Classifications

• • 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
  • A61K31/275—Nitriles; Isonitriles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics

Definitions

• the present invention relates to using 3-methanesulfonylpropionitrile (dapansutrile), or its pharmaceutically acceptable solvates, for treating asthma.
• Asthma is a common chronic disorder of the airways characterized by variable and recurring symptoms, reversible airway obstruction, bronchial hyperresponsiveness, and an underlying inflammation. Acute symptoms of asthma include cough, wheezing, shortness of breath and nocturnal awakening. Asthma is regarded as a chronic disease based on a condition of chronic airway inflammation together with airway hyperresponsiveness, with at least partially reversible airway obstruction.
• Th2 T-helper (Th2) cells appear to play a central role in the activation of the immune cascade that results in inflammation.
• Th2-derived cytokines include IL-5, which is needed for eosinophil differentiation and survival, and IL-4 which is important for Th2 cell differentiation and with IL-13 is important for IgE formation and leads to overproduction of IgE and eosinophilia.
• bronchoconstrictor mediators such as histamine and cysteinyl-leukotrienes as well as inflammatory cytokines.
• Eosinophils contain inflammatory enzymes, generate leukotrienes, and express a wide variety of pro- inflammatory cytokines.
• Airway epithelial cells also play a role in the inflammatory process via release of cytokines such as eotaxin that direct and modify the inflammatory response.
• Acute and chronic inflammation can affect not only the airway caliber and airflow but also can increase the existing bronchial hyperresponsiveness to a variety of stimuli, which enhances susceptibility to bronchospasm.
• the airway smooth muscle cell can undergo proliferation, activation, contraction, and
• bronchial smooth muscle contraction occurs quickly to narrow the airways in response to exposure to a variety of stimuli including allergens or irritants. Allergen-induced acute bronchoconstriction results from an IgE-dependent release of mediators from mast cells that includes histamine, tryptase, leukotrienes, and prostaglandins that directly contract airway smooth muscle.
• the mechanisms influencing airway hyperresponsiveness are multiple and they include inflammation, dysfunctional neuroregulation, and airway remodeling.
• Airway remodeling involves structural changes such as thickening of the sub-basement membrane, subepithelial fibrosis, airway smooth muscle hypertrophy and hyperplasia, blood vessel proliferation and dilation with consequent permanent changes in the airway that increase airflow obstruction.
• Airway epithelium and endothelial cell function are also critically involved in asthma. Upon disease progression, epithelial subbasement membranes thicken with mucus hypersecretion and the formation of mucus plugs. Changes in endothelial cell integrity lead to edema, another key pathophysiology defining asthmatic change of the airway. These factors serve to further limit airflow.
• Asthma is characterized by dominant T helper type 2 (Th2) immune responses, including enhanced IL-4, IL-5 and IL-13 responses, allergen-specific immunoglobulin production, eosinophilia, airway inflammation, bronchoconstriction, and airway
• Th2 T helper type 2
• corticosteroids and P?-agonists anti-inflammatory and bronchodilator drugs. These drugs provide acceptable control of the disease for many asthmatics. However, it is estimated that 5 to 10% of the asthma patients have symptomatic disease despite treatment with this combination of corticosteroids and P?-agonists.
• FIG. 1 shows total numbers (mean ⁇ SEM) of leukocyte subpopulations (macrophage, lymphocyte, neutrophil, and eosinophil, from left to right) in bronchoalveolar lavage fluids on Day 29, 24 hours after the final ovalbumin (OVA) aerosol challenge and intraperitoneal dapansutrile dose.
• OVA ovalbumin
• FIG. 4 shows mean ⁇ SEM airway resistance toward methylcholine for in healthy, asthmatic, and dapansutrile-treated mice. ****p ⁇ 0.0001 between asthmatic and treated mice.
• FIG. 5 shows total numbers of leukocyte subpopulations (macrophage, lymphocyte, neutrophil, and eosinophil, from left to right, mean ⁇ SEM) in bronchoalveolar lavage fluids on Day 29, 24 hours after the final ovalbumin (OVA) aerosol challenge and oral dapansutrile dose.
• OVA ovalbumin
• FIG. 7 shows mean ⁇ SEM airway resistance toward methylcholine for in healthy, asthmatic, and dapansutrile-treated mice. **p ⁇ 0.01 between asthmatic and treated mice.
• 3-methanesulfonylpropionitrile which reduces the levels of IL-Ib and IL-6 in several whole animal models of local and systemic inflammation, is effective in treating asthma, reducing airway inflammation, reducing airway resistance, improving lung function, ameliorating asthma symptoms, and improving patient’s quality of life.
• the present invention is directed to a method of treating asthma.
• the method comprises the step of administering to a subject in need thereof an effective amount of a compound of 3-methanesulfonylpropionitrile (dapansutrile), or a pharmaceutically acceptable solvate thereof, to treat asthma.
• Solids are addition complexes in which the compound is combined with an acceptable solvent in some fixed proportion.
• Acceptable solvents include, but are not limited to, water, acetic acid, ethanol, and other appropriate organic solvents.
• the present method is effective in prophylactic treatment, which is a process of protecting against the development of asthma by a treatment of dapansutrile before the onset of asthma to affect pathogenesis.
• prophylactic treatment dapansutrile is administered to a patient in need thereof, before the onset of asthma.
• the present method is effective in therapeutic treatment after the onset of asthma, when the patient starts to show clinical signs and/or symptoms.
• the main functional changes of the lungs associated asthma include malfunctioning of the immune system, cellular infiltration composed primarily of eosinophils and neutrophils, acute and chronic inflammation, fluid accumulation (edema), excessive secretion of mucus, and changes in the airway walls that could lead to bronchial epithelial injury, fibrosis, and increased sensitivity to agents that cause bronchial constriction. These features need to be considered in order to develop treatments of the underlying disease process. Small animal models can be designed to mimic the airway inflammation, increased responsiveness to bronchial constrictors, changes in the airway wall, and changes in the migration of the eosinophils and neutrophils to the lungs.
• a mouse model of asthma via ovalbumin sensitization (Lunding, 2015b), for example, can be used to evaluate bronchodilator efficacy of dapansutrile.
• the present method for treating asthma is based on the properties of dapansutrile to reduce at least one of the following processes contributing to pathophysiology that accompanies this disorder: inflammation, excessive cell proliferation, airway and/or lung tissue edema, airway hyperreactivity, and bronchoconstriction.
• Indicia of efficacy for treating asthma by the present method include demonstrable improvement in measurable signs, symptoms and other variables clinically relevant to asthma. Such improvements include increased blood oxygen saturation, decreased hypoxia and hypercapnia, decreased need for supplemental oxygen, decreased frequency of coughing and/or wheezing, improved forced expiratory volume in one second (FEVi), improved forced vital capacity (FVC) or other physiologically relevant parameter of respiratory function, decreased need for mechanical ventilation, decreased amount of inflammatory cells infiltrating the lung, decreased levels of proinflammatory cytokines and chemokines, improved alveolar fluid clearance rate, decreased pulmonary edema as determined by any radiographic or other detection method such as amount of epithelial lining fluid, wet to dry lung weight, alveolar fluid clearance and/or radiographic visualization methods, increase in general quality of life, patient-reported or physician-observed signs such as ease of breathing, or decrease in severity of coughing and/or wheezing.
• radiographic or other detection method such as amount of epithelial lining fluid, wet to
• the present method treats asthma by (i) improving symptoms (daytime and nocturnal symptoms, limitation of activities, use of rescue medications), (ii) improving lung function such as peak expiratory flow (PEF) and/or forced expiratory volume in one second (FEV1), and/or (iii) reducing exacerbations (rate and severity).
• the present method improves Asthma Quality of Life Questionnaire (AQLQ) scores, which include the scores of symptoms, activity limitation, emotional function, and environmental exposure.
• the present invention has demonstrated that dapansutrile reduced airway resistance, reduced inflammatory cells (eosinophils and neutrophils) and mucus hyperproduction in broncho-alveolar lavage fluid, and reduced airway inflammation, in ovalbumin-induced allergic airway inflammation in mice.
• the present invention provides pharmaceutical compositions comprising one or more pharmaceutically acceptable carriers and an active compound of 3- methanesulfonylpropionitrile, or a pharmaceutically acceptable solvate thereof.
• the active compound or its pharmaceutically acceptable solvate in the pharmaceutical compositions in general is about 1-90% for a tablet formulation, about 1-100% for a capsule formulation, about 0.01-20%, or 0.05-20%, or 0.1-20%, or 0.2-15%, or 0.5-10%, or 1-5% (w/w), for a topical formulation; about 0.1-5% for an injectable formulation, 0.1-5% for a patch formulation,.
• the active compound used in the pharmaceutical composition in general is at least 90%, preferably 95%, or 98%, or 99% (w/w) pure.
• the pharmaceutical composition is in a dosage form such as tablets, capsules, granules, fine granules, powders, syrups, suppositories, injectable solutions, patches, or the like.
• the pharmaceutical composition is in the form of an aerosol suspension of respirable particles comprising the active compound, which the subject inhales.
• the respirable particles can be liquid or solid, with a particle size sufficiently small to pass through the mouth and larynx upon inhalation. In general, particles having a size of about 1 to 10 microns, preferably 1-5 microns, are considered respirable.
• the respirable particles including dapansutrile can be prepared into dry powder using well-known art of super critical fluid technology. In such a case, the compound is admixed with appropriate excipients and milled into a homogenous mass using suitable solvents or adjuvants. Following this, this mass is subjected to mixing using super critical fluid technology and suitable particle size distribution achieved.
• the particles in the formulation need to be within a desired particle size range such that the particles can be directly inhaled into the lungs using a suitable inhalation technique or introduced into the lungs via a mechanical ventilator.
• Pharmaceutically acceptable carriers which are inactive ingredients, can be selected by those skilled in the art using conventional criteria.
• Pharmaceutically acceptable carriers include, but are not limited to, non-aqueous based solutions, suspensions, emulsions, microemulsions, micellar solutions, gels, and ointments.
• the pharmaceutically acceptable carriers may also contain ingredients that include, but are not limited to, saline and aqueous electrolyte solutions; ionic and nonionic osmotic agents such as sodium chloride, potassium chloride, glycerol, and dextrose; pH adjusters and buffers such as salts of hydroxide, phosphate, citrate, acetate, borate; and trolamine; antioxidants such as salts, acids and/or bases of bisulfite, sulfite, metabisulfite, thiosulfite, ascorbic acid, acetyl cysteine, cysteine, glutathione, butylated hydroxyanisole, butylated hydroxytoluene, tocopherols, and ascorbyl palmitate; surfactants such as lecithin, phospholipids, including but not limited to
• methylcellulose and their salts petroleum derivatives such as mineral oil and white petrolatum; fats such as lanolin, peanut oil, palm oil, soybean oil; mono-, di-, and
• triglycerides polymers of acrylic acid such as carboxypolymethylene gel, and
• hydrophobically modified cross-linked acrylate copolymer comprising polysaccharides such as dextrans and glycosaminoglycans such as sodium hyaluronate.
• pharmaceutically acceptable carriers may be preserved against bacterial contamination using well-known preservatives, these include, but are not limited to, benzalkonium chloride, ethyl enediaminetetraacetic acid and its salts, benzethonium chloride, chlorhexidine, chlorobutanol, methylparaben, thimerosal, and phenylethyl alcohol, or may be formulated as a non-preserved formulation for either single or multiple use.
• a tablet formulation or a capsule formulation of the active compound may contain other excipients that have no bioactivity and no reaction with the active compound.
• Excipients of a tablet may include fillers, binders, lubricants and glidants, disintegrators, wetting agents, and release rate modifiers. Binders promote the adhesion of particles of the formulation and are important for a tablet formulation. Examples of binders include, but not limited to, carboxymethylcellulose, cellulose, ethyl cellulose, hydroxypropylmethylcellulose,
• methylcellulose karaya gum, starch, starch, and tragacanth gum, poly(acrylic acid), and polyvinylpyrrolidone.
• a patch formulation of the active compound may comprise some inactive ingredients such as 1,3-butylene glycol, dihydroxyaluminum aminoacetate, disodium edetate, D- sorbitol, gelatin, kaolin, methylparaben, polysorbate 80, povidone (polyvinylpyrrolidone), propylene glycol, propylparaben, sodium carboxymethylcellulose, sodium polyacrylate, tartaric acid, titanium dioxide, and purified water.
• a patch formulation may also contain skin permeability enhancer such as lactate esters (e.g., lauryl lactate) or diethylene glycol monoethyl ether.
• Topical formulations including the active compound can be in a form of gel, cream, lotion, liquid, emulsion, ointment, spray, solution, and suspension.
• the inactive ingredients in the topical formulations for example include, but not limited to, lauryl lactate
• emollient/permeation enhancer diethylene glycol monoethyl ether (emollient/permeation enhancer), DMSO (solubility enhancer), silicone elastomer (rheology/texture modifier), caprylic/capric triglyceride, (emollient), octisalate, (emollient/UV filter), silicone fluid
• emollient/diluent emollient/diluent
• squalene emollient
• sunflower oil emollient
• silicone dioxide thickening agent
• the present invention is directed to a method of treating Asthma.
• the method comprises the steps of first identifying a subject suffering from asthma or has a propensity to develop asthma, and administering to the subject the active compound dapansutrile, in an amount effective to treat asthma.
• “An effective amount,” as used herein, is the amount effective to treat asthma by ameliorating the pathological condition, reducing airway inflammation, reducing airway hyperresponsiveness, improving lung function, and/or reducing the symptoms of asthma. Any method for delivering the compound to the tissues of the lung, including local administration and systemic administration, is suitable for the present invention.
• Systemic administration includes oral, parenteral (such as intravenous, intramuscular, subcutaneous or rectal), and other systemic routes of administration.
• parenteral such as intravenous, intramuscular, subcutaneous or rectal
• other systemic routes of administration in systemic
• the active compound first reaches plasma and then distributes into target tissues.
• the active compound is delivered by local administration to the lung.
• Local administration includes inhalation and targeted drug delivery.
• Methods of inhalation include liquid instillation, instillation as a pressurized fluid preparation via metered dose inhaler or equivalent, inhalation of an aerosolized solution via nebulizer, inhalation of dry powder, and directing soluble or dried material into the air stream during mechanical ventilation.
• the pharmaceutical composition is administrated to a subject by inhalation of an aerosol suspension of respirable particles comprising the active compound.
• the respirable particles can be liquid or solid (e.g., dry powder), with a particle size sufficiently small to pass through the mouth and larynx upon inhalation; in general, particles ranging from about 1 to 10 microns, but more preferably 1-5 microns, in size are considered respirable.
• the surface concentrations of active compounds delivered via inhalation can vary according to compounds; but are generally lxlO 10 -lxlO 4 moles/liter, and preferably lxlO 8 - lxlO 5 moles/liter.
• the pharmaceutical composition is administrated orally to the subject.
• the dosage for oral administration is generally at least 0.1 mg/kg/day and less than 100 mg/kg/day or 200mg/kg/day.
• the dosage for oral administration is 1-100, or 5-50, or 10-50 mg/kg/day, for a human subject.
• the dosage for oral administration is 100-10,000 mg/day, and preferably 500-2000, 500-4000, 500-4000, 1000- 5000, 2000-5000, 2000-6000, or 2000-8000 mg/day for a human subject.
• the drug can be orally taken once, twice, three times, or four times a day.
• the pharmaceutical composition is administrated intravenously to the subject.
• the dosage for intravenous bolus injection or intravenous infusion is generally 0.03 to 20 and preferably 0.03 to 10 mg/kg/day.
• the pharmaceutical composition is administrated subcutaneously to the subject.
• the dosage for subcutaneous administration is generally 0.3-20, and preferably 0.3-3 mg/kg/day.
• Those of skill in the art will recognize that a wide variety of delivery mechanisms are also suitable for the present invention.
• the present invention is useful in treating a mammal subject, such as humans, horses, and dogs.
• the present invention is particularly useful in treating humans.
• a well-established mouse model of experimental allergic asthma (Sel 2008, Wegmann 2005, Wegmann 2007, Lunding 2015a) was used to evaluate dapansutrile as a therapeutic option in allergic bronchial asthma and to determine if dapansutrile would have an impact on airway inflammation and the development of airway hyperresponsiveness (AHR).
• AHR airway hyperresponsiveness
• Inflammation in this model is characterized by the infiltration of eosinophils as well as of TH2 cells and involves the subsequent development of AHR and mucus hyperproduction so that this model resembles the major pathophysiologic hallmarks of human bronchial asthma.
• mice were sensitized to OVA (ovalbumin) by three intraperitoneal (i.p.) injections of 10 pg OVA adsorbed to 150 mg aluminum hydroxide on days 1, 14, and 21.
• OVA ovalbuproin
• This sensitization results in an adoptive immune response against OVA with OVA-specific TH2 cells and the production of OVA-specific antibodies of the subclasses IgE and IgG4.
• mice were exposed three times to an OVA aerosol (1% w/v in PBS) on days 26, 27, and 28.
• OVA aerosol 1% w/v in PBS
• Healthy control animals were sham sensitized to PBS and
• Non-drug treated animals (asthmatic group) and drug-treated animals (treated group) were sensitized by OVA aerosol and subsequently challenged with OVA aerosol.
• the treatment group were treated with dapansutrile at 60 mg/kg at days 25, 26, 27, and 28 by intraperitoneal (i.p). injection, whereas the healthy group and the asthmatic group were administered with saline by intraperitoneal injection on days 25, 26, 27, and 28. Eight animals per group were used. All animals were sacrificed on day 29. The following readouts were measured according to Lunding, 2015b.
• BAL bronchoalveolar lavage
• inflammatory cell subpopulations eosinophils, macrophages, neutrophils, lymphocytes infiltrating the bronchoalveolar lumen were quantified using cyto-spinned and quick-diff-stained cells from bronchoalveolar lavage fluids (BALF). Further, inflammatory cell infiltration was recorded from hematoxylin and eosin (HE)-stained lung/airway cross-sections. AHR was assessed by recording airway resistance during a methacholine (MCh) provocation test in mice mechanically ventilated by a Buxco FinePoint RC unit.
• BALF bronchoalveolar lavage fluids
• Mucus hyperproduction was quantified in PAS (periodic acid-Schiff)-stained airway cross-sections undergoing systematic, uniform random sampling and subsequent stereologic analysis of mucus amount in the airways and mucus producing goblet cells in the airway mucosa.
• PAS peripheral acid-Schiff
• FIG. 1 shows total numbers of leukocyte subpopulations (macrophage, lymphocyte, neutrophil, and eosinophil, from left to right) on Day 29.
• Dapansutrile 60 mg/kg
• Dapansutrile 60 mg/kg
• three daily OVA aerosol challenges led to a significant reduction in eosinophils in BALF (FIG. 1). Comparing to asthmatic mice, treatment with dapansutrile resulted in an
• FIG. 2 shows that the number of inflammatory cells in lung tissue was significantly lower in asthmatic mice vs. dapansutrile-treated mice (**p ⁇ 0.01).
• the label on the y-axis reads "volume of inflammatory cell infiltrate per basal membrane area (prrrVpm 2 )"
• the inflammatory cells were counted within a specific distance around the airways using a microscope with the computer assisted stereological toolbox (CAST) system. These counts were set in ratio to the basal membrane to normalize within each microscopic slide to avoid slide-dependent differences.
• CAST computer assisted stereological toolbox
• FIG. 3 shows area of epithelial basal membrane covered by goblet cells in healthy, asthmatic, and treated mice. Comparing to asthmatic mice, Dapansutrile-treated animals displayed a significant reduction of goblet cells covering the airway mucosa (22.74% reduced to 17.67%, p ⁇ 0.01) as quantified by stereology of PAS-stained airway cross-sections.
• FIGs. 1-3 show that dapansutrile treatment in OVA-induced allergic airway inflammation model resulted in significant reduction of allergic airway inflammation and mucus production.
• Airway hyperresponsiveness was determined by measuring airway resistance on Day 29 in response to 100 mg/mL methacholine. The results are shown in FIG. 4.
• the airway resistance in response to methacholine was 5.61 cm FLO sec ml 1 in asthmatic mice and 3.93 cm FLO sec ml 1 in dapansutrile-treated mice. Dapansutrile treatment reduced airway resistance by about 60% when comparing with asthmatic mice. ****p ⁇ 0.0001 between asthmatic and treated mice. Baseline airway resistance of healthy animals was 2.83 cm FhO sec ml 1 .
• Cytometric bead arrays were used as a method to assess the concentration of cytokines of IFN-g, TNFa, IL-Ib, IL-4, IL-5, IL-6, IL-10, IL-13, and IL17A) in the BALF of Example 1.
• the beads in this array were coated with antibodies specific against a variety of cytokines, some relevant and known to be affected by NLRP3 signaling.
• the concentrations of all measured cytokines showed some reduction between asthmatic mice and dapansutrile-treated mice.
• Both IL-Ib and IL-6 concentration showed a statistically significant reduction between asthmatic mice and dapansutrile-treated mice (p ⁇ 0.001 and p ⁇ 0.05, respectively).
• Dapansutrile treatment oral) reduced allergic airway inflammation and airway resistance in mice
• mice model The experimental protocols of the mouse model were the same as those described in Example 1, except dapansutrile was administered orally by food.
• mice were fed ad libidum with food pellets containing 7.5 g/kg dapansutrile starting on day 22 for one week; the first aerosol challenge was on day 26.
• Mice typically consume about 4 g of food per day, resulting in an approximate daily dose of 0 mg/kg/day for control groups and 1,000 mg/kg/day for the treatment groups.
• This food pellet concentration (7.5g/kg of dapansutrile in food) in mouse chow resulted in a blood level nearly the same as that of humans treated orally with dapansutrile at doses of 1000 mg/day (40 pg/mL blood level; Marchetti 2018b)
• FIG. 6 shows that the number of inflammatory cells in lung tissue was significantly lower in asthmatic mice vs. dapansutrile-treated mice (p ⁇ 0.05).
• the label on the y-axis reads "volume of inflammatory cell infiltrate per basal membrane area (mhtUmhi 2 )".
• the inflammatory cells were counted within a specific distance around the airways using a microscope with the computer assisted stereological toolbox (CAST) system. These counts were set in ratio to the basal membrane to normalize within each microscopic slide to avoid slide-dependent differences.
• CAST computer assisted stereological toolbox
• Dapansutrile-treated mice Comparing to asthmatic mice, Dapansutrile-treated mice also displayed a prominent reduction of goblet cells covering the airway mucosa (-29%; 15.75% reduced to 11.16%), as quantified by stereology of P AS-stained airway cross-sections (data not shown).

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