Pharmaceutical formulations of potassium atp channel openers and uses thereof

Abstract

Provided are immediate or prolonged administration of certain potassium ATP (K ATP ) channel openers 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 K ATP channel openers that achieve these outcomes and reduce the incidence of adverse effects in treated individuals. Further provided are method of co-administering K ATP channel openers with other drugs to treat diseases of humans and animals.

1 .- 44 . (canceled) 
   
   
       45 . A method of reducing the incidence of adverse effects from administration of a K ATP  channel opener in the treatment of diseases or conditions, said method comprising one or more of the following: (a) administering the K ATP  channel opener as part of a pharmaceutical formulation that delays release of the K ATP  channel opener until gastric transit is complete, (b) administering the K ATP  channel opener as part of a pharmaceutical formulation that sustains release over more than 2 hours, (c) administering the K ATP  channel opener daily, wherein an initial dose of K ATP  channel opener is subtherapeutic and the dose is increased in a stepwise manner until a therapeutic dose is achieved, (d) administering a lowest effective dose of the K ATP  channel opener to achieve the desired therapeutic effect, and (e) optimizing the timing of administration of the K ATP  channel opener relative to meals. 
   
   
       46 .- 50 . (canceled) 
   
   
       51 . The method of  claim 45 , wherein said method comprises one or more of the following: (a) administering the K ATP  channel opener as part of a pharmaceutical formulation that delays release of the K ATP  channel opener until gastric transit is complete, (b) administering the K ATP  channel opener as part of a pharmaceutical formulation that sustains release over more than 2 hours, (c) administering the K ATP  channel opener daily, wherein an initial dose of K ATP  channel opener is subtherapeutic and the dose is increased in a stepwise manner until a therapeutic dose is achieved, and (d) administering a lowest effective dose of the K ATP  channel opener to achieve the desired therapeutic effect. 
   
   
       52 . The method of  claim 45 , wherein the pharmaceutical formulation a) delays the release of the K ATP  channel opener by one or more of the group consisting of:
 (i) use of pH sensitive polymeric coatings,   (ii) use of a hydrogel,   (iii) use of a film coating that controls the rate of diffusion of the drug from a coated matrix,   (iv) use of an erodible matrix that controls rate of drug release,   (v) use of polymer coated pellets, granules, or microparticles which can be further encapsulated or compressed into a tablet,   (vi) the use of an osmotic pump system, and   (vii) use of a compression coated tablet.   
   
   
       53 . The method of  claim 52 , wherein said pharmaceutical formulation a) delays release of the K ATP  channel opener by the use of a hydrogel. 
   
   
       54 . The method of  claim 53 , wherein said hydrogel comprises polyethylene oxide. 
   
   
       55 . The method of  claim 45 , wherein the pharmaceutical formulation b) delays the release of the K ATP  channel opener by use of one or more of the group consisting of:
 (i) application of a pH sensitive polymer or co-polymer as a compression coating on a tablet;   (ii) application of a pH sensitive polymer or co-polymer as a thin film on a tablet;   (iii) application of a pH sensitive polymer or co-polymer as a thin film to an encapsulation system;   (iv) application of a pH sensitive polymer or co-polymer to encapsulated microparticles,   (v) application of a non-aqueous-soluble polymer or copolymer as a compression coating on a tablet;   (vi) application of a non-aqueous-soluble polymer or co-polymer as a thin film on a tablet;   (vii) application of a non-aqueous soluble polymer as a thin film to an encapsulation system;   (viii) application of a non-aqueous soluble polymer to microparticles;   (ix) incorporation of the formulation in an osmotic pump system, and   (x) use of systems controlled by ion exchange resins,   wherein said pH sensitive polymer or co-polymer of (i), (ii), (iii), and (iv) is resistant to degradation under acid conditions.   
   
   
       56 . The method of  claim 55 , wherein said pH sensitive polymer or co-polymer of (i), (ii), (iii), and (iv) is a barrier to K ATP  channel opener release at pH≦3.0. 
   
   
       57 . The method of  claim 55 , wherein said pH sensitive polymer or co-polymer of (i), (ii), (iii), and (iv) is unstable at pH≧5.5. 
   
   
       58 . The method of  claim 55 , wherein the pharmaceutical formulation b) delays the release of the K ATP  channel opener by use of one or more of the group consisting of:
 (i) application of a pH sensitive polymer or co-polymer and a non-aqueous soluble polymer as a compression coating on a tablet;   (ii) application of a pH sensitive polymer or co-polymer and a non-aqueous soluble polymer as a thin film on a tablet;   (iii) application of a pH sensitive polymer or co-polymer and a non-aqueous soluble polymer as a thin film to an encapsulation system;   (iv) application of a pH sensitive polymer or co-polymer and a non-aqueous soluble polymer to encapsulated microparticles.   
   
   
       59 . The method of  claim 58 , wherein said pH sensitive polymer or co-polymer and said non-aqueous soluble polymer are applied as a blend. 
   
   
       60 . The method of  claim 45 , wherein said K ATP  channel opener is a K ATP  channel opener of formula II or III. 
   
   
       61 . The method of  claim 60 , wherein said K ATP  channel opener is diazoxide. 
   
   
       62 . The method of  claim 45 , wherein in step c) the number of steps is 2 to 10. 
   
   
       63 . The method of  claim 45 , wherein the maximum dose of said K ATP  channel opener is less than 2.5 mg/kg/day. 
   
   
       64 . The method of  claim 45 , wherein the maximum dose of said K ATP  channel opener is less than 1.75 mg/kg/day. 
   
   
       65 . The method of  claim 51 , wherein in step c) the number of steps is 2 to 10.