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 . A controlled release pharmaceutical formulation of a K ATP  channel opener of formula II or formula III.  
   
   
       2 . The formulation of  claim 1  for a single administration that contains between 10 and 100 mg of the K ATP  channel opener.  
   
   
       3 . The formulation of  claim 1  for a single administration that contains between 100 and 200 mg of the K ATP  channel opener.  
   
   
       4 . The formulation of  claim 1  for a single administration that contains between 200 and 300 mg of the K ATP  channel opener.  
   
   
       5 . The formulation of  claim 1  for a single administration that contains between 300 and 500 mg of the K ATP  channel opener.  
   
   
       6 . The formulation of  claim 1  for a single administration that contains between 500 mg and 2000 mg of the K ATP  channel opener.  
   
   
       7 . The formulation of  claim 1  wherein the K ATP  channel opener is diazoxide.  
   
   
       8 . The formulation of  claim 1  wherein the K ATP  channel opener is a salt of diazoxide other than a sodium salt.  
   
   
       9 . The formulation of  claim 1  obtained by at least one of the following: (a) particle size reduction involving comminution, spray drying, or other micronising technique, (b) the use of a pharmaceutical salt of the compounds of formula II or formula III, (c) the use of an ion exchange resin, (d) the use of inclusion complexes, (e) compaction of the compounds of formula II or formula III with a solubilizing agent including a low viscosity hypromellose, low viscosity metylcellulose or similarly functioning excipient or combinations thereof, (f) associating the compounds of formula II or formula III with a salt prior to formulation, (g) the use of a solid dispersion the compounds of formula II or formula III, (h) the use of a self emulsifying system, (i) the addition of one or more surfactants to the formulation or (j) the use of nanoparticles.  
   
   
       10 . The formulation of  claim 1  that is formulated for oral administration.  
   
   
       11 . The formulation of  claim 10  which includes at least one component that substantially inhibits release of the K ATP  channel opener from the formulation until after gastric transit.  
   
   
       12 . The formulation of  claim 11  wherein the component is 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, (h) a non-aqueous soluble polymer applied to microparticles, (i) incorporation of the formulation in an osmotic pump system, and (j) use of systems controlled by ion exchange resins, and (k) combinations of these approaches, wherein the pH sensitive polymer or co-polymer is resistant to degradation under acid conditions.  
   
   
       13 . The formulation of claims  1  further comprising a component that contributes to sustained release of the K ATP  channel opener over a period of 2-24 hours following administration.  
   
   
       14 . The formulation of  claim 13  wherein the time period is 2-4 hours following administration.  
   
   
       15 . The formulation of  claim 13  wherein the time period is 4-8 hours following administration.  
   
   
       16 . The formulation of  claim 13  wherein the time period is 8-24 hours following administration.  
   
   
       17 . The formulation of claims  13  wherein the component is: (a) a pH sensitive polymeric coating, (b) a hydrogel, (c) a film coating that controls the rate of diffusion of the drug from a coated matrix, (d) an erodable matrix that controls rate of drug release, (e) polymer coated pellets, granules or microparticles of drug which can be further encapsulated or compressed into a tablet, (f) an osmotic pump system containing the drug, (g) a compression coated tablet form of the drug, or (h) combinations thereof.  
   
   
       18 . The formulation of  claim 1  further comprising another pharmaceutically active agent.  
   
   
       19 . The formulation of  claim 18  wherein the other pharmaceutically active agent 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, or other obesity associated comorbidities, ischemic and reperfusion injury, or epilepsy, schizophrenia, mania, or other psychotic condition.  
   
   
       20 . The formulation of claims  1  wherein administration to an obese, overweight or obesity prone individual results in at least one of the following: (a) the inhibition of fasting insulin secretion (b) the inhibition of glucose stimulated insulin secretion, (c) the elevation of energy expenditure, (d) the elevation of beta oxidation of fat, or (e) inhibits hyperphagia for about 24 hours.  
   
   
       21 . The formulation of  claim 1  wherein administration to an obese, overweight or obesity prone individual results in at least one of the following: (a) the inhibition of fasting insulin secretion (b) the inhibition of glucose stimulated insulin secretion, (c) the elevation of energy expenditure, (d) the elevation of beta oxidation of fat, or (e) inhibits hyperphagia for about 18 hours.  
   
   
       22 . A salt of diazoxide other than a sodium salt.  
   
   
       23 . A pharmaceutical formulation of a K ATP  channel opener according to formula II or formula III that upon administration to an obese, overweight or obesity prone individual results in at least one of the following: (a) inhibition of fasting insulin secretion (b) inhibition of glucose stimulated insulin secretion, (c) elevation of energy expenditure, (d) elevation of beta oxidation of fat, or (e) inhibition of hyperphagia for about 24 hours.  
   
   
       24 . A pharmaceutical formulation of a K ATP  channel opener according to formula II or formula III that upon administration to an obese, overweight or obesity prone individual results in at least one of the following: (a) inhibition of fasting insulin secretion (b) inhibition of glucose stimulated insulin secretion, (c) elevation of energy expenditure, (d) elevation of beta oxidation of fat, or (e) inhibition of hyperphagia for about 18 hours.  
   
   
       25 . A method of inducing weight loss in an obese or overweight subject, comprising administering the formulation of  claim 10  no more than two times per 24 hours.  
   
   
       26 . A method of inducing weight loss in an obese or overweight subject, comprising administering the formulation of  claim 10  once per 24 hours.  
   
   
       27 . A method of maintaining a weight loss in an obese, overweight, or obesity prone subject, said method comprising administering the formulation of  claim 10  no more than two times per 24 hours.  
   
   
       28 . A method of maintaining a weight loss in an obese, overweight, or obesity prone subject, comprising administering the formulation of  claim 10  once per 24 hours.  
   
   
       29 . A method of inducing weight loss in an obese or overweight subject, comprising administering daily dosages of the pharmaceutical formulation of a K ATP  channel opener of formula II or formula III, wherein the daily dosages of the K ATP  formulation are between 50 and 180 mg.  
   
   
       30 . A method of treating obesity associated co-morbidities in an obese, overweight or obesity prone individual, said method comprising administering a therapeutically effective amount of a solid oral dosage form of a K ATP  channel opener of formula II or formula III no more than two times per 24 hours.  
   
   
       31 . The method of  claim 30  wherein said administering is once per 24 hours.  
   
   
       32 . A method of achieving weight loss in an obese individual, said method comprising administering a therapeutically effective amount of a solid oral dosage form of a K ATP  channel opener of formula II or formula III no more than two times per 24 hours.  
   
   
       33 . The method of  claim 32  wherein said administering is once per 24 hours.  
   
   
       34 . A method of elevating energy expenditure in an overweight, obese or obesity prone individual, said method comprising administering an effective amount of a solid oral dosage form of a K ATP  channel opener of formula II or formula III no more than two times per 24 hours.  
   
   
       35 . The method of  claim 34  wherein said administering is once per 24 hours.  
   
   
       36 . A method of elevating beta oxidation of fat in an overweight, obese or obesity prone individual, said method comprising administering an effective amount of a solid oral dosage form of a K ATP  channel opener of formula II or formula III no more than two times per 24 hours.  
   
   
       37 . The method of  claim 36  wherein said administering is once per 24 hours.  
   
   
       38 . A method of preventing the transition to diabetes of a prediabetic individual comprising administering an effective amount of K ATP  channel opener of formula II or formula III no more than two times per 24 hours.  
   
   
       39 . The method of  claim 38  wherein said administering is once per 24 hours.  
   
   
       40 . A method of restoring normal glucose tolerance to a diabetic individual comprising administering an effective amount of K ATP  channel opener of formula II or formula III.  
   
   
       41 . A method of restoring normal glucose tolerance to a prediabetic individual comprising administering an effective amount of K ATP  channel opener of formula II or formula III.  
   
   
       42 . A method of delaying or preventing the progression of diabetes comprising administering an effective amount of K ATP  channel opener of formula II or formula III no more than two times per 24 hours.  
   
   
       43 . The method of  claim 42  wherein said administering is once per 24 hours.  
   
   
       44 . A method of treating obesity or obesity associated co-morbidities or other diseases or conditions involving K ATP  channels by co-administration of an effective amount of a solid oral dosage form of a K ATP  channel opener of formula II or formula III and a drug that is selected from the group consisting of Sibutramine, Orlistat, Rimonabant, a non-thiazide diuretic, a drug that lowers cholesterol, a drug that raises HDL cholesterol, a drug that lowers LDL cholesterol, a drug that lowers blood pressure, a drug that is an anti-depressant, a drug that improves insulin sensitivity, a drug that improves glucose utilization or uptake, a drug that is an anti-epileptic, a drug that is an anti-inflammatory, a drug that is an appetite suppressant, a drug that lowers circulating triglycerides, and a drug that is used to induced weight loss in an overweight or obese individual.  
   
   
       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 achieved by any of the following: (a) the use of a pharmaceutical formulation that delays release of the the method of preventing weight gain, dyslipidemia or impaired glucose tolerance in a subject treated with an anti-psychotic drug involving the administration of a pharmaceutical formulation of a K ATP  channel opener until gastric transit is complete, (b) the use of a pharmaceutical formulation that sustains release over more than 2 hours, (c) initiating dosing at subtherapeutic levels and in a stepwise manner increasing dose daily until the therapeutic dose is achieved wherein the number of steps is 2 to 10, (d) use of the lowest effective dose to achieve the desired therapeutic effect, and (e) optimizing the timing of administration of dose within the 24 hours and relative to meals.  
   
   
       46 . A method of preventing weight gain, dyslipidemia or impaired glucose tolerance in a subject treated with an anti-psychotic drug, the method comprising administering a pharmaceutical formulation of a K ATP  channel opener.  
   
   
       47 . A method of treating weight gain, dyslipidemia or impaired glucose tolerance in a subject treated with an anti-psychotic drug, the method comprising administering a pharmaceutical formulation of a K ATP  channel opener.  
   
   
       48 . A method of treating diseases characterized by obesity, hyperphagia, dyslipidemia, or decreased energy expenditure including (a) Prader Willi Syndrome, (b) Froelich's syndrome, (c) Cohen syndrome, (d) Summit Syndrome, (e) Alstrom, Syndrome, (f) Borjesen Syndrome, (g) Bardet-Biedl Syndrome, or (h) hyperlipoproteinemia type I, II, III, and IV comprising administering a pharmaceutical formulation of a K ATP  channel opener.  
   
   
       49 . A pharmaceutical formulation of a K ATP  channel opener of formula II or formula III further comprising a pharmaceutically active agent other than the K ATP  channel opener of formula II or formula III.  
   
   
       50 . The formulation of  claim 49  wherein the other pharmaceutically active agent 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, or other obesity associated comorbidities, ischemic and reperfusion injury, epilepsy, schizophrenia, mania, and other psychotic condition.