Oral formulations of diphenylsulfonamide endothelin and angiotensin ii receptor agonists to treat elevated blood pressure and diabetic nephropathy

Abstract

Methods of administering and pharmaceutical compositions of a biphenyl sulfonamide compound which is a dual angiotensin and endothelin receptor antagonist are disclosed for treating diseases.

What is claimed is: 
     
         1 . A method of treating an endothelin-dependent or angiotensin II-dependent disorder in a human subject in need thereof which comprises administering a compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, in an amount from about 50 mg/day to about 1000 mg/day. 
       
     
     
         2 . The method of  claim 1 , wherein the endothelin-dependent or angiotensin II-dependent disorder is chronic elevated blood pressure, persistently elevated blood pressure, or diabetic nephropathy. 
     
     
         3 . The method of any of  claims 1 - 2 , wherein the amount of compound of formula I, or a pharmaceutically acceptable salt thereof, administered to the human subject is from about 200 mg/day to about 800 mg/day. 
     
     
         4 . The method of  claim 3 , wherein the amount of compound of formula I, or a pharmaceutically acceptable salt thereof, administered to the human subject is about 400 mg/day. 
     
     
         5 . The method of any of  claims 1 - 4 , wherein the systolic blood pressure of the human subject is decreased to below at least 160 mmHg. 
     
     
         6 . The method of any of  claims 1 - 5 , wherein the diastolic blood pressure of the human subject is decreased to below at least 140 mmHg. 
     
     
         7 . The method of any of  claims 1 - 6 , wherein the systolic or diastolic blood pressure of the human subject is decreased by at least 5 mmHg as compared to the systolic or diastolic blood pressure prior to treatment. 
     
     
         8 . The method of any of  claim 1 - 7 , wherein the systolic blood pressure of less than 140 mmHg or diastolic blood pressure of less than 90 mmHg is reached within 12 weeks of administration of the compound of formula I, or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The method of any of  claims 1 - 8 , wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at a frequency not greater than twice a day. 
     
     
         10 . The method of  claim 9 , wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at a frequency not greater than once a day. 
     
     
         11 . A pharmaceutical composition comprising a compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         and pharmaceutically acceptable excipients, 
         for use in treating an endothelin-dependent or angiotensin II-dependent disorder in a subject in need thereof, wherein the amount of compound of formula I, or a pharmaceutically acceptable salt thereof, is from about 50 mg to about 1000 mg. 
       
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein the endothelin-dependent or angiotensin II-dependent disorder is chronic elevated blood pressure, persistently elevated blood pressure, or diabetic nephropathy. 
     
     
         13 . The pharmaceutical composition of any of  claims 11 - 12 , wherein the amount of compound of formula I, or a pharmaceutically acceptable salt thereof, is from about 200 mg to about 800 mg. 
     
     
         14 . The pharmaceutical composition of  claim 13 , wherein the amount of compound of formula I, or a pharmaceutically acceptable salt thereof, is about 400 mg. 
     
     
         15 . The pharmaceutical composition of any of  claims 11 - 14 , wherein the use in treating the endothelin-dependent or angiotensin II-dependent disorder is decreasing the systolic blood pressure of the human subject so that it is below least 160 mmHg. 
     
     
         16 . The pharmaceutical composition of any of  claims 11 - 15 , wherein the use in treating the endothelin-dependent or angiotensin II-dependent disorder is decreasing the systolic or diastolic blood pressure of the human subject by at least 5 mmHg as compared to the systolic or diastolic blood pressure prior to treatment. 
     
     
         17 . The pharmaceutical composition of any of  claims 11 - 16 , wherein the systolic blood pressure of less than 140 mmHg or diastolic blood pressure of less than 90 mmHg is reached within 16 weeks of administration of the compound of formula I, or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The pharmaceutical composition of any of  claims 11 - 17 , wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at a frequency not greater than twice a day. 
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered at a frequency not greater than once a day. 
     
     
         20 . A pharmaceutical composition comprising
 from about 100 mg to about 800 mg of the compound of formula I:   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and 
         at least one excipient, 
         wherein the compound of formula I comprises greater than about 35% w/w of the composition, and 
         the excipients comprise from about 5% to about 65% w/w of the composition. 
       
     
     
         21 . The composition of  claim 20 , wherein each excipient is individually selected from the group consisting of microcrystalline cellulose, hydroxypropylcellulose, poloxamer 188, sodium starch glycolate, lactose monohydrate, and croscarmellose sodium. 
     
     
         22 . The composition of any of  claims 20 - 21 , wherein the compound of formula I comprises from about 40% to about 65% w/w of the composition. 
     
     
         23 . The composition of any of  claims 20 - 22 , wherein one excipient is microcrystalline cellulose. 
     
     
         24 . The composition of  claim 23 , wherein the microcrystalline cellulose comprises from about 5% to about 65% w/w of the composition. 
     
     
         25 . The composition of any of  claims 23 - 24 , wherein the microcrystalline cellulose is silicified microcrystalline cellulose. 
     
     
         26 . The composition of any of  claims 20 - 25 , wherein one excipient is poloxamer 188. 
     
     
         27 . The composition of  claim 26 , wherein the poloxamer 188 comprises from about 0.1% to about 10% w/w of the composition. 
     
     
         28 . The composition of any of  claims 20 - 27 , wherein the compound of formula I is provided in an amount selected from the group consisting of about 100 mg, about 200 mg, about 400 mg, and about 800 mg. 
     
     
         29 . A tablet comprising from about 100 mg to about 800 mg of a compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, having a hardness of at least 4 Kp. 
       
     
     
         30 . A pharmaceutical composition comprising from about 100 mg to about 800 mg the compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, having at least an 85 percent release of the compound of formula I, or a pharmaceutically acceptable salt thereof, within 45 minutes using U.S. Pharmacopeia (USP) type II dissolution Apparatus I at 50 rpm or 60 rpm in 0.1N HCl. 
       
     
     
         31 . A method of treating chronic or persistently elevated blood pressure, comprising identifying an individual in need of such treatment, and administering the composition of any of  claims 20 - 30  to said individual. 
     
     
         32 . A method of making a pharmaceutical composition comprising blending together from about 100 mg to about 800 mg of the compound of formula I, and one or more excipients, wherein the one or more excipients comprise from about 5% to about 65% w/w of the composition. 
     
     
         33 . A pharmaceutical composition comprising
 from about 100 mg to about 800 mg of the compound of formula I:   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and 
         microcrystalline cellulose which comprises about 29% w/w of the composition, croscarmellose sodium which comprises about 5% w/w of the composition, hydroxypropylcellulose which comprises about 3% w/w of the composition, poloxamer 188 which comprises about 5% w/w of the composition, colloidal silicone dioxide which comprises about 0.1% w/w of the composition, and magnesium stearate which comprises about 0.5% w/w of the composition. 
       
     
     
         34 . A pharmaceutical composition comprising
 from about 100 mg to about 800 mg of the compound of formula I:   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and 
         microcrystalline cellulose which comprises about 22% w/w of the composition, lactose monohydrate which comprises about 11% w/w of the composition, sodium lauryl sulfate which comprises about 1% w/w of the composition, croscarmellose sodium which comprises about 5% w/w of the composition, hydroxypropylcellulose which comprises about 3.0% w/w of the composition, colloidal silicone dioxide which comprises about 0.1% w/w of the composition, and magnesium stearate which comprises about 1% w/w of the composition. 
       
     
     
         35 . A pharmaceutical composition comprising
 from about 100 mg to about 800 mg of the compound of formula I:   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and 
         microcrystalline cellulose which comprises about 29% w/w of the composition, croscarmellose sodium which comprises about 5% w/w of the composition, hydroxypropylcellulose which comprises about 3% w/w of the composition, poloxamer 188 which comprises about 5% w/w of the composition, colloidal silicone dioxide which comprises about 0.1% w/w of the composition, and magnesium stearate which comprises about 1% w/w of the composition.