Formoterol/steroid bronchodilating compositions and methods of use thereof

Abstract

Bronchodilating compositions and methods are provided. The compositions are intended for administration as a nebulized aerosol. In certain embodiments, the compositions contain formoterol, or a derivative thereof, and a steroidal anti-inflammatory agent. Methods for treatment, prevention, or amelioration of one or more symptoms of bronchoconstrictive disorders using the compositions provided herein are also provided.

What is claimed is:  
     
         1 . A method for the treatment, prevention, or amelioration of one or more symptoms of bronchoconstrictive disorders, comprising administering to a subject in need of such treatment an effective amount of a pharmaceutical composition comprising (i) formoterol, or a derivative thereof; and (ii) a steroidal anti-inflammatory agent, or a derivative thereof; 
 in a pharmacologically suitable fluid, wherein the composition is stable during long term storage and the fluid comprises water.    
     
     
         2 . The method of  claim 1 , wherein the composition has an estimated shelf-life of greater than 1 month usage time at 25° C. and greater than or equal to 1 year storage time at 5° C.  
     
     
         3 . The method of  claim 2 , wherein greater than about 80% of the initial formoterol is present in the composition after 1 month usage time at 25° C. and 1 year storage time at 5° C.  
     
     
         4 . The method of  claim 1 , wherein the pharmacologically suitable fluid comprises a polar solvent.  
     
     
         5 . The method of  claim 4 , wherein the polar solvent is a protic solvent.  
     
     
         6 . The method of  claim 5 , wherein the composition further comprises a tonicity adjusting agent.  
     
     
         7 . The method of  claim 6 , wherein the tonicity adjusting agent is ammonium carbonate, ammonium chloride, ammonium lactate, ammonium nitrate, ammonium phosphate, ammonium sulfate, ascorbic acid, bismuth sodium tartrate, boric acid, calcium chloride, calcium disodium edetate, calcium gluconate, calcium lactate, citric acid, dextrose, diethanolamine, dimethylsulfoxide, edetate disodium, edetate trisodium monohydrate, fluorescein sodium, fructose, galactose, glycerin, lactic acid, lactose, magnesium chloride, magnesium sulfate, mannitol, polyethylene glycol, potassium acetate, potassium chlorate, potassium chloride, potassium iodide, potassium nitrate, potassium phosphate, potassium sulfate, proplyene glycol, silver nitrate, sodium acetate, sodium bicarbonate, sodium biphosphate, sodium bisulfite, sodium borate, sodium bromide, sodium cacodylate, sodium carbonate, sodium chloride, sodium citrate, sodium iodide, sodium lactate, sodium metabisulfite, sodium nitrate, sodium nitrite, sodium phosphate, sodium propionate, sodium succinate, sodium sulfate, sodium sulfite, sodium tartrate, sodium thiosulfate, sorbitol, sucrose, tartaric acid, triethanolamine, urea, urethan, uridine or zinc sulfate.  
     
     
         8 . The method of  claim 7 , wherein the tonicity adjusting agent is sodium chloride.  
     
     
         9 . The method of  claim 1 , wherein the pharmacologically suitable fluid comprises a buffer.  
     
     
         10 . The method of  claim 9 , wherein the buffer is citric acid/phosphate, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, Mcllvaine, phosphate, Prideaux-Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagen), veronal acetate, MES (2-(N-morpholino)ethanesulfonic acid), BIS-TRIS (bis(2-hydroxyethyl)iminotris(hydroxymethyl)methane), ADA (N-(2-acetamido)-2-iminodiacetic acid), ACES (N-(carbamoylmethyl)-2-aminoethanesulfonaic acid), PIPES (piperazine-N,N′-bis(2-ethanesulfonic acid)), MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid), BIS-TRIS PROPANE (1,3-bis(tris(hydroxymethyl)methylamino)propane), BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonaic acid), MOPS (3-(N-morpholino)propanesulfonic acid), TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES (N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid), DIPSO (3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonic acid), MOBS (4-(N-morpholino)butanesulfonic acid), TAPSO (3-(N-tris(hydroxymethyl)methylamino)-2-hydroxy-propanesulfonic acid), tris(hydroxymethylaminomethane, HEPPSO (N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonicacid), POPSO (piperazine-N,N′-bis(2-hydroxypropanesulfonicacid)), TEA (triethanolamine), EPPS (N-(2-hydroxyethyl)piperazine-N′-(3-propane-sulfonic acid), TRICINE (N-tris(hydroxymethyl)methylglycine), GLY-GLY (glycylglycine), BICINE (N,N-bis(2-hydroxyethyl)glycine), HEPBS (N-(2-hydroxyethyl)piperazine-N′-(4-butanesulfonic acid)), TAPS (N-tris(hydroxy-methyl)methyl-3-aminopropanesulfonic acid), or AMPD (2-amino-2-methyl-1,3-propanediol) buffer.  
     
     
         11 . The method of  claim 10 , wherein the buffer is citrate buffer.  
     
     
         12 . The method of  claim 11 , wherein the buffer concentration is from about 0.01 mM to about 150 mM.  
     
     
         13 . The method of  claim 12 , wherein the buffer concentration is from about 1 mM to about 20 mM.  
     
     
         14 . The method of  claim 13 , wherein the buffer concentration is about 5 mM.  
     
     
         15 . The method of  claim 7 , wherein the ionic strength of the composition is about 0 to about 0.4.  
     
     
         16 . The method of  claim 15 , wherein the ionic strength of the composition is about 0.05 to about 0.16.  
     
     
         17 . The method of  claim 1 , wherein the pH of the composition is about 2.0 to about 8.0.  
     
     
         18 . The method of  claim 17 , wherein the pH of the composition is about 4.0 to about 6.0.  
     
     
         19 . The method of  claim 18 , wherein the pH of the composition is about 4.5 to about 5.5.  
     
     
         20 . The method of  claim 19 , wherein the pH of the composition is about 5.0.  
     
     
         21 . The method of  claim 1 , wherein the formoterol free base concentration in the composition is about 5 μg/mL to about 2 mg/mL.  
     
     
         22 . The method of  claim 21 , wherein the formoterol free base concentration in the composition is about 10 μg/mL to about 1 mg/mL.  
     
     
         23 . The method of  claim 22 , wherein the formoterol free base concentration in the composition is about 50 μg/mL to about 200 μg/mL.  
     
     
         24 . The method of  claim 23 , wherein the formoterol free base concentration in the composition is about 59 μg/mL.  
     
     
         25 . The method of  claim 23 , wherein the formoterol free base concentration in the composition is about 118 μg/mL.  
     
     
         26 . The method of  claim 7 , wherein the composition further comprises a buffer.  
     
     
         27 . The method of  claim 26 , wherein the buffer is citric acid/phosphate, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, Mcllvaine, phosphate, Prideaux-Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagen), veronal acetate, MES (2-(N-morpholino)ethanesulfonic acid), BIS-TRIS (bis(2-hydroxyethyl)iminotris(hydroxymethyl)methane), ADA (N-(2-acetamido)-2-iminodiacetic acid), ACES (N-(carbamoylmethyl)-2-aminoethanesulfonaic acid), PIPES (piperazine-N,N′-bis(2-ethanesulfonic acid)), MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonicacid), BIS-TRIS PROPANE (1,3-bis(tris(hydroxymethyl)methylamino)propane), BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonaic acid), MOPS (3-(N-morpholino)propanesulfonic acid), TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES (N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid), DIPSO (3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonic acid), MOBS (4-(N-morpholino)butanesulfonic acid), TAPSO (3-(N-tris(hydroxymethyl)methylamino)-2-hydroxy-propanesulfonic acid), tris(hydroxymethylaminomethane, HEPPSO (N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonicacid), POPSO (piperazine-N,N′-bis(2-hydroxypropanesulfonic acid)), TEA (triethanolamine), EPPS (N-(2-hydroxyethyl)piperazine-N′-(3-propane-sulfonic acid), TRICINE (N-tris(hydroxymethyl)methylglycine), GLY-GLY (glycylglycine), BICINE (N,N-bis(2-hydroxyethyl)glycine), HEPBS (N-(2-hydroxyethyl)piperazine-N′-(4-butanesulfonic acid)), TAPS (N-tris(hydroxy-methyl)methyl-3-aminopropanesulfonic acid), or AMPD (2-amino-2-methyl-1,3-propanediol) buffer.  
     
     
         28 . The method of  claim 27 , wherein the buffer is citrate buffer.  
     
     
         29 . The method of  claim 28 , wherein the buffer concentration is from about 0.01 mM to about 150 mM.  
     
     
         30 . The method of  claim 29 , wherein the buffer concentration is from about 1 mM to about 20 mM.  
     
     
         31 . The method of  claim 30 , wherein the buffer concentration is about 5 mM.  
     
     
         32 . The method of  claim 26 , wherein the ionic strength of the composition is about 0 to about 0.4.  
     
     
         33 . The method of  claim 31 , wherein the ionic strength of the composition is about 0.05 to about 0.16.  
     
     
         34 . The method of  claim 26 , wherein the pH of the composition is about 2.0 to about 8.0.  
     
     
         35 . The method of  claim 34 , wherein the pH of the composition is about 4.0 to about 6.0.  
     
     
         36 . The method of  claim 35 , wherein the pH of the composition is about 4.5 to about 5.5.  
     
     
         37 . The method of  claim 36 , wherein the pH of the composition is about 5.0.  
     
     
         38 . The method of  claim 26 , wherein the formoterol free base concentration in the composition is about 5 μg/mL to about 2 mg/mL.  
     
     
         39 . The method of  claim 38 , wherein the formoterol free base concentration in the composition is about 10 μg/mL to about 1 mg/mL.  
     
     
         40 . The method of  claim 39 , wherein the formoterol free base concentration in the composition is about 50 μg/mL to about 200 μg/mL.  
     
     
         41 . The method of  claim 40 , wherein the formoterol free base concentration in the composition is about 59 μg/mL.  
     
     
         42 . The method of  claim 40 , wherein the formoterol free base concentration in the composition is about 118 μg/mL.  
     
     
         43 . The method of  claim 41 , wherein the buffer is citrate buffer.  
     
     
         44 . The method of  claim 41 , wherein the buffer concentration is about 5 mM.  
     
     
         45 . The method of  claim 41 , wherein the ionic strength of the composition is about 0.05 to about 0.16.  
     
     
         46 . The method of  claim 41 , wherein the pH of the composition is about 5.0.  
     
     
         47 . The method of  claim 41 , wherein the buffer is citrate buffer; the buffer concentration is about 5 mM; the ionic strength of the composition is about 0.05 to about 0.16; and the pH of the composition is about 5.0.  
     
     
         48 . The method of  claim 42 , wherein the buffer is citrate buffer.  
     
     
         49 . The method of  claim 42 , wherein the buffer concentration is about 5 mM.  
     
     
         50 . The method of  claim 42 , wherein the ionic strength of the composition is about 0.05 to about 0.16.  
     
     
         51 . The method of  claim 42 , wherein the pH of the composition is about 5.0.  
     
     
         52 . The method of  claim 42 , wherein the buffer is citrate buffer; the buffer concentration is about 5 mM; the ionic strength of the composition is about 0.05 to about 0.16; and the pH of the composition is about 5.0.  
     
     
         53 . The method of  claim 10 , wherein the buffer comprises citric acid/phosphate buffer, acetate buffer, citrate buffer or phosphate buffer.  
     
     
         54 . The method of  claim 26 , wherein the buffer comprises citric acid/phosphate buffer, acetate buffer, citrate buffer or phosphate buffer.  
     
     
         55 . The method of  claim 1 , wherein the steroidal anti-inflammatory agent is beclomethasone dipropionate (BDP), beclomethasone monopropionate (BMP), flunisolide, triamcinolone acetonide, dexamethasone, tipredane, ciclesonid, rofleponide, mometasone, mometasone furoate, RPR 106541, fluticasone or fluticasone propionate or budesonide, or a derivative thereof.  
     
     
         56 . The method of  claim 55 , wherein the steroidal anti-inflammatory agent is budesonide or fluticasone propionate, or a derivative thereof.  
     
     
         57 . The method of  claim 56 , wherein the steroidal anti-inflammatory agent is budesonide, or a derivative thereof.  
     
     
         58 . The method of  claim 57 , wherein the budesonide concentration in the composition is about 5 μg/mL to about 2 mg/mL.  
     
     
         59 . The method of  claim 57 , wherein the budesonide concentration in the composition is about 75 μg/mL to about 500 μg/mL.  
     
     
         60 . The method of  claim 57 , wherein the budesonide concentration in the composition is about 125 μg/mL or about 250 μg/mL.  
     
     
         61 . The method of  claim 56 , wherein the steroidal anti-inflammatory agent is fluticasone propionate.  
     
     
         62 . The method of  claim 61 , wherein the concentration of fluticasone propionate in the composition is about 5 μg/mL to about 2 mg/mL.  
     
     
         63 . The method of  claim 62 , wherein the concentration of fluticasone propionate in the composition is about 75 μg/mL to about 1000 μg/mL.  
     
     
         64 . The method of  claim 63 , wherein the concentration of fluticasone propionate in the composition is about 125 μg/mL or about 250 μg/mL.  
     
     
         65 . The method of  claim 47 , wherein the steroidal anti-inflammatory agent is budesonide or fluticasone propionate.  
     
     
         66 . The method of  claim 52 , wherein the steroidal anti-inflammatory agent is budesonide or fluticasone propionate.  
     
     
         67 . The method of  claim 1 , wherein the composition is a solution.  
     
     
         68 . The method of  claim 1 , wherein the composition is a suspension.  
     
     
         69 . The method of  claim 12 , wherein the buffer concentration is from about 1 mM to about 50 mM.  
     
     
         70 . The method of  claim 69 , wherein the buffer concentration is about 20 mM.  
     
     
         71 . The method of  claim 29 , wherein the buffer concentration is from about 1 mM to about 50 mM.  
     
     
         72 . The method of  claim 71 , wherein the buffer concentration is about 20 mM.  
     
     
         73 . The method of  claim 41 , wherein the buffer concentration is about 20 mM.  
     
     
         74 . The method of  claim 41 , wherein the buffer is citrate buffer; the buffer concentration is about 20 mM; the ionic strength of the composition is about 0.05 to about 0.16; and the pH of the composition is about 5.0.  
     
     
         75 . The method of  claim 42 , wherein the buffer concentration is about 20 mM.  
     
     
         76 . The method of  claim 42 , wherein the buffer is citrate buffer; the buffer concentration is about 20 mM; the ionic strength of the composition is about 0.05 to about 0.16; and the pH of the composition is about 5.0.  
     
     
         77 . The method of  claim 1 , wherein the composition further comprises an anticholinergic agent.  
     
     
         78 . The method of  claim 77 , wherein the anticholinergic agent is ipratropium bromide, oxitropium bromide, atropine methyl nitrate, tiotropium bromide or glycopyrronium bromide.  
     
     
         79 . The method of  claim 78 , wherein the anticholinergic agent is ipratropium bromide.  
     
     
         80 . The method of  claim 79 , wherein the ipratropium bromide concentration in the composition is about 5 μg/mL to about 5 mg/mL.  
     
     
         81 . The method of  claim 78 , wherein the anticholinergic agent is tiotropium bromide.  
     
     
         82 . The method of  claim 79 , wherein the tiotropium bromide concentration in the composition is about 5 μg/mL to about 5 mg/mL.  
     
     
         83 . The method of  claim 1 , further comprising administering one or more of (a) to (j) as follows: (a) a β 2 -adrenoreceptor agonist; (b) a dopamine (D 2 ) receptor agonist; (c) an IL-5 inhibitor; (d) an antisense modulator of IL-5; (e) a tryptase inhibitor; (f) a tachykinin receptor antagonist; (g) milrinone or milrinone lactate; (h) a leukotriene receptor antagonist; (i) a 5-lypoxygenase inhibitor; or (j) an anti-IgE antibody; simultaneously with, prior to or subsequent to the formoterol/steroidal anti-inflammatory agent composition.  
     
     
         84 . The method of  claim 65 , further comprising administering one or more of (a) to (j) as follows: (a) a β 2 -adrenoreceptor agonist; (b) a dopamine (D 2 ) receptor agonist; (c) an IL-5 inhibitor; (d) an antisense modulator of IL-5; (e) a tryptase inhibitor; (f) a tachykinin receptor antagonist; (g) milrinone or milrinone lactate; (h) a leukotriene receptor antagonist; (i) a 5-lypoxygenase inhibitor; or (j) an anti-IgE antibody; simultaneously with, prior to or subsequent to the formoterol/steroidal anti-inflammatory agent composition.  
     
     
         85 . The method of  claim 66 , further comprising administering one or more of (a) to (j) as follows: (a) a β 2 -adrenoreceptor agonist; (b) a dopamine (D 2 ) receptor agonist; (c) an IL-5 inhibitor; (d) an antisense modulator of IL-5; (e) a tryptase inhibitor; (f) a tachykinin receptor antagonist; (g) milrinone or milrinone lactate; (h) a leukotriene receptor antagonist; (i) a 5-lypoxygenase inhibitor; or (j) an anti-IgE antibody; simultaneously with, prior to or subsequent to the formoterol/steroidal anti-inflammatory agent composition.  
     
     
         86 . A method for the treatment, prevention, or amelioration of one or more symptoms of bronchoconstrictive disorders, comprising: 
 (i) administering an effective amount of a pharmaceutical composition comprising formoterol, or a derivative thereof, in a pharmacologically suitable fluid, wherein the composition is stable during long term storage and the fluid comprises water; and    (ii) simultaneously with, prior to, or subsequent to administerin the formoterol composition, administering an effective amount of a pharmaceutical composition comprising a steroidal anti-inflammatory agent in a pharmacologically acceptable carrier.    
     
     
         87 . The method of  claim 86 , wherein the steroidal anti-inflammatory agent is beclomethasone dipropionate (BDP), beclomethasone monopropionate (BMP), flunisolide, triamcinolone acetonide, dexamethasone, tipredane, ciclesonid, rofleponide, mometasone, mometasone furoate, RPR 106541, fluticasone or fluticasone propionate or budesonide, or a derivative thereof.  
     
     
         88 . The method of  claim 87 , wherein the steroidal anti-inflammatory agent is fluticasone propionate or budesonide, or a derivative thereof.  
     
     
         89 . The method of  claim 87 , wherein the steroidal anti-inflammatory agent is budesonide, or a derivative thereof.  
     
     
         90 . The method of  claim 87 , wherein the steroidal anti-inflammatory agent is fluticasone propionate, or a derivative thereof.  
     
     
         91 . The method of  claim 1 , wherein the bronchoconstrictive disorder is asthma, bronchial asthma, allergic asthma, intrinsic asthma, late asthma, airway hyper-responsiveness, chronic obstructive pulmonary diseases (COPDs), COPD associated with cigarette smoking, COPD associated with infections, COPD associated with environmental pollution, COPD associated with occupational dust exposure, chronic bronchitis, emphysema, cor pulmonale associated with pulmonary hypertension, cor pulmonale associated with right ventricular hypertrophy, or cor pulmonale associated with right heart failure.  
     
     
         92 . The method of  claim 41 , wherein the bronchoconstrictive disorder is asthma, bronchial asthma, allergic asthma, intrinsic asthma, late asthma, airway hyper-responsiveness, chronic obstructive pulmonary diseases (COPDs), COPD associated with cigarette smoking, COPD associated with infections, COPD associated with environmental pollution, COPD associated with occupational dust exposure, chronic bronchitis, emphysema, cor pulmonale associated with pulmonary hypertension, cor pulmonale associated with right ventricular hypertrophy, or cor pulmonale associated with right heart failure.  
     
     
         93 . The method of  claim 42 , wherein the bronchoconstrictive disorder is asthma, bronchial asthma, allergic asthma, intrinsic asthma, late asthma, airway hyper-responsiveness, chronic obstructive pulmonary diseases (COPDs), COPD associated with cigarette smoking, COPD associated with infections, COPD associated with environmental pollution, COPD associated with occupational dust exposure, chronic bronchitis, emphysema, cor pulmonale associated with pulmonary hypertension, cor pulmonale associated with right ventricular hypertrophy, or cor pulmonale associated with right heart failure.