic acid, venlafaxine, viloxazine, vitamin E, zimeldine, ziprasidone, zolmitriptan, zolpidem, zopiclone, and combinations thereof.

Pharmaceutical Compositions and Kits

In certain embodiments, this disclosure relates to pharmaceutical composition, containers, and kits comprising diroximel fumarate for use in pulmonary administration and optionally comprising another active agent such as a bronchodilator, corticosteroid, anticholinergic, antimuscarinic, mucolytic agent, anti-inflammatory agent, antibiotic, anti-viral agent, beta-2 agonist, cystic fibrosis drug, or combinations thereof.

In certain embodiments, the pharmaceutical composition is contained in a container comprising an aerosolizing propellant. In certain embodiments, the aerosolizing propellant is compressed air, ethanol, nitrogen, carbon dioxide, nitrous oxide, hydrofluoroalkanes (HF As), 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, chlorofluorocarbon, or combinations thereof.

In certain embodiments, the container is a pressurized or unpressurized container. In certain embodiments, the container is a manual pump spray, inhaler, meter-dosed inhaler, dry powder inhaler, nebulizer, vibrating mesh nebulizer, jet nebulizer, or ultrasonic wave nebulizer. Tn certain embodiments, the pharmaceutical composition is an aerosol suspension, a dry powder, or a liquid suspension.

In certain embodiments, the pharmaceutical composition is an inhalation pharmaceutical formulation prepared for delivery as a nasal spray or an inhaler, such as a metered dose inhaler (MDI).

In certain embodiments, the container is a nebulizer comprising diroximel fumarate for use in pulmonary administration into a mist, optionally using an aqueous saline solution, inhaled through a mouthpiece or face mask.

In certain embodiments, this disclosure relates to the production of a medicament comprising diroximel fumarate for therapeutic uses reported herein.

In certain embodiments, the pharmaceutical composition optionally comprises a pharmaceutical carrier, and that the pharmaceutical composition optionally comprises further therapeutic agents, respiratory agents, anti-inflammatory agents, etc. In certain embodiments, a pharmaceutical composition is in the form of a liquid comprising pH buffering agents and optionally salts and/or saccharide or polysaccharide.

In certain embodiments, this disclosure relates to pharmaceutical compositions comprising diroximel fumarate and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutically acceptable excipient is selected from lactose, sucrose, mannitol, triethyl citrate, dextrose, cellulose, methyl cellulose, ethyl cellulose, hydroxyl propyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, croscarmellose sodium, polyvinyl N-pyrrolidone, crospovidone, ethyl cellulose, povidone, methyl and ethyl acrylate copolymer, polyethylene glycol, fatty acid esters of sorbitol, lauryl sulfate, gelatin, glycerin, glyceryl monooleate, silicon dioxide, titanium dioxide, talc, corn starch, carnauba wax, stearic acid, sorbic acid, magnesium stearate, calcium stearate, castor oil, mineral oil, calcium phosphate, starch, carboxymethyl ether of starch, iron oxide, triacetin, acacia gum, esters, or salts thereof.

Compositions may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable (such as olive oil, sesame oil) and injectable organic esters such as ethyl oleate. These compositions may also contain preserving, emulsifying, and dispensing agents. Prevention of the action of microorganisms may be controlled by addition of any of various antibacterial, antiviral, and antifungal agents, example, parabens, chlorobutanol, phenol, sorbic acid, and the like.

Liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.

In certain embodiments, the pharmaceutical composition is used as a buccal or nasal spray. In certain embodiments, the pharmaceutical compositions are in a form for inhalation. In certain embodiments, the pharmaceutical composition comprises diroximel fumarate and a propellant. In certain embodiments, an aerosolizing propellant is compressed air, ethanol, nitrogen, carbon dioxide, nitrous oxide, hydrofluoroalkanes (HFAs), or combinations thereof.

In certain embodiments, the disclosure contemplates a pressurized or unpressurized container comprising diroximel fumarate. In certain embodiments, the container is a manual pump spray, inhaler, meter-dosed inhaler, dry powder inhaler, nebulizer, vibrating mesh nebulizer, jet nebulizer, or ultrasonic wave nebulizer.

In certain embodiments, this disclosure contemplates kits comprising pharmaceutical compositions comprising diroximel fumarate and optionally another therapeutic agent in same or separate pharmaceutical composition or container. The kits may contain a transfer device such a needle, syringe, cannula, capillary tube, pipette, or pipette tip.

In certain embodiments, diroximel fumarate may be contained in a storage container, dispensing container, sealed, or unsealed, such a vial, bottle, ampule, blister pack, or box. In certain embodiments, other agents may be contained in a storage container, sealed, or unsealed, such a vial, bottle, ampule, blister pack, or box.

In certain embodiments, the kit further comprises written instructions for using diroximel fumarate as reported herein and optionally other agents for treating and/or preventing a condition in a subject as reported herein. Tn certain embodiments, this disclosure relates to uses of diroximel fumarate in the production of a medicament for treating conditions disclosed herein.

Dosing is dependent on severity and responsiveness of the disease state to be treated, and the course of treatment lasting from several days to several months, or until a cure is effected or a diminution of the disease state is achieved. Optimal dosing schedules can be calculated from measurements of drug accumulation in the body of the patient. Optimum dosages may vary depending on the relative potency of individual agents. Generally, it can be estimated based on amounts found to be effective in in vitro and in vivo animal models. In general, dosage is from 0.01 pg to 1 g per kg of body weight, and may be given once or more daily, weekly, monthly, or yearly, or even once every 2 to 10 years. Following successful treatment, it may be desirable to have the patient undergo maintenance therapy to prevent the recurrence of the disease state.