Treatment of chronic cough, breathlessness and dyspnea

Abstract

The present invention relates to methods for treating patients with chronic cough with nalbuphine compositions as well as treating cough, breathlessness, or dyspnea associated with IPF with nalbuphine compositions, wherein the method provides a therapeutic effect in a patient.

1 - 77 . (canceled) 
     
     
         78 . A method of treating chronic cough in a patient in need thereof, the method comprising orally administering an effective amount of nalbuphine or a pharmaceutically acceptable salt or ester thereof to the patient. 
     
     
         79 . The method of  claim 78 , wherein the chronic cough is selected from refractory chronic cough, unexplained chronic cough, unexplained and refractory chronic cough, or cough hypersensitivity syndrome. 
     
     
         80 . The method of  claim 78 , wherein the chronic cough is refractory to treatment with tramadol. 
     
     
         81 . The method of  claim 78 , wherein the chronic cough is refractory chronic cough. 
     
     
         82 . The method of  claim 78 , wherein the patient in need of a treatment of chronic cough is a patient with a lung disease. 
     
     
         83 . The method of  claim 82 , wherein the lung disease is an interstitial lung disease. 
     
     
         84 . The method of  claim 83 , wherein the interstitial lung disease is selected from the group consisting of interstitial pneumonia, hypersensitivity pneumonitis, sarcoidosis, asbestosis, bronchiolitis obliterans, histiocytosis X, chronic eosinophilic pneumonia, collagen vascular disease, granulomatous vasculitis, Goodpasture's syndrome and, pulmonary alveolar proteinosis 
     
     
         85 . The method of  claim 82 , wherein the lung disease is a chronic obstructive pulmonary lung disease (COPD). 
     
     
         86 . The method of  claim 85 , wherein the COPD is associated with a condition selected from the group consisting of emphysema, chronic bronchitis and Alpha-1-antitrypsin (AAt) deficiency. 
     
     
         87 . The method of claim  8485  wherein the COPD is associated with an irritant selected from the group consisting of cigarette smoke, secondhand smoke, pipe smoke, air pollution and workplace exposure to dust, smoke or fumes. 
     
     
         89 . The method of  claim 78 , wherein the administration provides in the patient a mean AUCtau from about 40 nghr/mL to about 800 nghr/mL. 
     
     
         90 . The method of  claim 78 , wherein the administration provides in the patient a mean AUCtau from about 40 nghr/mL to about 200 nghr/mL. 
     
     
         91 . The method of  claim 78 , wherein the administration provides in the patient a mean Cmax of from about 5 ng/mL to about 85 ng/mL. 
     
     
         92 . The method of  claim 78 , wherein the administration provides in the patient a mean Cmax of from about 6.28 ng/mL to about 82.78 ng/mL. 
     
     
         93 . The method of  claim 78 , wherein a total daily dose of about 27 mg to about 324 mg of an Equivalent Amount of Nalbuphine Free Base is administered. 
     
     
         94 . The method of  claim 78 , wherein a total daily dose of about 324 mg of an Equivalent Amount of Nalbuphine Free Base is administered. 
     
     
         95 . The method of  claim 78 , wherein an Equivalent Amount of Nalbuphine Free Base of about 27 mg to about 162 mg is administered twice daily. 
     
     
         96 . The method of  claim 78 , wherein about 27 mg of the Equivalent Amount of Nalbuphine Free Base is administered once a day. 
     
     
         97 . The method of  claim 78 , wherein about 27 mg of the Equivalent Amount of Nalbuphine Free Base is administered twice a day. 
     
     
         98 . The method of  claim 78 , wherein about 54 mg of the Equivalent Amount of Nalbuphine Free Base is administered once a day. 
     
     
         99 . The method of  claim 78 , wherein about 54 mg of the Equivalent Amount of Nalbuphine Free Base is administered twice a day. 
     
     
         100 . The method of  claim 78 , wherein about 108 mg of the Equivalent Amount of Nalbuphine Free Base is administered once a day. 
     
     
         101 . The method of  claim 78 , wherein about 108 mg of the Equivalent Amount of Nalbuphine Free Base is administered twice a day. 
     
     
         102 . The method of  claim 78 , wherein about 162 mg of the Equivalent Amount of Nalbuphine Free Base is administered once a day. 
     
     
         103 . The method of  claim 78 , wherein about 162 mg of the Equivalent Amount of Nalbuphine Free Base thereof is administered twice a day. 
     
     
         104 . The method of  claim 78 , wherein the administering is for at least about 1 week. 
     
     
         105 . The method of  claim 78 , wherein the administering is for about 8 weeks, 10 weeks, 12 weeks, 24 weeks or 50 weeks. 
     
     
         106 . The method of  claim 78 , further comprising titrating the dose of nalbuphine or a pharmaceutically acceptable salt or ester thereof for at least one week until a steady state is achieved in the patient. 
     
     
         107 . The method of  claim 106 , wherein the titrating further comprises administering an initial dose of from about 14 mg to about 27 mg of the Equivalent Amount of Nalbuphine Free Base once a day, and then titrated to an effective dose. 
     
     
         108 . The method of  claim 106 , wherein the titrating further comprises administering an initial dose of about 27 mg of the Equivalent Amount of Nalbuphine Free Base once or twice a day. 
     
     
         109 . The method of  claim 106 , wherein the titrating comprises administering nalbuphine or a pharmaceutically acceptable salt or ester thereof in increments ranging from about 13 mg to about 54 mg of the Equivalent Amount of Nalbuphine Free Base. 
     
     
         110 . The method of  claim 106 , wherein the titrating comprises administering nalbuphine according to the dose schedule provided in the following table (expressed as Equivalent Amount of Nalbuphine Free Base): 
       
         
           
                 
                 
                 
                 
               
                     
                     
                 
                     
                   Day 
                   AM dosage (mg) 
                   PM dosage (mg) 
                 
                     
                     
                 
                     
                 
                 
                 
                 
                 
               
                     
                   Day 1 
                   0 
                   27 
                 
                     
                   Day 2 
                   0 
                   27 
                 
                     
                   Day 3 
                   27 
                   27 
                 
                     
                   Day 4 
                   27 
                   27 
                 
                     
                   Day 5 
                   27 
                   54 
                 
                     
                   Day 6 
                   54 
                   54 
                 
                     
                   Day 7 
                   54 
                   54 
                 
                     
                   Day 8 
                   54 
                   54 
                 
                     
                   Day 9 
                   54 
                   108 
                 
                     
                   Day 10 
                   90 
                   108 
                 
                     
                   Day 11 
                   90 
                   108 
                 
                     
                   Day 12 
                   108 
                   108 
                 
                     
                   Day 13 
                   108 
                   108 
                 
                     
                   Day 14 
                   108 
                   108 
                 
                     
                   Day 15 
                   108 
                   108 
                 
                     
                   Day 16 
                   108 
                   162 
                 
                     
                   Day 17 
                   162 
                   162 
                 
                     
                     
                 
             
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         111 . The method of  claim 78 , wherein after the treating the patient experiences a reduction of cough that is characterized by at least a 30% reduction in daytime cough frequency measured using a cough count monitor device compared to prior to the treating. 
     
     
         112 . The method of  claim 78 , wherein after the treating the patient experiences a reduction of cough that is characterized by at least a 50% reduction in daytime cough frequency measured using a cough count monitor device compared to prior to the treating. 
     
     
         113 . The method of  claim 78 , wherein after the treating the patient experiences a reduction of cough severity that is characterized by at least a one point reduction in Numerical Rating Scale cough (NRS) value compared to prior to the treating. 
     
     
         114 . The method of  claim 78 , wherein after the treating the patient experiences a reduction of cough that is characterized by at least a 1.0 point reduction in the EXACT-Respiratory Symptoms (ERS -cough subscale score compared to prior to the treating. 
     
     
         115 . The method of  claim 78 , wherein after the treating the patient experiences a reduction of cough that is characterized by at least a 1.0 point reduction in the EXACT-Respiratory Symptoms (E-RSTm) chest symptoms subscale score compared to prior to the treating. 
     
     
         116 . The method of  claim 78 , wherein the nalbuphine or a pharmaceutically acceptable salt or ester thereof is nalbuphine hydrochloride. 
     
     
         117 . The method of  claim 78 , wherein the nalbuphine or a pharmaceutically acceptable salt or ester thereof is in the form of an extended release oral dosage form. 
     
     
         118 . The method of  claim 78 , wherein the nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered in a formulation comprising nalbuphine hydrochloride, mannitol, hydroxypropyl cellulose, locust bean gum, xanthan gum, calcium sulfate dihydrate, fumaric acid and magnesium stearate. 
     
     
         119 . The method of  claim 78 , wherein the nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered in combination with one or more therapeutic agents selected from nintedanib and pirfenidone. 
     
     
         120 . The method of  claim 78 , wherein the cough associated with a condition is asthma, gastroesophageal reflux disease (GERD)/esophageal irritation from other causes, upper airway disease or postnasal drip. 
     
     
         121 . The method of  claim 78 , wherein after the treating the patient experiences a reduction of cough that is characterized by at least a 70% reduction in daytime cough frequency measured using a cough count monitor device compared to prior to the treating. 
     
     
         122 . The method of  claim 106 , wherein titrating comprises administering ascending doses of nalbuphine or a pharmaceutically acceptable salt thereof until an effective dose is achieved, wherein the effective dose is between about 27 mg once daily to about 324 mg of the Equivalent Amount of Nalbuphine Free Base daily. 
     
     
         123 . The method of  claim 122 , wherein titrating comprises administering ascending doses of nalbuphine or a pharmaceutically acceptable salt thereof in increments of about 27 mg or about 54 mg of the Equivalent Amount of Nalbuphine Free Base. 
     
     
         124 . The method of  claim 123 , wherein the effective dose is a total daily dose of about 27 mg, about 54 mg, about 81 mg, about 109 mg, about 163 mg, about 217 mg, or about 327 mg of the Equivalent Amount of Nalbuphine Free Base. 
     
     
         125 . The method of  claim 78 , wherein after the treating the patient experiences a reduction of cough that is characterized by at least a 30% reduction in 24-hour cough frequency measured using a cough count monitor device compared to prior to the treating. 
     
     
         126 . The method of  claim 78 , wherein after the treating the patient experiences a reduction of cough that is characterized by at least a 50% reduction in 24-hour cough frequency measured using cough count monitor device compared to prior to the treating. 
     
     
         127 . The method of  claim 78 , wherein after the treating the patient experiences a reduction of cough that is characterized by at least a 70% reduction in 24-hour cough frequency measured using a cough count monitor device compared to prior to the treating. 128. (New) The method of  claim 117 , wherein the extended release oral dosage form comprises a pharmaceutical diluent, a hydrophilic compound and a cross-linking agent. 
     
     
         129 . The method of  claim 117 , wherein the extended release oral dosage form comprises about 8% to about 30% by weight of a hydrophilic compound and about 5% to about 20% by weight of a cross-linking agent. 
     
     
         130 . The method of  claim 129 , wherein the cross-linking agent is calcium sulfate dihydrate. 
     
     
         131 . The method of  claim 129 , wherein the hydrophilic compound is locust bean gum, xanthan gum, or a mixture thereof 
     
     
         132 . The method of  claim 117 , wherein the extended release oral dosage form comprises nalbuphine hydrochloride, mannitol, hydroxypropyl cellulose, locust bean gum, xanthan gum, calcium sulfate dihydrate, and magnesium stearate. 
     
     
         133 . The method of  claim 117 , wherein the extended release oral dosage form comprises about 15% to about 25% by weight of locust bean gum, about 10% to about 20% by weight of xanthan gum, about 50% to about 85% by weight of mannitol and about 5% to 15% by weight of calcium sulfate dihydrate.