Salts of potassium atp channel openers and uses thereof

Abstract

Provided are immediate or prolonged administration of certain salts of K ATP channel openers such as diazoxide to a subject to achieve novel pharmacodynamic, pharmacokinetic, therapeutic, physiological, metabolic and compositional outcomes in the treatment of diseases or conditions involving K ATP channels. Also provided are pharmaceutical formulations, methods of administration and dosing of the salts that achieve these outcomes and reduce the incidence of adverse effects in treated individuals. Further provided are method of co-administering the salts with other drugs to treat diseases of humans and animals.

1 . A pharmaceutical formulation comprising:
 i.) a salt of a K ATP  channel opener selected from the group consisting of Formula III and Formula IV, and a counter ion as shown below   
     
       
         
         
             
             
         
       
       wherein:
 R 1  is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, and cycloalkyl provided however that when R 1  is a substituted lower alkyl then the substituent does not include an amino group; 
 R 2a  is hydrogen; 
 R 2b  is hydrogen; 
 R 3  is selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, cycloalkyl and substituted cycloalkyl provided however that 
 R 3  is selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, cycloalkyl and substituted cycloalkyl provided however that when R 3  is a substituted lower alkyl, then the substituent does not include an amino group; 
 R 4  is selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, cycloalkyl and substituted cycloalkyl provided however that when R 4  is a substituted lower alkyl, then the substituent does not include an amino group, and 
 
       ii.) a pharmaceutically active agent other than the K ATP  channel opener. 
     
   
   
       2 . The formulation of  claim 1  wherein said K ATP  channel opener is diazoxide. 
   
   
       3 . The formulation of  claim 1  wherein said K ATP  channel opener is diazoxide and said counter ion is choline. 
   
   
       4 . The formulation of  claim 1  wherein said K ATP  channel opener is diazoxide and said counter ion is hexamethyl hexamethylene diammonium. 
   
   
       5 . The formulation of  claim 1  wherein said formulation is a sustained release formulation. 
   
   
       6 . The formulation of  claim 5  wherein said sustained release formulation has a period of release 8 to 24 hours following administration. 
   
   
       7 . The formulation of  claim 5  wherein said sustained release formulation has a period of release 2 to 30 hours following administration. 
   
   
       8 . The formulation of  claim 1  wherein said pharmaceutically active agent other than a K ATP  channel opener is an agent useful for the treatment of a condition selected from the group consisting of obesity, prediabetes, diabetes, hypertension, depression, elevated cholesterol, fluid retention, obesity associated co-morbidities ischemic and reperfusion injury, epilepsy, schizophrenia, mania, other psychotic conditions, elevated triglycerides, elevated low-density lipoprotein bound cholesterol, and hyperlipidemia. 
   
   
       9 . The formulation of  claim 5  wherein said pharmaceutically active agent other than a K ATP  channel opener is an agent useful for the treatment of a condition selected from the group consisting of obesity, prediabetes, diabetes, hypertension, depression, elevated cholesterol, fluid retention, obesity associated co-morbidities, ischemic and reperfusion injury, epilepsy, schizophrenia, mania, other psychotic conditions, elevated triglycerides, elevated low-density lipoprotein bound cholesterol, and hyperlipidemia. 
   
   
       10 . The formulation of  claim 1  for a single administration that contains between 10 and 2000 mg of the salt. 
   
   
       11 . The formulation of  claim 1  for a single administration that contains between 200 and 500 mg of the salt. 
   
   
       12 . The formulation of  claim 1  wherein said formulation is a delayed release formulation. 
   
   
       13 . The formulation of  claim 12  wherein said delayed release formulation further comprises at least one component that substantially inhibits release of the K ATP  channel opener until after gastric transit. 
   
   
       14 . The formulation of  claim 12  wherein said delayed release formulation further comprises a component selected from the group consisting of:
 (a) a pH sensitive polymer or co-polymer applied as a compression coating on a tablet;   (b) a pH sensitive polymer or co-polymer applied as a thin film on a tablet;   (c) a pH sensitive polymer or co-polymer applied as a thin film to an encapsulation system;   (d) a pH sensitive polymer or co-polymer applied to encapsulated microparticles;   (e) a non-aqueous-soluble polymer or copolymer applied as a compression coating on a tablet;   (f) a non-aqueous-soluble polymer or co-polymer applied as a thin film on a tablet;   (g) a non-aqueous soluble polymer applied as a thin film to an encapsulation system, and   (h) a non-aqueous soluble polymer applied to microparticles;   wherein the pH sensitive polymer or co-polymer of (a), (b), (c), and (d) is resistant to degradation under acid conditions.   
   
   
       15 . The formulation of  claim 12  wherein said delayed release formulation exhibits sustained release of the K ATP  channel opener following gastric transit. 
   
   
       16 . The formulation of  claim 15  wherein the formulation comprises a component selected from the group consisting of:
 (a) a pH sensitive polymeric coating;   (b) a hydrogel;   (c) a film coating that controls the rate of diffusion of the salt from a coated matrix;   (d) an erodable matrix that controls rate of salt release;   (e) polymer coated pellets, granules or microparticles of salt which can be further encapsulated or compressed into a tablet;   (f) an osmotic pump system containing the salt;   (g) a compression coated tablet form of the salt; and   (h) combinations thereof.