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.

What is claimed is: 
     
         1 . A method of treating idiopathic pulmonary fibrosis (IPF) cough, breathlessness or dyspnea comprising orally administering an effective amount of nalbuphine or a pharmaceutically acceptable salt or ester thereof to a patient in need of such treatment. 
     
     
         2 . The method of  claim 1 , wherein prior to said treatment the patient's daytime cough severity is at least 4 on the Cough Severity Numerical Rating scale. 
     
     
         3 . The method of  claim 1 , wherein prior to said treatment the patient's daytime average cough count is at least 15 per hour measured using a cough count monitor device. 
     
     
         4 . The method of  claim 1 , wherein the IPF cough is chronic cough. 
     
     
         5 . The method of  claim 1 , wherein the IPF cough is refractory chronic cough. 
     
     
         6 . The method of  claim 1 , wherein the IPF cough is refractory to treatment with an antitussive agent selected from gefapixant, serlopitant, and orvepitant. 
     
     
         7 . The method of  claim 1 , wherein the IPF cough, breathlessness, or dyspnea is refractory to treatment with μ-opioid agonists. 
     
     
         8 . The method of  claim 1 , wherein the IPF cough is refractory to treatment with pirfenidone. 
     
     
         9 . The method of  claim 1 , wherein the IPF cough, breathlessness, or dyspnea is refractory to treatment with nintedanib. 
     
     
         10 . The method of  claim 1 , wherein the IPF cough is refractory to treatment with thalidomide. 
     
     
         11 . The method of  claim 1 , wherein the IPF cough is refractory to treatment with cromolyn sodium. 
     
     
         12 . The method of  claim 1 , wherein the patient is also treated for a disease selected from the group consisting of pulmonary hypertension, obstructive sleep apnea, lung cancer, COPD/emphysema, ischemic heart disease and GERD. 
     
     
         13 . A method of treating chronic cough comprising orally administering an effective amount of nalbuphine or a pharmaceutically acceptable salt or ester thereof to a patient in need of such treatment. 
     
     
         14 . The method of  claim 13 , wherein the chronic cough is selected from refractory chronic cough, unexplained chronic cough, unexplained and refractory chronic cough. 
     
     
         15 . The method of  claim 14 , wherein the chronic cough is refractory to treatment with tramadol. 
     
     
         16 . The method of  claim 13 , wherein the patient in need of a treatment of chronic cough is a patient without a lung disease. 
     
     
         17 . The method of  claim 13 , wherein the patient in need of a treatment of chronic cough is a patient with a lung disease. 
     
     
         18 . The method of  claim 17 , wherein the lung disease is an interstitial lung disease. 
     
     
         19 . The method of  claim 18 , wherein the interstitial lung disease is selected from the group consisting of hypersensitivity pneumonitis, sarcoidosis, asbestosis, bronchiolitis obliterans, histiocytosis X, chronic eosinophilic pneumonia, collagen vascular disease, granulomatous vasculitis, Goodpasture's syndrome and, pulmonary alveolar proteinosis 
     
     
         20 . The method of  claim 17 , wherein the lung disease is a chronic obstructive pulmonary lung disease (COPD). 
     
     
         21 . The method of  claim 20 , wherein the COPD is associated with a condition selected from the group consisting of emphysema, chronic bronchitis and Alpha-1-antitrypsin (AAt) deficiency. 
     
     
         22 . The method of  claim 20 , 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. 
     
     
         23 . A method of treating cough hypersensitivity disorder comprising orally administering an effective amount of nalbuphine or a pharmaceutically acceptable salt or ester thereof to a patient in need of such treatment. 
     
     
         24 . The method of any one of  claim 1 ,  13  or  23 , wherein about 14 mg of the Equivalent Amount of Nalbuphine Free Base is administered once a day. 
     
     
         25 . The method of any one of  claim 1 ,  13  or  23 , wherein about 14 mg of the Equivalent Amount of Nalbuphine Free Base is administered twice a day. 
     
     
         26 . The method of any one of  claim 1 ,  13  or  23 , wherein about 27 mg of the Equivalent Amount of Nalbuphine Free Base is administered once a day. 
     
     
         27 . The method of any one of  claim 1 ,  13  or  23 , wherein about 27 mg of the Equivalent Amount of Nalbuphine Free Base is administered twice a day. 
     
     
         28 . The method of any one of  claim 1 ,  13  or  23 , wherein about 54 mg of the Equivalent Amount of Nalbuphine Free Base is administered once a day. 
     
     
         29 . The method of any one of  claim 1 ,  13  or  23 , wherein about 54 mg of the Equivalent Amount of Nalbuphine Free Base is administered twice a day. 
     
     
         30 . The method of any one of  claim 1 ,  13  or  23 , wherein about 81 mg of the Equivalent Amount of Nalbuphine Free Base is administered once a day. 
     
     
         31 . The method of any one of  claim 1 ,  13  or  23 , wherein about 81 mg of the Equivalent Amount of Nalbuphine Free Base is administered twice a day. 
     
     
         32 . The method of any one of  claim 1 ,  13  or  23 , wherein about 108 mg of the Equivalent Amount of Nalbuphine Free Base is administered once a day. 
     
     
         33 . The method of any one of  claim 1 ,  13  or  23 , wherein about 108 mg of the Equivalent Amount of Nalbuphine Free Base is administered twice a day. 
     
     
         34 . The method of any one of  claim 1 ,  13  or  23 , wherein about 162 mg of the Equivalent Amount of Nalbuphine Free Base is administered once a day. 
     
     
         35 . The method of any one of  claim 1 ,  13  or  23 , wherein about 162 mg of the Equivalent Amount of Nalbuphine Free Base thereof is administered twice a day. 
     
     
         36 . The method of any one of  claim 1 ,  13  or  23 , wherein about 324 mg of the Equivalent Amount of Nalbuphine Free Base is administered once a day. 
     
     
         37 . The method of any one of  claim 1 ,  13  or  23 , wherein said administering is for about 8 weeks, 10 weeks, 12 weeks, 24 weeks or 50 weeks. 
     
     
         38 . The method of any one of  claim 1 ,  13  or  23 , wherein said administering is for at least about 1 week. 
     
     
         39 . The method of  claim 1 , 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. 
     
     
         40 . The method of any one of  claim 1 ,  13  or  23 , further comprising titrating the dose of nalbuphine or a pharmaceutically acceptable salt or ester thereof for about 2 weeks until a steady state is achieved in the patient. 
     
     
         41 . The method of any one of  claim 1 ,  13  or  23 , further comprising titrating the dose of nalbuphine or a pharmaceutically acceptable salt or ester thereof for about 7 to 30 days until a steady state is achieved in the patient. 
     
     
         42 . The method of any one of  claim 1 ,  13  or  23 , further comprising titrating the dose of the nalbuphine or a pharmaceutically acceptable salt or ester thereof for about 14 to 20 days until a steady state is achieved in the patient. 
     
     
         43 . The method of  claim 39 , wherein said titrating comprises administering ascending doses of nalbuphine or a pharmaceutically acceptable salt or ester thereof until a steady state is achieved in the patient. 
     
     
         44 . The method of  claim 39 , wherein said titrating comprises administering ascending doses of nalbuphine or a pharmaceutically acceptable salt or ester thereof until an effective amount of 27 mg or 324 mg is achieved in the patient. 
     
     
         45 . The method of  claim 39 , wherein said titrating further comprises administering an initial dose of about 27 mg once or twice a day. 
     
     
         46 . The method of  claim 39 , wherein said titrating comprises administering nalbuphine or a pharmaceutically acceptable salt or ester thereof in increments ranging from about 13 mg to about 54 mg. 
     
     
         47 . The method of  claim 39 , wherein said 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 
                 
                     
                     
                 
             
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         48 . The method of any one of  claim 1 ,  13  or  23 , wherein after said treating the patient experiences a substantial reduction in cough compared to prior to said treating. 
     
     
         49 . The method of any one of  claim 1 ,  13  or  23 , wherein after said treating the patient experiences a reduction of cough that is characterized by an at least 1.3 point decline in the total score on the patient's Leicester Cough Questionnaire score. 
     
     
         50 . The method of any one of  claim 1 ,  13  or  23 , wherein after said treating the patient experiences a reduction of cough that is characterized by at least a 30% reduction in daytime cough frequency measured using cough count monitor device. 
     
     
         51 . The method of any one of  claim 1 ,  13  or  23 , wherein after said treating the patient experiences a reduction of cough severity that is characterized by at least a three point reduction in Numerical Rating Scale cough (NRS) value. 
     
     
         52 . The method of any one of  claim 1 ,  13  or  23 , wherein after said treating the patient experiences a reduction in cough that is characterized by at least a 4 point improvement in cough quality of life questionnaire (CQLQ) total value. 
     
     
         53 . The method of any one of  claim 1 ,  13  or  23 , wherein after said treating the patient experiences a reduction of cough that is characterized by at least a 5 point reduction in the patient's St. George's Questionnaire for the IPF population (SGRQ-I) total score. 
     
     
         54 . The method of  claim 1 , wherein after said treating the patient experiences a reduction of cough that is characterized by at least a one point reduction in each of the components of the patient's St. George's Questionnaire (SGRQ-I) score. 
     
     
         55 . The method of any one of  claim 1 ,  13  or  23 , wherein after said 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-RS™) cough subscale score. 
     
     
         56 . The method of any one of  claim 1 ,  13  or  23 , wherein after said 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-RS™) chest symptoms subscale score. 
     
     
         57 . The method of  claim 1 , wherein after said treating the patient experiences a substantial reduction in breathlessness compared to prior to said treating. 
     
     
         58 . The method of  claim 1 , wherein after said treating the patient experiences a reduction of breathlessness that is characterized by at least a 1.0 point reduction in the EXACT-Respiratory Symptoms (E-RS™) breathlessness subscale score. 
     
     
         59 . The method of  claim 1 , wherein after said treating the patient experiences a substantial reduction in dyspnea compared to prior to said treating. 
     
     
         60 . The method of  claim 1 , wherein after said treating the patient experiences a reduction of dyspnea that is characterized by at least a 1.0 point reduction in the EXACT-Respiratory Symptoms (E-RS™) breathlessness subscale score connected to activity. 
     
     
         61 . The method of  claim 1 , wherein after said treating the patient experiences a reduction of dyspnea that is characterized by at least a one point change in the Borg dyspnea scale value total score. 
     
     
         62 . The method of  claim 1 , wherein after said treating the patient experiences a reduction of dyspnea that is characterized by at least a one point change in any of the Borg dyspnea scale domains (sensory-perceptual, affective distress or symptom impact). 
     
     
         63 . The method of  claim 1 , wherein after said treating the patient experiences a reduction of dyspnea that is characterized by at least a 3 point reduction in the numerical rating scale dyspnea value. 
     
     
         64 . The method of  claim 1 , wherein after said treating the patient experiences a reduction of dyspnea that is characterized by at least a one category change in the Modified Medical Research Council Scale. 
     
     
         65 . The method of  claim 1 , wherein after said treating the patient experiences a reduction of dyspnea that is characterized by at least a one category change in at least one of the 7 questions of the PROMIS Pool v1.0 Dyspnea Emotional Response Scale. 
     
     
         66 . The method of  claim 1 , wherein after said treating the patient experiences a reduction of dyspnea that is characterized by at least a one category change in at least one of the 10 questions of the PROMIS Item Bank v1.0 Dyspnea Severity-Short Form 10a Scale. 
     
     
         67 . The method of  claim 1 , wherein after said treatment the patient experiences a reduction of dyspnea that is characterized by at least a one category change in at least one of the 4 items or a one category change in the question “I have been short of breath” of the PROMIS Item Bank v1.0 Dyspnea Characteristics Scale compared to prior to the treatment. 
     
     
         68 . The method of  claim 1 , wherein after said treating the patient experiences a substantial reduction in fatigue. 
     
     
         69 . The method of  claim 1 , wherein after said treating the patient experiences a reduction of fatigue that is characterized by at least a one category change in at least one of the 7 questions of the PROMIS Item Bank v1.0 Fatigue Short Form 7a Scale. 
     
     
         70 . The method of  claim 1 , wherein after said treating the patient experiences a substantial reduction in the rate of pulmonary fibrosis compared to prior to said treating as quantified by objective measures (chest x-ray, pulmonary function tests, etc.). 
     
     
         71 . The method of  claim 1 , wherein after said treating the patient experiences a substantial reduction in the hospitalization rate based on improvement in the dyspnea, breathlessness or cough status. 
     
     
         72 . The method of  claim 1 , wherein after said treating the patient experiences a substantial reduction in morbidity and mortality as a result of the lessening incidence of acute exacerbations of IPF (AE-IPF) related to deterioration of lung function and/or lessening of breathing difficulties secondary to an interruption in the “dyspnea cycle” positive feedback loop of progressively more frequent episodes of dyspnea of increasing intensity. 
     
     
         73 . The method of  claim 1 , wherein the nalbuphine or a pharmaceutically acceptable salt or ester thereof is administered in conjunction with one or more drugs that treat IPF cough, breathlessness, or dyspnea. 
     
     
         74 . The method of  claim 73 , wherein the one or more drugs that treat IPF cough, breathlessness, or dyspnea is selected from the group consisting of pirfenidone, nintedanib, N-acetylcysteine, cromolyn sodium, thalidomide, gefapixant, serlopitant, and orvepitant. 
     
     
         75 . The method of any one of  claim 1 ,  13  or  23 , wherein the nalbuphine or a pharmaceutically acceptable salt or ester thereof is nalbuphine hydrochloride. 
     
     
         76 . The method of any one of  claim 1 ,  13  or  23 , wherein the nalbuphine or a pharmaceutically acceptable salt or ester thereof is in the form of an extended release oral dosage form. 
     
     
         77 . The method of any one of  claim 1 ,  13  or  23 , 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.