WO2023225107A1 - Fumarate de diroximel, méthodes d'administration par inhalation, utilisations pharmaceutiques et compositions - Google Patents
Fumarate de diroximel, méthodes d'administration par inhalation, utilisations pharmaceutiques et compositions Download PDFInfo
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- WO2023225107A1 WO2023225107A1 PCT/US2023/022569 US2023022569W WO2023225107A1 WO 2023225107 A1 WO2023225107 A1 WO 2023225107A1 US 2023022569 W US2023022569 W US 2023022569W WO 2023225107 A1 WO2023225107 A1 WO 2023225107A1
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- WIPO (PCT)
- Prior art keywords
- nebulizer
- certain embodiments
- diroximel fumarate
- subject
- fumarate
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/402—1-aryl substituted, e.g. piretanide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
Definitions
- IPF idiopathic pulmonary 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.
- ROS reactive oxygen species
- Grzegorzewska et al. report dimethyl fumarate ameliorates pulmonary arterial hypertension and lung fibrosis by targeting multiple pathways. Sci. Rep. 2017, 7, 41605.
- 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).
- 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.
- this disclosure relates to methods of treating established pro-fibrotic phenotypes by administering diroximel fumarate or derivatives to a subject in need thereof.
- the subject is a human.
- 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.
- diroximel fumarate inhibits the development or progression of fibrosis.
- diroximel fumarate promotes the reversal of established fibrosis.
- 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.
- 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.
- this disclosure relates to pharmaceutical compositions, containers, and kits comprising diroximel fumarate thereof for use in pulmonary administration and optionally comprising another active agent.
- the container is a pressurized or unpressurized container.
- the container is a manual pump spray, inhaler, meter-dosed inhaler, dry powder inhaler, nebulizer, vibrating mesh nebulizer, jet nebulizer, or ultrasonic wave nebulizer.
- 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.
- DRF diroximel fumarate
- 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.
- DRF diroximel fumarate
- 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.
- 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 SircolTM assay.
- Figure 3C shows data on static lung compliance (Cst) as determined by FlexiVentTM.
- 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.
- 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.
- the term "about” is synonymous with the term “approximately.”
- 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.
- 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.
- 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:
- Subject refers to any animal, preferably a human patient, livestock, rodent, monkey, or domestic pet.
- 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.
- 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).
- CFTR
- 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.
- prodrug refers to an agent that is converted into a biologically active form in vivo, i.e., a “metabolite.”
- 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.
- 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).
- this disclosure relates to treating a subject by inhalation to the lung with diroximel fumarate inhibiting pro-fibrotic phenotypes and reversing IPF lung fibroblasts.
- diroximel fumarate 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).
- MS-ILD multiple sclerosis associated interstitial lung disease
- multiple sclerosis occurs in adults greater than 20, 40, or 55 years old.
- 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.
- 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.
- 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.
- 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.
- administration is by intratracheal instillation, e.g., using a syringe.
- administration is by inhalation of diroximel fumarate through a nostril or the mouth.
- 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.
- diroximel fumarate is administered daily or twice daily for more than one, two, three, four, five, or six weeks, or more than two months.
- the subject is diagnosed with pulmonary fibrosis, bronchiectasis, or cystic fibrosis.
- the subject is diagnosed with a bacterial infection or viral infection.
- diroximel fumarate is administered in combination with another active agent such as a bronchodilator, corticosteroid, antimuscarinic, antibiotic, nintedanib, pirfenidone, or combinations thereof.
- another active agent such as a bronchodilator, corticosteroid, antimuscarinic, antibiotic, nintedanib, pirfenidone, or combinations thereof.
- 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.
- a beta-2 agonist such as salbutamol, salmeterol, formoterol and vilanterol
- an anticholinergic such as ipratropium, tiotropium, aclidinium, or glycopyrronium
- an antimuscarinic such as atropine or scopolamine, or theophylline.
- diroximel fumarate is administered in combination with a bronchodilator such as albuterol, formoterol, or levalbuterol or salts thereof.
- a bronchodilator such as albuterol, formoterol, or levalbuterol or salts thereof.
- diroximel fumarate is administered in combination with a mucolytic agent such as bromhexine or salts thereof.
- 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.
- an anti-inflammatory agent such as a corticosteroid, fluticasone, or salts thereof.
- 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.
- 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.
- 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.
- a cystic fibrosis drug such as lumacaftor, elexacaftor, ivacaftor, tezacaftor, cavosonstat, olacaftor, posenacaftor, galicaftor, navocaftor, deutivacaftor, nesolicaftor, or combinations thereof.
- 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.
- 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 sal
- 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.
- 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.
- the pharmaceutical composition is contained in a container comprising an aerosolizing propellant.
- 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.
- the container is a pressurized or unpressurized container.
- the container is a manual pump spray, inhaler, meter-dosed inhaler, dry powder inhaler, nebulizer, vibrating mesh nebulizer, jet nebulizer, or ultrasonic wave nebulizer.
- the pharmaceutical composition is an aerosol suspension, a dry powder, or a liquid suspension.
- 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).
- MDI metered dose inhaler
- 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.
- this disclosure relates to the production of a medicament comprising diroximel fumarate for therapeutic uses reported herein.
- the pharmaceutical composition optionally comprises a pharmaceutical carrier, and that the pharmaceutical composition optionally comprises further therapeutic agents, respiratory agents, anti-inflammatory agents, etc.
- a pharmaceutical composition is in the form of a liquid comprising pH buffering agents and optionally salts and/or saccharide or polysaccharide.
- this disclosure relates to pharmaceutical compositions comprising diroximel fumarate and a pharmaceutically acceptable excipient.
- 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, cast
- 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.
- 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.
- 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
- 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.
- the disclosure contemplates a pressurized or unpressurized container comprising diroximel fumarate.
- the container is a manual pump spray, inhaler, meter-dosed inhaler, dry powder inhaler, nebulizer, vibrating mesh nebulizer, jet nebulizer, or ultrasonic wave nebulizer.
- 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.
- diroximel fumarate may be contained in a storage container, dispensing container, sealed, or unsealed, such a vial, bottle, ampule, blister pack, or box.
- other agents may be contained in a storage container, sealed, or unsealed, such a vial, bottle, ampule, blister pack, or box.
- 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.
- 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.
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Abstract
La présente divulgation concerne des utilisations du fumarate de diroximel par administration pulmonaire dans le traitement, la prévention ou la réversion de la fibrose, par exemple la fibrose pulmonaire, la fibrose pulmonaire idiopathique (FPI). Dans certains modes de réalisation, la divulgation concerne des méthodes d'inhibition du développement et/ou de la progression de la fibrose pulmonaire par administration de fumarate de diroximel ou de ses dérivés à un individu le nécessitant. Dans certains modes de réalisation, la présente divulgation concerne des méthodes de traitement de phénotypes pro-fibrotiques établis, par administration de fumarate de diroximel ou de ses dérivés à un individu le nécessitant. Dans certains modes de réalisation, l'individu est un humain.
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US20210299079A1 (en) * | 2018-12-06 | 2021-09-30 | Flagship Pioneering Innovations V, Inc. | Monomethyl fumarate-carrier conjugates and methods of their use |
US20210309696A1 (en) * | 2018-09-14 | 2021-10-07 | Jiangyin Usun Pharmaceutical Co., Ltd. | New conjugates of montelukast and peptides |
US20210346402A1 (en) * | 2020-05-07 | 2021-11-11 | Ensemble Group Holdings | Methods of treatment for disease from coronavirus exposure |
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US20210309696A1 (en) * | 2018-09-14 | 2021-10-07 | Jiangyin Usun Pharmaceutical Co., Ltd. | New conjugates of montelukast and peptides |
US20210299079A1 (en) * | 2018-12-06 | 2021-09-30 | Flagship Pioneering Innovations V, Inc. | Monomethyl fumarate-carrier conjugates and methods of their use |
US20210346402A1 (en) * | 2020-05-07 | 2021-11-11 | Ensemble Group Holdings | Methods of treatment for disease from coronavirus exposure |
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BÁRBARA FERNANDES PINTO; LORENA NATASHA BRITO RIBEIRO; GISELA BEVILACQUA ROLFSEN FERREIRA DA SILVA; CAMILA SIMÕES FREITAS; LUCAS K: "Inhalation of dimethyl fumarate-encapsulated solid lipid nanoparticles attenuate clinical signs of experimental autoimmune encephalomyelitis and pulmonary inflammatory dysfunction in mice", CLINICAL SCIENCE, vol. 136, no. 1, 7 January 2022 (2022-01-07), pages 81 - 101, XP009551185, ISSN: 0143-5221, DOI: 10.1042/CS20210792 * |
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