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US009765043B2 (12 ) United States Patent (10 ) Patent No. : US 9 ,765 ,043 B2 Cowen et al. ( 45 ) Date of Patent : Sep. 19, 2017

(54 ) SALTS OF POTASSIUM ATP CHANNEL 2004 / 0058009 Al 3 / 2004 Ruddy et al. 2004 /0072216 A1 4/ 2004 Johnson et al. OPENERS AND USES THEREOF 2004 /0204472 Al 10 /2004 Briggs et al . 2009 / 0062264 Al 3 /2009 Cowen et al. (71 ) Applicant: Essentialis , Inc. , Carlsbad , CA (US ) 2009 /0149451 A1 6 / 2009 Cowen ( 72 ) Inventors : Neil M . Cowen , Carlsbad, CA (US ) ; 2012 /0238554 AL 9 / 2012 Cowen et al . Richard C . Pasternak, New York , NY FOREIGN PATENT DOCUMENTS (US ) GB 982072 A 2 / 1965 @(73 ) Assignee : Essentialls , Inc. , Redwood City , CA WO WO 98 / 10786 A1 3 / 1998 (US ) OTHER PUBLICATIONS ( * ) Notice : Subject to any disclaimer , the term of this patent is extended or adjusted under 35 Standridge et al . “ Diazoxide down - regulates leptin and lipid U . S . C . 154 (b ) by 161 days . metabolizing enzymes in adipose tissue of Zucker rats ” The FASEB Journal, Aug . 2016 , vol. 14 , No. 3 , pp . 455 -460 .* Coskun et al. “ Treatment of hypertriglyceridemia - induced acute (21 ) Appl. No. : 14 /466 ,852 pancreatitis with insulin ” Przeglad Gastroenterologiczny, 2015 , vol. 10 , No ., pp . 18 -22 . * ( 22 ) Filed : Aug . 22 , 2014 J. G . Cannon Chapter Nineteen in Burgers Medicinal Chemistry and Drug Discovery , Fifth Edition , vol. I: Principles and Practice , (65 ) Prior Publication Data Wiley - Interscience 1995 , pp . 783 - 802, 784 .* US 2014 /0364425 A1 Dec. 11, 2014 Drug Delivery Technologies online article Dong et al , “ L - ORSOR SOFTCAPSTM for controlled Release of Non - Aqueous Liquid For mulations ." Related U .S . Application Data Remington : The Science and Practice of Pharmacy , Remington 's (63 ) Continuation of application No. Pharmaceutical Sciences , 19th ed . , Mack Publishing Co . , Eason , PA , vol . 2 , p . 1457 , ( 1995 ) . PCT/ US2013 / 027676 , filed on Feb . 25 , 2013. U . S . Pharmacopeia , Chapter 711 Dissolution /Physical Tests , p . (60 ) Provisional application No . 61/ 603 ,923 , filed on Feb . 2412 - 2414 ( 2005 ) . 27 , 2012 Aguilar - Bryan et al. , “ Toward Understanding the Assembly and Structure of KATP Channels ” , Aguilar - Bryan , et al. , Physiological (51 ) Int. Cl. Reviews, vol . 78 , No . 1 , Jan . 1998 , 227 - 245 . Aizawa et al ., " Prophylaxis of genetically determined diabetes by A6IK 31/ 549 ( 2006 .01 ) diazoxide : a study in rat model of naturally occurring obese diabe C07D 285 /24 ( 2006 .01 ) tes. ” , Aizawa et al. , Prophylaxis of genetically determined diabetes A61K 45 / 06 ( 2006 .01 ) by diazoxide : a study in rat model of naturally occurring obese A61K 31/ 14 ( 2006 .01 ) diabetes, The Journal of Pharmacology and Experimental Thera A61K 31/ 192 ( 2006 .01 ) peutics, 1995 , vol. 275 , No . 1 , pp . 194 - 199 . A6IK 31/ 202 ( 2006 .01 ) Alemzadeh et al. , “ Beneficial Effect of Diazoxide in Obese A61K 31/ 655 ( 2006 .01 ) Hyperinsulinemic Adults” , Journal of Clinical Endocrinology and A61K 31/ 44 ( 2006 . 01 ) Metabolism , vol. 83 , No. 6 , 1998 , pp . 1911 - 1915 . (52 ) U . S . CI. Alemzadeh et al. , “ Chronic suppression of insulin by diazoxide ???CPC ...... CO7D 285 /24 ( 2013 .01 ); A61K 31/ 14 alters the activities of key enzymes regulating hepatic ( 2013 .01 ); A61K 31/ 192 ( 2013 .01 ) ; A61K gluconeogenesis in Zucker rats , ” European Journal of Endocrinol 31/ 202 (2013 .01 ) ; A61K 31/ 44 ( 2013. 01 ) ; ogy, 2002 , vol. 146 , pp . 871- 879 . A61K 31 /549 ( 2013 .01 ) ; A61K 31 /655 (Continued ) ( 2013 .01 ) ; A61K 45 / 06 ( 2013 .01 ) ( 58 ) Field of Classification Search Primary Examiner — Kendra D Carter CPC ...... A61K 31/ 549 ; CO7D 285/ 24 See application file for complete search history. (57 ) ABSTRACT ( 56 ) References Cited Provided are immediate or prolonged administration of U . S . PATENT DOCUMENTS certain salts of Karp channel openers such as diazoxide to a subject to achieve novel pharmacodynamic , pharmacoki 2 , 986 , 573 A 5 / 1961 Topliss et al. netic , therapeutic , physiological, metabolic and composi 4 ,880 ,830 A 11/ 1989 Rhodes et al. 5 ,284 , 845 A 2 / 1994 Paulsen tional outcomes in the treatment of diseases or conditions 5 , 399 ,359 A 3 / 1995 Baichwal involving Kftp channels . Also provided are pharmaceutical 5 ,415 , 871 A 5 / 1995 Pankhania et al. formulations , methods of administration and dosing of the 5 ,629 , 045 A 5 / 1997 Veech et al . salts that achieve these outcomes and reduce the incidence 5 , 656 ,667 A 8 / 1997 Breivik et al. 6 ,022 , 562 A 2 / 2000 Autant et al. of adverse effects in treated individuals . Further provided are 6 ,197 , 795 B1 3 / 2001 Levin et al. method of co - administering the salts with other drugs to 6 , 361 , 795 B1 . 3 / 2002 Kuczynski et al. treat diseases of humans and animals . 2002 / 0035106 A1 3 / 2002 Hansen et al. 2003 /0035106 A1 2 / 2003 Yeh et al. 2003 /0149043 Al 8 / 2003 Hamanaka et al. 6 Claims, 54 Drawing Sheets US 9 ,765 ,043 B2 Page 2

References Cited therapy ” , Clinical Therapeutics, Excerpta Medica , Princeton , NJ, ( 56 ) US, vol . 30 , No. 2 , Feb . 1 , 2008 , pp . 294 - 306 . Fozard et al ., “ Potassium Channel Openers ” , Prog Respir Res . OTHER PUBLICATIONS Basel, Karger, vol. 31, 2001, 77 -80 . Alemzadeh et al. , “ Modification of insulin resistance by diazoxide Fredrickson et al. , “ A System for Phenotyping in obese Zucker rats ” , Endocrinology , 1993 , 133 : 2 , pp . 705 -712 . Hyperlipoproteinemia ” , Fredrickson , DS , Lees, LS , Circulation , Alemzadeh et al. , “ Antiobesity effect of diazoxide in obese zucker Mar. 1965, vol. 31, No. 3. , pp . 321- 327 . rats ” , Metabolism _ Clinical and Experimental, vol . 45, Issue 3 , pp . Gulstrand et al. , “ Improved beta cell function after short -term 334 - 341 , 1996 . treatment with diazoxide in obese subjects with type 2 diabetes” , Alemzadeh et al. , “ Diazoxide attenuates insulin secretion and Diabetes Metab , 2002 , vol. 28 , pp . 448 -456 . hepatic liogenesis in zucker diabetic fatty rats ” , (Med Sci Monit, Gutman et al. , “ Diazoxide Prevents the Development of Hormonal 2005 ; 11 ( 12 ): BR439 -448 . and Metabolic Abnormalities Present in Rats Fed a Sucrose Rich Alemzadeh et al. , “ Diazoxide enhances adipose tissue protein Diet " , Horm . metabol. Res. 1985 , vol. 17 , pp . 491- 494 . kinase B activation and glucose transporter- 4 expression in obese Harold et al. , “ Eicosapentaenoic Acid Ethyl Ester (AMR101 ) Zucker rats ” , Med Sci Monit , 2004 ; 10 ( 3 ): BR53 -60 . Therapy in Patients With Very High Triglyceride Levels ( from the Alemzadeh et al. , “ Effect of Diazoxide on Brian Capillary Insulin Multi - center, placebo - controlled . Randomized , double -blind . Receptor Binding and Food Intake in Hyperphagic Obese Zucker 12 -week study with an open -label Extension [Marine ] Trial) ” , Rats” , Alemzadeh et al. , Endocrinology , 1999 , vol. 140 , No. 7, American Journal of Cardiology, Canners Publishing Co ., Newton . 3197 - 3202 . MA . US , vol. 108 , No . 5 , Apr. 24 , 2011 , pp . 682- 690 . Alemzadeh et al ., “ Modulation of Adipoinsular Axis in Prediabetic Honey et al ., “ Clinical and haemodynamic effects of diazoxide in Zucker Diabetic Fatty Rats by Diazoxide” , Endocrinology vol. 145 , primary pulmonary hypertension ” , Clinical and hemodynamic No. 12 , 2004 , pp . 5476 -5484 . effects of diazoxide in primary pulmonary hypertension , Thorax Babenko et al. , " A View of Sur/ KIR6 .X , KATP Channels” , Annu . 1980 , 35 ( 4 ) , pp . 269 - 276 . Rev . Physiol. , 1998 , 60 :667 -687 . Isomoto et al . , “ A Novel Sulfonylurea Receptor Forms with BIR Babenko et al. , “ Pharmaco - topology of Sulfonylurea Receptors ” , J ( Kir6 . 2 ) a Smooth Muscle Type ATP -sensitive K + Channel ” , J . Biol. Biol Chem , 2000 , 275 ( 2 ), pp . 717 -720 . Chem ., 1996 , 271 (40 ), pp . 24321 - 24324 . Beaumont et al. , “ Classification of Hyperlipidaemias and Matzno et al. , “ A possible mechanism of action of a new potassium Hyperlipoproteinaemias” , Bull World Health Org , vol. 43 , No. 6 , channel opener, AL0671, on lipid metabolism in obese Zucker rats ” , 1970 , pp . 891 - 915. The Journal of Pharmacology and Experimental Therapeutics, 1994 , Bertolino et al . , “ Modulation of AMPA / kainate receptors by ana vol. 271, pp . 1666 - 1671 . logues of diazoxide and cyclothiazide in thin slices of rat hip Mussche et al. , “ Oral diazoxide contraindicated in severe hyperten pocampus ” , Georgetown Institute for the Neurosciences, George sion with renal failure ” , Clinical Nephrology , Dustri Verlag , town University Medical School vol. 1 , No . 4 , 1993 , pp . 267 - 278 . Nuenchen - Deisenhofen , DE, Jan . 1 , 1975 , vol. 4 , No. 3 , pp . 99 - 103 . Bjork et al. , “ Induction of “ B ” - Cell Rest in Type 1 Diabetes: Studies Okada et al. , “ Effects of the K + Channel Opener KRN4884 on the on the effects of octreotide and diazoxide ” , Diabetes Care 1998 , Cardiovascular Metabolic Syndrome Model in Rats ” , Journal of 21( 3 ), pp . 427 -430 . Cardiovascular Pharmacology ; Feb . 2000 , vol. 35 , Issue 2 , pp . Bjorklund et al. , “ Glucose - Induced [Ca2 + ] Abnormalities in Human 287 - 293 . Pancreatic Islets ” , Diabetes, 49 : 1840 -1848 ( 2000 ), 2000 , 1840 Ortqvist et al ., “ Temporary Preservation of “ B ” -Cell Function by 1848 . Diazoxide Treatment in Childhood Type 1 Diabetes ” , Diabetes Care Calesnick et al. , “ Importance of dissolution rates in producing 2004 , 27 ( 9 ) , pp . 2191- 2197 . effective diazoxide blood levels in man ” , J . Pharm . Sci ., 1965 , vol. Ouedraogo et al ., “ 2 - Alkyl- 3 - Alkylamino - 2H - Benzo - and 54 , pp . 1277 - 1280 . Pyridothiadiazine 1 , 1- Dioxides: From K + ATP Channel Openers to Chan et al. , “ Reversibility of primary pulmonary hypertension Ca + + Channel Blockers ? ” , Biol. Chem ., 2002 , 383 , pp . 1759 - 1768 . during six years of treatment with oral diazoxide ” , BrHeart J 1987, PCT/ US2013 /027676 , “ International Search Report and Written 57 ( 2 ), pp . 207 - 209 . Opinion ” , Jun . 21 , 2013 . Cosgrove et al. , “ BPDZ 154 Activates Adenosine 5' - Triphosphate Qvigstad et al ., “Nine weeks of bedtime diazoxide is well tolerated Sensitive Potassium Channels : In Vitro Studies Using Rodent and improves “ B ” -cell function in subjects with Type 2 diabetes” , Insulin -Secreting Cells and Islets Isolated from Patients with Hyper Diabetic Medicine , 2004 , vol. 21, pp . 73 -76 . insulinism ” , J . Clin . Endocrinol . Metab . , 2002 , vol. 87 , pp . 4860 Ratzmann et al. , “ Effect of pharmacological suppression of insulin 4868 . secretion on tissue sensitivity to insulin in subjects with moderate Dabrowski et al ., “ The Novel Diazoxide Analog 3 - Isopropylamino obesity ” , International Journal of Obesity 1983, 7 (5 ), pp . 453 -458 . 7 -Methoxy - 4H01 , 2 , 4 - Benzothiadiazine 1 , 1 -Dioxide Is a Selective Reddy et al . , “ Once -Daily Sustained -Release Matrix Tablets of Kr6 . 2 /SUR1 Channel Opener " , Diabetes , Jun . 2002 , vol. 51, No. 6 , Nicorandil: Formulation and In Vitro Evaluation ” , AAPS pp . 1896 - 1906 . PharmSciTech , 2003 , vol. 4 , No. 4 , pp . 1 -9 . Dasbach et al . , “ Investigation of the Influence of Polyethylene Roth et al. , “ Prescription Omega -3 Fatty Acid as an Adjunct to Oxide in a Compression Coated Controlled Release Tablet Con Fenofibrate Therapy in Hypertriglyceridemic Subjects ” , J . taining a Water- Soluble Active ” , Poster at AAPS Annual Meeting , Cardiovasc Pharmacol. Sep . 2009 , 54 ( 3 ) , p . 196 - 203 . Oct. 26 - 30 , 2003 . Schou et al. , “ Synthesis and pharmacological evaluation of 4H - 1, 4 De Tullio et al ., “ Toward Tissue -Selective Pancreatic B - Cells KATP benzothiazine - 2 -carbonitrile 1 , 1 - dioxide and NO ( 2 Channel Openers Belonging to 3 - Alkylamino - 7 -halo -4H - 1 , 2 , 4 cyanomethylsulfonylphenyl) acylamide derivatives as potential acti benzothiadiazine 1, 1 - Dioxides” , J. Med . Chem ., 2003 , vol. 46 , pp . vators of ATP sensitive potassium channels ” , Bioorg . Med . Chem ., 3342 - 3353 . 2005 , vol. 13 , pp . 141 - 155 . D ’ Hahan et al. , “ Pharmacological plasticity of cardiac ATP -sensi Schwanstecher et al. , “ Potassium channel openers require ATP to tive potassium channels toward diazoxide revealed by ADP” , bind to and act through sulfonylurea receptors” , EMBO J. , 1998 , PNAS , 1999 , 96 ( 21 ) , pp . 12162 - 12167. vol. 17 , pp . 5529 -5535 . EP13754866 . 5 , “ Extended European Search Report ” , Jun . 23 , 2015 , Schwartz et al. , “ Cardioprotection by multiple preconditioning 7 pages. cycles does not require mitochondrial KATP channels in pigs” , Am Escande et al ., “ The Potassium Channel Opener Cromakalim (BRL J Physiol Heart Circ Physiol 2002 , vol . 283 , pp . H1538 -H1544 . 34915 ) Activates ATP -Dependent K + Channels in Osolated Cardiac Squarcia et al. , “ Primary pulmonary hypertension in childhood : Myocytes” , Biochem Biophys Res Communications, 1988 , vol. familial aspects " , Pediatr Med Chir 1981 , 3 (6 ), pp . 467 - 472 . 154 , pp . 620 -625 . Surwit et al . , “ Diazoxide Restores ” B3“ -Adrenergic Receptor Func Fazio et al ., “Management of mixed dyslipidemia in patients with or tion in Diet- Induced Obesity and Diabetes ” , Endocrinology , 2000 , at risk for cardiovascular disease: A role for combination fibrate vol. 141, No . 10 , pp . 3630 - 3637 . US 9 ,765 ,043 B2 Page 3

( 56 ) References Cited OTHER PUBLICATIONS Tavers et al. , “ Expression and function of ATP -dependent potassium channels in late post- infarction remodeling ” , J Mol Cell Cardiol 2007 , vol. 42 , pp . 1016 - 1025 . Trube et al ., " Opposite effects of tolbutamide and diazoxide on the ATP -dependent K + channel in mouse pancreatic “ B ” -cells ” , Pflugers Archiv , Nov. 1986 , vol. 407 , Issue 5 , pp . 493 -499 . Wang et al. , “ Novel pharmacological preconditioning with diazoxide attenuates myocardial stunning in coronary artery bypass grafting " , Eur J Cardiothorac Surg 2003 , 24 ( 6 ), pp . 967 -973 . Wang et al. , “ The Anti - Inflammatory Effect of Diazoxide in Coro nary artery bypass grafting” , Shock 2004 , vol. 22, No . 1, pp . 23 - 28 . Wigand et al. , “ Downregulation of Insulin Receptors in Obese Man ” , Diabetes 1979 , 28 ( 4 ) , pp . 287 - 291. Xu et al. , “ Antihypertensive drugs clonidine , diazoxide, hydralazine and furosemide regulate the production of cytokines by placentas and peripheral blood mononuclear cells in normal pregnancy ” , J. Hypertension , 2006 , vol . 24 , pp . 915 - 922 . Yokoyama et al . , “ Effect of KRN4884 on lipid metabolism in hyperlipidemic rats ” , Gen . Pharmac ., 30 , 1998 , pp . 233 - 237 . Yokoyama et al ., “ Effects of KRN4884 , a Novel Pyridinecarboxamidine Type K ( ATP ) Channel Opener, on Serum Triglyceride Levels in Rats ” , British Journal of Pharmacology , vol. 120 , Issue 8 , Apr. 1997 , pp . 1471- 1476 . * cited by examiner U . S . Patent Sep . 19, 2017 Sheet 1 of 54 US 9, 765 ,043 B2

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10% 50% 40% 30% 20% -50% -60% -70% -80% -90% : Change % Median US 9 , 765 ,043 B2 SALTS OF POTASSIUM ATP CHANNEL Potassium channel openers (PCOs or KCOs; also referred OPENERS AND USES THEREOF to as channel activators or channel agonists ), are a structur ally diverse group of compounds with no apparent common CROSS -REFERENCE TO RELATED pharmacophore linking their ability to antagonize the inhi APPLICATIONS bition of K tp channels by intracellular nucleotides . Diaz oxide is a PCO that stimulates Kamp channels in pancreatic This application is a continuation of PCT International B - cells ( see Trube et al. , Pfluegers Arch Eur J Physiol, 407 , 493 - 99 (1986 )) . Pinacidil and chromakalim are PCOs that application serial number PCT/ US2013 / 027676 , filed on activate sarcolemmal potassium channels ( see Escande et Feb . 25 , 2013 , which claims priority to U . S . Ser . No . 10 al. , Biochem Biophys Res Commun , 154 , 620 - 625 ( 1988 ) ; 61 /603 ,923 , filed on Feb . 27 , 2012 , each ofwhich is hereby Babenko et al. , J Biol Chem , 275 ( 2 ) , 717 - 720 (2000 ) ) . incorporated by reference in its entirety . Responsiveness to diazoxide has been shown to reside in the 6th through 11th predicted transmembrane domains ( TMD6 FIELD OF THE INVENTION 11 ) and the first nucleotide - binding fold (NBF1 ) of the 15 SUR1 subunit . The present invention relates to salts of potassium ATP Diazoxide, which is a nondiuretic benzothiadiazine (KATP ) channel openers , methods of preparing such salts , derivative having the formula 7 - chloro - 3 -methyl - 2H - 1 , 2 , 4 and methods of use thereof for treatment of a variety of benzothiadiazine 11 . 1 -- dioxide (empiricaler formula diseases and conditions, including for example , type 1 and CgH CIN202S ), is commercialized in three distinct formu type 2 diabetes, hypertension , dyslipidemia , nonalcoholic 20 lations to treat two different disease indications : ( 1 ) hyper steatohepatitis , pulmonary hypertension , myocardial infarc tensive emergencies and ( 2 ) hyperinsulinemic hypoglyce tion and arrhythmias following myocardical infarction and mic conditions. Hypertensive emergencies are treated with poly - cystic ovarian syndrome. Hyperstat IV , an aqueous formulation of diazoxide for intravenous use, adjusted to pH 11 .6 with sodium hydroxide . BACKGROUND OF THE INVENTION 25 Hyperstat IV is administered as a bolus dose into a periph eral vein to treat malignant hypertension or sulfonylurea The following description of the background of the inven overdose . In these uses , diazoxide acts to open potassium tion is provided as an aid in understanding the invention and channels in vascular smooth muscle and pancreatic beta is not admitted to describe or constitute prior art to the cells , stabilizing the membrane potential at the resting level, invention . 30 resulting in vascular smooth muscle relaxation and suppres ATP -sensitive potassium (KATP ) channels play important sion of insulin release , respectively . roles in a variety of tissues by coupling cellular metabolism Hyperinsulinemic hypoglycemic conditions are treated to electrical activity . The Karp channelhas been identified as with Proglycem® , an oral pharmaceutical version of diaz an octameric complex of two unrelated proteins , which oxide useful for administration to infants, children and assemble in a 4 : 4 stoichiometry . The first is a pore forming 35 adults . It is available as a chocolate mint flavored oral subunit , Kir6 . x , which forms an inwardly rectifying K + suspension , which includes 7 .25 % alcohol, sorbitol, choco channel; the second is an ABC (ATP binding cassette ) late cream flavor, propylene glycol, magnesium aluminum transporter , also known as the sulfonylurea receptor ( SURx ) silicate , carboxymethylcellulose sodium , mint flavor , (Babenko et al. , Annu . Rev. Physiol ., 60 :667 -687 ( 1998 ) . sodium benzoate , methylparaben , hydrochloric acid to The Kir6 . x pore forming subunit is common for many types 40 adjust the pH , poloxamer 188 , propylparaben and water. of KATP channels, and has two putative transmembrane Diazoxide is also available as a capsule with 50 or 100 mg domains (identified as TM1 and TM2) , which are linked by of diazoxide including lactose and magnesium stearate . In a pore loop (H5 ) . The subunit that comprises the SUR these uses, diazoxide activated K tp channels in insulin receptor includes multiple membrane - spanning domains and secreting cells thereby blunting the hypersecreting condi two nucleotide -binding folds. 45 tions . According to their tissue localization , Kate channels exist Myocardial remodeling late after infarction is associated in different isoforms or subspecies resulting from the assem - with increased incidence of fatal arrhythmias . Heteroge bly of the SUR and Kir subunits in multiple combinations. neous prolongation of the action potential in the surviving The combination of the SUR1 with the Kir6 . 2 subunits myocardium is one of the predominant causes . Sarcolemmal (SUR1 / Kir6 .2 ) typically forms the adipocyte and pancreatic 50 ATP - dependent potassium (KATP ) channels are important B -cell type Kamp channels , whereas the SUR2A /Kir6 . 2 and metabolic sensors regulating electrical activity of cardio the SUR2B /Kir6 . 2 or Kir6 . 1 combinations typically form myocytes and are capable of considerably shortening the the cardiac type and the smooth muscle type Kamp channels , action potential. Tavares et al. (Expression and function of respectively (Babenko et al. , Annu . Rev. Physiol . , 60 :667 - ATP - dependent potassium channels in late post - infarction 687 ( 1998 ) ) . There is also evidence that the channel may 55 remodeling, J Mol Cell Cardiol 42: 1016 - 1025 ( 2007 ) ) stud include Kir2 .x subunits . This class of potassium channels ied the effect of diazoxide on late post infarction remodeling are inhibited by intracellular ATP and activated by intracel- in rats . Cardiomyocytes were obtained from the infarct lular nucleoside diphosphates . Such Kate channels link the border zone , the septum and the right ventricle of rat hearts metabolic status of the cells to the plasma membrane poten - 10 weeks after coronary occlusion when rats developed tial and in this way play a key role in regulating cellular 60 signs of heart failure . Expression of the conductance subunit activity. In most excitatory cells , Kate channels are closed Kir6 .1 , but not Kir6 . 2 , and of all SUR regulatory subunits under normal physiological conditions and open when the was increased up to 3 - fold in cardiomyocytes from the tissue is metabolically compromised ( e .g . when the (ATP : infarct border zone . Concomitantly , there was a prominent ADP ) ratio falls ). This promotes K + efflux and cell hyper - response of the Kate current to diazoxide that was not polarization , thereby preventing voltage- dependent Ca2 + 65 detectable in control cardiomyocytes . The action potential channels (VDCCs ) from opening . (Prog . Res Research , was prolonged in cardiomyocytes from the infarct border ( 2001 ) 31 :77 - 80 ) . zone (74 ms) relative to sham ( 41 ms) . However, activation US 9 , 765 , 043 B2 of the Kate channels by diazoxide reduced action potential Current oral formulations of diazoxide are labeled for duration to 42 ms. In myocytes of the septum and right dosing two or three times per day at 8 or 12 hour intervals . ventricle , expression of channel subunits , duration of action Most subjects receiving diazoxide are dosed three times per potential, and sensitivity to diazoxide were only slightly day . Commercial and experimental formulations of diazox increased relative to shams. The authors suggested that 5 ide are characterized by rapid drug release following inges drugs selectively activating diazoxide -sensitive sarcolem - tion with complete release in approximately 2 hours . Unless malKtp channels should be considered in the prevention of indicated differently , the term “ approximately ” when used in arrhythmias in post - infarction heart failure . the context of a numeric value , refer to the stated numeric Schwartz et al . ( Cardioprotection by multiple precondi- value + / - 10 % . In the context of two -theta angles from tioning cycles does not require mitochondrial KATP chan - 10 XRPD studies, the term approximately refers to + / - 5 % of nels in pigs , Am J Physiol Heart Circ Physiol 283 :H1538 the stated numeric value . H1544 (2002 ) studied the effects of diazoxide Current oral formulations of diazoxide in therapeutic use preconditioning on infarct size in pigs. Diazoxide was result in a range of adverse side effects including dyspepsia , administered 3 . 5 mg/ kg , 1 ml/ min IV to in barbital- anesthe - nausea , diarrhea, fluid retention , edema, reduced rates of tized open - chest pigs subjected to 30 min of complete 15 excretion of sodium , chloride , and uric acid , hyperglycemia , occlusion of the left anterior descending coronary artery and vomiting , abdominal pain , ileus , tachycardia , palpitations , 3 h of reflow . Infarct size (percentage of the area at risk ) after and headache . (See e. g ., current packaging insert for Pro 30 min of ischemia in controls was 35 .19 . 9 % (n = 7 ). glycem® ). Oral treatment with diazoxide is used in indi Diazoxide infusion significantly limited infarct size viduals experiencing serious disease where failure to treat ( 14 .627 . 4 % , n = 7 ) . Similar results have been demonstrated in 20 results in significant morbidity and mortality . The adverse rat and rabbit models. side effects from oral administration are tolerated because Diazoxide administered either as an IV bolus or orally has the benefits of treatment are substantial. The adverse side been used to treat pulmonary hypertension . For example , effects profile of oral diazoxide limit the utility of the drug Chan et al. (Reversibility of primary pulmonary hyperten - in treating obese subjects at doses within the labeled range sion during six years of treatment with oral diazoxide, Br 25 of 3 to 8 mg/ kg per day. Heart J 57 ( 2 ): 207 - 209 (1987 )) reported the successful treat. The effect of diazoxide in animal models of diabetes and ment of a 32 year old woman with pulmonary hypertension . obesity ( e . g . obese and lean Zucker rats ) has been previously Her symptoms resolved completely with oral diazoxide and reported . See e .g . Alemzadeh et al. , Endocrinology 133 : 705 the pulmonary arterial pressure was reduced to normal levels 712 ( 1993 ) ; Alemzadeh et al. , Metabolism 45 : 334 - 341 over a period of six years . When diazoxide was discontinued 30 ( 1996 ) ; Alemzadeh et al. , Endocrinology 140 :3197 -3202 on two separate occasions pulmonary hypertension recurred . ( 1999 ) ; Stanridge et al. , FASEB J 14 :455 -460 ( 2000 ) ; Squarcia et al. (Primary pulmonary hypertension in child - Alemzadeh et al. , Med Sci Monit 10 ( 3 ) : BR53 -60 ( 2004 ) ; hood : familial aspects , Pediatr Med Chir 3 (6 ): 467 -472 Alemzadeh et al. , Endocrinology 145 ( 12 ): 3476 - 3484 ( 1981) ) suggested that among alternative vasodilators avail (2004 ); Aizawa et al. , I of Pharma Exp Ther 275 ( 1 ): able for the experimental treatment of pulmonary hyperten - 35 194 - 199 ( 1995 ); and Surwit et al ., Endocrinology 141: 3630 sion diazoxide appears to have some advantages because it 3637 ( 2000 ) . reduces not only pulmonary arteriolar resistance , but also The effect of diazoxide in humans with obesity or diabetes pulmonary artery pressure , without producing tachycardia . has been previously reported . See e . g . , Wigand et al . , Honey et al. (Clinical and hemodynamic effects of diaz - Diabetes 28 ( 4 ) :287 - 291 ( 1979 ) , evaluation of diazoxide on oxide in primary pulmonary hypertension , Thorax 35 ( 4 ) : 40 insulin receptors ; Ratzmann et al ., Int J Obesity 7 ( 5 ) : 453 269- 276 ( 1980 ) ) studied the effects of IV and oral diazoxide 458 ( 1983 ) , glucose tolerance and insulin sensitivity in on primary pulmonary hypertension . In their study diazox - moderately obese patients ; Marugo et al ., Boll Spec It Biol ide was injected into the pulmonary artery in nine patients Sper 53 : 1860 - 1866 ( 1977 ) , moderate dose diazoxide treat with primary pulmonary hypertension . There was no sig - ment on weight loss in obese patients ; Alemzadeh et al. , J nificant change in pulmonary artery pressure, which fell by 45 Clin Endocr Metab 83 : 1911 - 1915 ( 1998 ), low dose diazox more than 10 mmHg in only two patients . The pulmonary ide treatment on weight loss in obese hyperinsulinemic blood flow increased in all patients as a result of a fall in patients ; Guldstrand et al ., Diabetes and Metabolism pulmonary vascular resistance (by 4 to 17 units ) . Systematic 2 8 :448 - 456 ( 2002 ) , diazoxide in obese type II diabetic vascular resistance also fell as expected in all patients . Oral patients; Ortqvist et al. , Diabetes Care 27 ( 9 ) :2191 -2197 diazoxide was given to seven patients , two of whom showed 50 (2004 ) , beta - cell function measured by circulating C - peptide sustained clinical improvement while remaining on treat- in children at clinical onset of type 1 diabetes ; Bjork et al. , ment (400 to 600 mg daily ) . Five patients were unable to Diabetes Care 21 ( 3 ) : 427 - 430 ( 1998 ), effect of diazoxide on tolerate the drug , because of nausea and sickness (two ) , residual insulin secretion in adult type I diabetes patients ; peripheral edema requiring large doses of diuretics ( four ), and Qvigstad et al. , Diabetic Medicine 21 : 73 - 76 ( 2004 ) . diabetes (three ) , and postural hypotension ( one) . Hirsutism 55 The effect of potassium channel openers on lipid levels was troublesome in the two patients remaining on treatment has been reported . Gutman et al. (Horm Metab Res 1985 They concluded that diazoxide may be useful in the man - 17 ( 10 ) :491 - 494 ) studied the effect of diazoxide on an animal agement of some patients with primary pulmonary hyper- model with elevated triglycerides. Normal Wistar rats fed an tension , but its use is limited by the frequency of side effects . isocaloric , sucrose - rich (63 % ) diet ( SRD ) , were reported to Several experimental formulations of diazoxide have 60 develop glucose intolerance and elevated triglyceride levels been tested in humans and animals . These include an oral in plasma ( P ) as well as in heart ( H ) and liver ( L ) tissue . This solution tested in pharmacodynamic and pharmacokinetic metabolic state was reported to be accompanied by hyper studies and a tablet formulation under development in the insulinism both in vivo and in vitro , consistent with a state early 1960 ' s as an anti - hypertensive , but never commercial- of insulin resistance . Gutman et al. , administered diazoxide ized (see Calesnick et al ., J. Pharm . Sci. 54 : 1277 - 1280 65 ( 120 mg /kg / day ) together with the diet ( SRD + DZX ) for 22 ( 1965) ; Reddy et al. , AAPS Pharm Sci Tech 4 ( 4 ) : 1 - 98 , 9 days . Control groups fed a standard chow (STD ) or the STD ( 2003 ) ; U .S . Pat. No . 6 ,361 , 795 ) . plus diazoxide (STD + DZX ) were included in the study . US 9 , 765 , 043 B2 Gutman et al. , suggested that diazoxide could prevent the U . S . Pat . No . 6 , 197 , 765 describes administration of diaz development of hyperinsulinism , glucose intolerance and oxide for treatment for syndrome- X , and resulting compli elevated levels of triacylglycerol in plasma, heart and liver cations , that include hyperlipidemia , hypertension , central present in animals fed on a sucrose rich diet . obesity , hyperinsulinemia and impaired glucose tolerance . Yokoyama et al. (Gen Pharmacol 1998 30 ( 2 ) :233 - 237 ) 5 According to this reference , diazoxide interferes with pan studied the effects of KRN4884 on lipid metabolism in creatic islet function by ablating endogenous insulin secre hyperlipidemic rats . KRN4884 is a novel pyridinecarbox tion resulting in a state of insulin deficiency and high blood amidine type potassium channel opener. Oral administration glucose levels equivalent to that of diabetic patients that of KRN4884 ( 1 - 10 mg/ kg / day ) for 14 days was reported to depend on exogenous insulin administration for normaliza 10 tion of their blood glucose levels . dose dependently reduce serum triglyceride levels in Zucker U . S . Pat . No . 2 , 986 , 573 describes the preparation of rats . The reductions in serum triglyceride were associated diazoxide and its use for the treatment of hypertension . The with reductions in triglyceride in chylomicron and very low patent asserts that alkali metal salts may be prepared by density lipoprotein . KRN4884 produced no change in serum methods well- known in the art for the preparation of a salt insulin and glucose levels in Zucker rats . KRN4884 exhib 15 of a strong base with a weak acid . It also alleges a specific ited a similar triglyceride lowering effect in diet -induced method for making a sodium salt of diazoxide . This patent hyperlipidemic rats . In a second study with KRN4884 ( I does not provide any evidence to support the formation of Cardiovasc Pharmacol 2000 35 ( 2 ) : 287 - 293 ) , these authors any salt of diazoxide . used high - fructose diet rats which developed hypertension , U . S . Pat . No . 5 ,629 , 045 describes diazoxide for topical hypertriglyceridemia , increased total cholesterol/ HDL 20 ophthalmic administration . (high -density lipoprotein )- cholesterol ratio , and hyperinsu - WO 98 / 10786 describes use of diazoxide in the treatment linemia , and reported that KRN4884 treatment significantly of X - syndrome including obesity associated therewith . increased lipoprotein lipase (LPL ) activity in muscle and U . S . Patent publication no . 2003 /0035106 describes diaz tended to increase LPL activity in adipose tissue . Hepatic oxide containing compounds for reducing the consumption triglyceride lipase activity was not affected by KRN4884 25 of fat -containing foods. administration . U . S . Patent Publication No. 2004 /0204472 describes the Matzno et al. ( J Pharmacol Exp Ther 1994 271 ( 3 ) : 1666 - use of a Cox - 2 inhibitor plus diazoxide in the treatment of 71 ) studied the effect of ( + ) - N - ( 6 - amino - 3 -pyridil ) - N '- [ ( 1S , obesity . Also described therein is the use of a Cox - 2 inhibitor 2R ,4R )- bicyclo -[ 2 .2 .1 ]hept - 2 -yl ] - N " -cyanoguanidine plus a pharmaceutically acceptable salt of diazoxide, hydrochloride (ALO671 ) , a cyanoguanidine -derivative 30 wherein acceptable cations include alkali metals and alka potassium channel opener, on serum lipid and lipoprotein line earth metals . levels in obese Zucker rats . Serial administration ( for 1 or 2 U .S . Patent Publication No . 2002/ 0035106 describes use weeks ) of AL0671 (5 mg/ kg /day ) was reported to signifi - ofKamp channel agonists for reducing the consumption of fat cantly decrease serum total triglyceride , chylomicron and containing food . This application mentions pharmaceuti very - low - density lipoprotein levels with increasing high - 35 cally acceptable acid addition salts , pharmaceutically density lipoprotein cholesterol, whereas low - density lipo acceptable metal salts and optionally alkylated ammonium protein levels did not change . AL0671 (5 mg/ kg / day ) also salts , but does not disclose or describe how to prepare any was reported to increase lipoprotein lipase activities 4 - fold such salts . This patent also does not provide any evidence to and hepatic triglyceride lipase activities 3 - fold in posthepa - support the formation of any salt of a KATP channel agonist. rin plasma. The authors suggested that AL0671 activates 40 U .K . Patent GB982072 describes the preparation and use both lipoprotein lipase and hepatic triglyceride lipase activi- of diazoxide and derivatives for the treatment of hyperten ties through its potassium channel -opening activity followed sion and peripheral vascular disorders . This patent mentions by decreasing triglyceride - rich lipoproteins in genetically non - toxic alkali metals salts but does not disclose or obese hyperlipemic rats. describe how to prepare any such salts . This patent does not Alemzadeh and Tushaus (Med Sci Monit , 2005; 11 ( 12 ) : 45 provide any evidence to support the formation of any salt of BR439 - 448 ) studied the effect of 8 weeks of diazoxide diazoxide or its derivatives . treatment ( 150 mg/ kg / day ) on triglyceride biosynthesis in Zucker Diabetic Fatty ( ZDF ) rats . They reported that diaz SUMMARY OF THE INVENTION oxide treatment significantly reduced expression of sterol regulatory element- binding protein - 1c, fatty acid synthase , 50 The current invention relates to methods of preparation acetyl CoA carboxylase , hormone - sensitive lipase , and per - and use of formulations that include alkali metal, tertiary oxisome proliferator agonist receptor- y , without altering amine and ammonium salts of diazoxide and diazoxide expressions of acyl CoA oxidase , peroxisome proliferator derivatives. It has been surprisingly found that it is difficult receptor - a , and carnitine palmitoyl transferase - 1 . Also to produce salts of diazoxide and derivatives . In particular, reported was that diazoxide treatment decreased hepatic 55 the inventors have been unable to reproduce formation of a triglycerides, long chain acyl- CoA and cholesterol contents . diazoxide salt using the method asserted in U . S . Pat. No . U . S . Pat. No . 5 , 284 ,845 describes a method for normal - 2 , 986 ,573 . Contrary to what is reported in the literature , salt izing blood glucose and insulin levels in an individual formation with diazoxide and derivatives depends on a exhibiting normal fasting blood glucose and insulin levels proper selection of solvent and counter- ion . and exhibiting in an oral glucose tolerance test , elevated 60 Provided herein are pharmaceutical formulations of KTP glucose levels and at least one insulin level abnormality channel openers and their use for treatment of various selected from the group consisting of a delayed insulin peak , diseases and conditions including but not limited to type 1 an exaggerated insulin peak and a secondary elevated insulin and type 2 diabetes, hypertension , dyslipidemia , nonalco peak . According to this reference , the method includes holic steatohepatitis (NASH ) pulmonary hypertension , myo administering diazoxide in an amount from about 0 . 4 to 65 cardial infarction and arrhythmias following myocardical about 0 . 8 mg/ kg body weight before each meal in an amount infarction , and poly - cystic ovarian syndrome. Such formu effective to normalize the blood glucose and insulin levels . lations are characterized as being bioavailable . A KTP US 9 , 765 ,043 B2 channel opener as used herein has any one or more of the least one quaternary ammonium ion ( e . g ., diethylaminoetha following properties : ( 1 ) opening SURx /Kiro . y potassium nol, triethylamine , hydroxyethylpyrrolidine , choline and channels where x = 1 . 2A or 2B and y = 1 or 2 : ( 2 ) binding to hexamethylhexamethylenediammonium , and the like ) . the SURX subunit of KATP channels ; and ( 3 ) inhibiting KATP channel openers defined by Formula II are as fol glucose induced release of insulin following administration 5 10 of the compound in vivo . Preferably , Kate channel openers are Karp channel openers with all three properties. KATP Formula II channel openers as defined herein are preferably salts pre 7 pared from the compounds of Formulae I -VIII , as set forth - below . Z - RI In another aspect, the present invention also provides salts of the compounds defined by Formulae I -VIII . Salts of B

Formulae I - IV provided herein include monovalent alkali 0 metal salts and monovalent and divalent salts of organic compounds, preferably organic compounds which include 15 an ammonium moiety . Salts of Formulae V -VIII are also provided herein , preferably prepared with monovalent and wherein : divalent counter - ions. R ! is selected from the group consisting of hydrogen , KATP channel openers defined by Formula I are as fol lower alkyl, substituted lower alkyl, cycloalkyl, and 20 substituted cycloalkyl provided however that when R lows: is a substituted lower alkyl or a substituted cycloalkyl, then the substituent does not include an amino group ; Formula I R ? " is hydrogen ; R X is a 1 , 2 or 3 atom chain , wherein each atom is 25 independently selected from carbon , sulfur and nitro ? gen , and each atom is optionally substituted with halo gen , hydroxyl , lower alkyl, substituted lower alkyl, * R2a lower alkoxy, cycloalkyl , substituted cycloalkyl, or substituted lower alkoxy , provided however that when an atom of the chain is substituted with substituted 30 lower alkyl, substituted cycloalkyl or substituted lower wherein : alkoxy , then the substituent does not include an amino R ! is selected from the group consisting of hydrogen , group ; lower alkyl, substituted lower alkyl, cycloalkyl , and wherein ring B is saturated , monounsaturated , polyun substituted cycloalkyl provided however that when R ! saturated or aromatic ; is a substituted lower alkyl or a substituted cycloalkyl, 35 and all bioequivalents including salts , prodrugs and iso then the substituent does not include an amino group ; mers thereof. R24 is hydrogen ; In particular embodiments of Formula II , X is C ( R )C X is a 1 , 2 or 3 atom chain , wherein each atom is ( R ' ) , wherein Ra and Rºare independently selected from the independently selected from carbon , sulfur and nitro - group consisting of hydrogen , halogen , lower alkyl, substi gen , and each atom is optionally substituted with halo - 40 tuted lower alkyl, cycloalkyl, substituted cycloalkyl , lower gen , hydroxyl, lower alkyl, substituted lower alkyl, alkoxy , substituted lower alkoxy , sulfonyl, and the like . In lower alkoxy , cycloalkyl, substituted cycloalkyl, or further embodiments , Ra and R ' are independently selected substituted lower alkoxy, provided however that when from the group consisting of hydroxyl , substituted oxy , an atom of the chain is substituted with substituted substituted thiol, alkylthio , substituted alkylthio , sulfinyl, lower alkyl, substituted lower alkoxy or substituted 45 sulfonyl , substituted sulfinyl, substituted sulfonyl, alkyl cycloalkyl, then the substituent does not include an sulfinyl, alkylsulfonyl, nitro and the like . In preferred amino group ; embodiment, Ring B does not include any heteroatoms . wherein ring B is saturated , monounsaturated , polyun - Salts of embodiments of the channel openers defined by saturated or aromatic ; Formula II may be prepared from the following : ( a ) metal and all bioequivalents including salts , prodrugs and iso - 50 hydroxides, preferably alkali metal hydroxides ( e . g ., NaOH mers thereof. and KOH ) and ( b ) organic hydroxides , preferably organic In particular embodiments ofFormula I, X is C ( R ) C ( R ), compounds which include at least one tertiary amine or at wherein Ra and R are independently selected from the least one quaternary ammonium ion ( e . g ., diethylaminoetha group consisting of hydrogen , halogen , lower alkyl, substi - nol, triethylamine , hydroxyethylpyrrolidine , choline and tuted lower alkyl, cycloalkyl, substituted cycloalkyl, lower 55 hexamethylhexamethylenediammonium , and the like ) . alkoxy , substituted lower alkoxy, sulfonyl, and the like . In KATP channel openers defined by Formula III are as further embodiments , R™ andR are independently selected follows: from the group consisting of hydroxyl, substituted oxy, substituted thiol, alkylthio , substituted alkylthio , sulfinyl, sulfonyl, substituted sulfinyl, substituted sulfonylalkylsulfi - 60 Formula III nyl, alkylsulfonyl, and the like . In a preferred embodiment, P3 Ring B does not include any heteroatoms. Salts of embodiments of the channel openers defined by Formula I may be prepared from the following : ( a ) metal R4 2a hydroxides, preferably alkali metal hydroxides ( e . g . , NaOH 65 and KOH ) and ( b ) organic hydroxides , preferably organic compounds which include at least one tertiary amine or at US 9 , 765 ,043 B2 10 wherein : In particular embodiments of Formula IV , R is a lower Rl is selected from the group consisting of hydrogen , alkyl, (preferably ethyl or methyl) ; R26 is hydrogen ; and R3 lower alkyl , substituted lower alkyl, and cycloalkyl and R4 are each independently halogen . provided however that when Rl is a substituted lower In another embodiment of Formula IV , R ' is methyl ; R25 alkyl, then the substituent does not include an amino 5 is hydrogen ; R * is selected from the group consisting of group ; hydrogen , halogen , lower alkyl, substituted lower alkyl, R2a is hydrogen ; cycloalkyl, and substituted cycloalkyl; and R * is chlorine . R3 is selected from the group consisting of hydrogen , Salts of embodiments of the channel openers defined by halogen , lower alkyl , substituted lower alkyl, Formula IV may be prepared from the following: ( a ) metal cycloalkyl and substituted cycloalkyl provided how - 10 hydroxides, preferably alkali metal hydroxides ( e . g . , NaOH ever that when Rº is a substituted lower alkyl, then the and KOH ) and (b ) organic hydroxides , preferably organic substituent does not include an amino group ; compounds which include at least one tertiary amine or at R4 is selected from the group consisting of hydrogen , least one quaternary ammonium ion ( e . g ., diethylaminoetha halogen , lower alkyl , substituted lower alkyl, 15 nol, triethylamine , hydroxyethylpyrrolidine , choline and cycloalkyl and substituted cycloalkyl provided how - hexamethylhexamethylenediammonium , and the like ). ever that when R * is a substituted lower alkyl, then the Kate channel openers defined by Formula V are as substituent does not include an amino group ; follows: and all bioequivalents including salts , prodrugs and iso mers thereof. 20 In particular embodiments of Formula III, R ' is a lower Formula V alkyl , (preferably ethyl or methyl ); R20 is hydrogen ; and R3 and R * are each independently halogen . WRI In another embodiment of Formula III , Rl is methyl; R2a BLAZa is hydrogen ; R * is selected from the group consisting of 25 220 hydrogen , halogen , lower alkyl, substituted lower alkyl, cycloalkyl, and substituted cycloalkyl; and R4 is chlorine. Salts of embodiments of the channel openers defined by Formula III may be prepared from the following: ( a ) metal wherein : hydroxides , preferably alkali metal hydroxides ( e . g ., NaOH 20 R is selected from the group consisting of optionally and KOH ) and (b ) organic hydroxides , preferably organic substituted amino , optionally substituted alkyl, option compounds which include at least one tertiary amine or at ally substituted cycloalkyl, optionally substituted het least one quaternary ammonium ion ( e . g ., diethylaminoetha erocyclyl, optionally substituted heterocyclylalkyl, nol, triethylamine , hydroxyethylpyrrolidine, choline and optionally substituted aryl, optionally substituted het hexamethylhexamethylenediammonium , and the like ) . 35 eroaryl, and optionally substituted heteroarylalkyl; KATP channel openers defined by Formula IV are as R24 is selected from the group consisting ofhydrogen , and follows: lower alkyl; X is a 1, 2 or 3 atom chain , wherein each atom is independently selected from carbon , sulfur and nitro Formula IV 40 gen , and each atom is optionally substituted with halo gen , hydroxyl, optionally substituted lower alkyl, z NR optionally substituted lower alkoxy, optionally substi tuted cycloalkyl, or optionally substituted amino ; wherein ring B is saturated , monounsaturated , polyun 45 saturated or aromatic ; wherein at least one of Rl or a substituent of X includes an amino group ; wherein : and all bioequivalents including salts , prodrugs and iso Riis selected from the group consisting of hydrogen , 50 mers thereof. lower alkyl, substituted lower alkyl, and cycloalkyl In particular embodiments of Formula V , X is C ( R ) C provided however that when R1 is a substituted lower (R ' ) , wherein Ra and R are independently selected from the alkyl, then the substituent does not include an amino group consisting of hydrogen , halogen , optionally substi group ; tuted lower alkyl, optionally substituted cycloalkyl, option R26 is hydrogen ; 55 ally substituted lower alkoxy, amino , sulfonylamino, amino R * is selected from the group consisting of hydrogen , sulfonyl, sulfonyl , and the like . Preferably R includes at halogen , lower alkyl, substituted lower alkyl, least one substituent containing an amino group . In further cycloalkyl and substituted cycloalkyl provided how embodiments , Rº and R are independently selected from the ever that when R is a substituted lower alkyl, then the group consisting of hydroxyl, substituted oxy , substituted substituent does not include an amino group ; 60 thiol, alkylthio , substituted alkylthio , sulfinyl, sulfonyl, sub R4 is selected from the group consisting of hydrogen , stituted sulfinyl, substituted sulfonyl, substituted sulfo halogen , lower alkyl, substituted lower alkyl, nylamino , substituted amino , substituted amine, alkylsulfi cycloalkyl and substituted cycloalkyl provided how nyl, alkylsulfonyl, alkylsulfonylamino , and the like . In a ever that when R4 is a substituted lower alkyl, then the preferred embodiment, Ring B does not include any het substituent does not include an amino group ; 65 eroatoms. and all bioequivalents including salts , prodrugs and iso - KATP channel openers defined by Formula VI are as mers thereof. follows: US 9, 765 ,043 B2 12 R24 is selected from the group consisting of hydrogen , Formula VI lower alkyl, and substituted lower alkyl; R3 is selected from the group consisting of hydrogen , ? RI halogen , optionally substituted lower alkyl, optionally substituted amino , optionally substituted cycloalkyl and optionally substituted aryl; R4 is selected from the group consisting of hydrogen , halogen , optionally substituted lower alkyl, optionally substituted amino , optionally substituted cycloalkyl 10 and optionally substituted aryl; wherein : wherein at least one of R ' , R3 and R4 includes a substitu Rl is selected from the group consisting of optionally ent containing an amino group ; substituted amino , optionally substituted alkyl, option and all bioequivalents including salts , prodrugs and iso ally substituted cycloalkyl, optionally substituted het mers thereof. erocyclyl, optionally substituted heterocyclylalkyl, 15 Preferably , R ' includes a substituent containing an amino optionally substituted aryl, optionally substituted het group . In particular embodiments of Formula VII ; R eroaryl, and optionally substituted heteroarylalkyl; includes an amino substituent, R2a is hydrogen ; and R3 and R25 is selected from the group consisting of hydrogen and R * are each independently halogen . lower alkyl; 20 In another embodiment of Formula VII , R24 is hydrogen ; X is a 1 , 2 or 3 atom chain , wherein each atom is R3 is selected from the group consisting of hydrogen , independently selected from carbon , sulfur and nitro - halogen , lower alkyl , substituted lower alkyl, amino , sub gen , and each atom is optionally substituted with halo - stituted amino , cycloalkyl, and substituted cycloalkyl; and gen , hydroxyl, optionally substituted lower alkyl, R4 is chlorine. optionally substituted lower alkoxy, optionally substi - 25 Kate channel openers defined by Formula VIII are as tuted cycloalkyl, or optionally substituted amino ; follows: wherein ring B is saturated , monounsaturated , polyun saturated or aromatic ; wherein at least one of R ' or a substituent of X includes Formula VIII an amino group ; 30 R 25 and all bioequivalents including salts , prodrugs and iso A??? N . mers thereof. In particular embodiments of Formula VI, X is C ( R ) C ( R ) , wherein Rº and R are independently selected from the group consisting of hydrogen , halogen , lower alkyl, substi 35 tuted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkoxy , substituted lower alkoxy , amino , sulfonylamino , aminosulfonyl , sulfonyl, and the like . In further embodi- wherein : ments , Rº and R ” are independently selected from the group 40 R ' is selected from the group consisting of optionally consisting of hydroxyl, substituted oxy , substituted thiol, substituted amino , optionally substituted alkyl, option alkylthio , substituted alkylthio , sulfinyl , sulfonyl, substi ally substituted cycloalkyl, optionally substituted het tuted sulfinyl , substituted sulfonyl, substituted sulfo erocyclyl, optionally substituted heterocyclylalkyl, nylamino , substituted amino , substituted amine , alkylsulfi optionally substituted aryl, optionally substituted het nyl, alkylsulfonyl, alkylsulfonylamino , and the like . 45 eroaryl, and optionally substituted heteroarylalkyl; Preferably R includes at least one substituent containing an R25 is selected from the group consisting of hydrogen , amino group . In a preferred embodiment , Ring B does not lower alkyl, and substituted lower alkyl; include any heteroatoms. R3 is selected from the group consisting of hydrogen , KATP channel openers defined by Formula VII are as halogen , optionally substituted lower alkyl, optionally 5050 substituted amino , optionally substituted cycloalkyl follows: and optionally substituted aryl; R4 is selected from the group consisting of hydrogen , Formula VII halogen , optionally substituted lower alkyl, optionally R3 R substituted amino , optionally substituted cycloalkyl 55 and optionally substituted aryl; wherein at least one of R ' , R3 and R4 includes a substitu ent containing an amino group ; U R2a and all bioequivalents including salts , prodrugs and iso mers thereof. 60 Preferably Rl includes a substituent containing an amino wherein : group . In particular embodiments of Formula VII, R2b is R ! is selected from the group consisting of optionally hydrogen ; and R3 and R4 are each independently halogen . substituted amino , optionally substituted alkyl, option - In another embodiment of Formula VII , R25 is hydrogen ; ally substituted cycloalkyl, optionally substituted het - R is selected from the group consisting of hydrogen , erocyclyl, optionally substituted heterocyclylalkyl, 65 halogen , lower alkyl, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted het - optionally substituted amino , and optionally substituted eroaryl , and optionally substituted heteroarylalkyl; cycloalkyl; and R4 is chlorine. US 9 , 765 ,043 B2 13 14 Unless otherwise indicated , reference in this application channel opener per kg of the subject 's body weight, or to KatP channel openers should be understood to refer to between 5 - 10 mg of the K ATP channel opener per kg of the KATP channel openers based upon a salt of one of the subject’ s body weight, or between 10 - 15 mg of the KATP compounds described by Formulae I - VIII and having one or channel opener per kg of the subject’ s body weight, or more , and preferably all three , of the following properties : 5 between 15 - 20 mg of the K tp channel opener per kg of the ( 1 ) opening SURx /Kirá . y potassium channels, wherein x = 1 , subject' s body weight. 2A or 2B and y = 1 or 2 ; ( 2 ) binding to the SURx subunit of Also provided herein are controlled release pharmaceuti Kate channels ; and (3 ) inhibiting glucose induced release of cal formulations containing Kate channel openers selected insulin following administration of the compound in vivo . from salts of Formulae 1 -VIII , which can be obtained by at Such KATP channel openers preferably have the structure of 10 least one of the following : (a ) particle size reduction involv any of the compounds of Formula I -VIII , or more preferably ing comminution , spray drying , or other micronising tech Formula III -IV where ring B or its equivalent does not niques, ( b ) use of an ion exchange resin , ( c ) use of inclusion include any heteroatoms. More preferably , the structure is complexes, for example cyclodextrin , (d ) compaction of the diazoxide . Structural variants or bioequivalents of any of the Karp channel opener with a solubilizing agent including a compounds defined by Formulae I- VIII , such as derivatives , 15 low viscosity hypromellose , low viscosity methylcellulose salts , prodrugs or isomers , are also contemplated herein . or similarly functioning excipient or combinations thereof, Specifically , salts of compounds of Formula I- IV wherein ( e ) associating the Kate channel opener with a salt prior to the cation is selected from a cation of an alkali metal or an formulation , (f ) use of a solid dispersion of the Karp channel organic compound which includes a tertiary amine or a opener , ( g ) use of a self emulsifying system , ( h ) addition of quaternary ammonium ion . Preferably , when the salt 20 one or more surfactants to the formulation , ( i ) use of includes an anion of diazoxide and a sodium cation , the salt nanoparticles, or (j ) combinations of these approaches. is not in a form suitable for intravenous use . In other Further provided herein are controlled release pharma embodiments , when the anion is diazoxide in a solution ceutical formulations containing Kamp channel openers suitable for intravenous use , the cation is not sodium . In selected from salts of the compounds defined by Formulae alternate embodiments , in solutions suitable for intravenous 25 I - VIII , which include at least one component that substan use , when the cation is sodium , the anion is not an anion of tially inhibits release of the Karp channel activator from the diazoxide . In certain embodiments , when the salt includes an formulation until after gastric transit . As used herein , “ sub anion of diazoxide and a sodium cation , the salt is not in stantially inhibits ” means less than 15 % release , more pref liquid form . More preferably, Kamp channel openers con - erably at least less than 10 % release , or even more prefer templated herein are salts of compounds of Formulae III and 30 ably at least less than 5 % release of the drug from the IV wherein the cation is selected from sodium , potassium , formulation during gastric transport . Release can be mea choline or hexamethyl hexamethylene diammonium . Other sured in a standard USP based in - vitro gastric dissolution Ktp channel openers that are contemplated for use herein assay in a calibrated dissolution apparatus . See e . g . , U . S . include BPDZ 62 , BPDZ 73 , NN414 , BPDZ 154 . Pharmacopeia , Chapter 711 ( 2005 ) . Also provided herein are salts of compounds of Formula 35 Also provided are oral pharmaceutical formulations of the V - VIII , wherein at least one substituent of the compound of Kamp channel openers selected from the salts of the com Formulae V - VIII includes an amino group . In another pounds of Formulae I -VIII , which include at least one embodiment, the compound of Formula V - VIII forms the component that substantially inhibits release of the KATP anion of the salt and a monovalent or divalent metal forms channel opener from the formulation until after gastric the cation . In other embodiments , the cation includes a 40 transit. Substantial inhibition of drug release during gastric tertiary amino or quaternary ammonium group . transit is achieved by inclusion of a component in the In vitro analysis of glucose induced release of insulin via formulation selected from the group consisting of: ( a ) a pH Ktp channel openers can be determined using rat islets as sensitive polymer or co -polymer applied as a compression provided by De Tullio et al ., J . Med . Chem ., 46 :3342 -3353 coating on a tablet, ( b ) a pH sensitive polymer or co - polymer ( 2003 ) , or by using human islets as provided by Björklund 45 applied as a thin film on a tablet, (c ) a pH sensitive polymer et al ., Diabetes, 49 : 1840 - 1848 ( 2000 ) . or co -polymer applied as a thin film to an encapsulation Provided herein are formulations, such as controlled system , ( d ) a pH sensitive polymer or co -polymer applied to release pharmaceutical formulations , of Kamp channel open - encapsulated microparticles , ( e ) a non -aqueous - soluble ers and bioequivalents thereof, which include salts of the polymer or copolymer applied as a compression coating on compounds of Formulae I - VIII . In one embodiment, the salt 50 a tablet , ( f ) a non - aqueous - soluble polymer or co - polymer can be formulated for controlled release following oral applied as a thin film on a tablet , ( g ) a non - aqueous soluble administration . Such formulations contain in a single admin polymer applied as a thin film to an encapsulation system , istration dosage between 10 and 100 mg, between 25 and and ( h ) a non - aqueous soluble polymer applied to micropar 100 mg, between 100 and 200 mg, between 200 and 300 mg, ticles, wherein the pH sensitive polymer or co -polymer is between 300 and 500 mg or between 500 and 2000 mg of the 55 resistant to degradation under acid conditions. Alternatively , salt of the KatP channel openers provided in Formulae substantial inhibition of drug release during gastric transport I - VIII. In certain embodiments , the dosage of the KATP can also be achieved by incorporation of the formulation in channel openers contained in a formulation may be deter- an osmotic pump system , by use of systems controlled by mined based on the weight of the subject for which it is to ion exchange resins , or by combinations of any of the above be administered , i .e ., the formulation may contain in a single 60 approaches . administration dosage between 0 . 1 - 20 mg of the KATP Also provided herein are controlled release pharmaceuti channel opener per kg of the subject' s body weight, or cal formulations of Kamp channel openers selected from salts between 0 . 1 - 0 . 5 mgof the Karp channel opener per kg of the of the compounds of Formulae I- VIII , wherein the formu subject' s body weight; or between 0 . 5 - 1 mg of the KATP lation includes at least one component that contributes to channel opener per kg of the subject ' s body weight ; or 65 sustained release of a KATP channel opener over an extended between 1 - 2 mg of the KATP channel opener per kg of the period , e . g . , over a period of 2 - 24 hours following admin subject ’ s body weight, or between 2 - 5 mg of the KATP istration , or over a period of 2 - 4 hours following adminis US 9 , 765 ,043 B2 15 16 tration , or over a period of 4 - 8 hours following administra about 55 % by weight of a polymer as described herein . For tion , or over a period of more than 8 - 24 hours following example , the polymer may be selected from the group administration . These formulations are characterized in hav consisting of polyethylene oxide and cellulose . Cellulose ing one of the following components : ( a ) a pH sensitive suitable for use in such formulations may be selected from polymeric coating , ( b ) a hydrogel coating , ( c ) a film coating 5 hydroxypropylmethyl cellulose , hydroxypropylcellulose , that controls the rate of diffusion of the drug from a coated ethylcellulose , methylcellulose , carboxymethylcellulose , matrix , (d ) an erodable matrix that controls rate of drug and a mixture of any two or more thereof. Various polyeth release , ( e ) polymer coated pellets , granules or micropar - ylene oxides may be used in the formulations , including ticles of drug which can be further encapsulated or com - those selected from PEO N750 , PEO 303 or a mixture pressed into a tablet , ( f ) an osmotic pump system containing 10 thereof . the drug , ( g ) a compression coated tablet form of the drug , Provided herein are methods of using any of the salts of or ( h ) combinations of any of the approaches of ( a ) - ( f) the compounds of Formulae I - VIII and formulations thereof. above . For example , provided herein is a method of treating hypo As used herein , an erodable matrix is the core of a tablet glycemia, the method comprising orally administering to a formulation that , upon exposure to a suitable aqueous envi- 15 subject in need thereof, a controlled release formulation of ronment , begins a process of disintegration which facilitates a Ktp channel opener selected from the salts of the com the release of drug from the matrix . The rate of release of pounds of Formulae I -VIII . drug from the tablet is controlled both by the solubility of the Further provided herein is a method of treating obesity drug and the rate of disintegration of the matrix . associated co -morbidities in an obese , overweight or obesity The above formulations may further comprise one or 20 prone subject , the method comprising administering a thera more additional pharmaceutically active agents ( other than peutically effective amount of a solid oral dosage form of a KATP channel openers selected from the salts of the com KATP channel opener selected from the salts of the com pounds of Formulae I - VIII) useful for the treatment of a pounds of Formulae I - VIII, or controlled release pharma condition selected from the group consisting of obesity , ceutical formulation of a Ktp channel opener selected from prediabetes , diabetes , hypertension , depression , elevated 25 the salts of the compounds of Formulae I- VIII . In a preferred cholesterol, fluid retention , other obesity associated co - embodiment, administration is no more than two times per morbidities , ischemic and reperfusion injury , epilepsy, cog - 24 hours , or once per 24 hours . nitive impairment, schizophrenia , mania , other psychotic Yet further provided herein is a method of achieving diseases , and the like . weight loss in an obese overweight, or obesity prone subject , Further provided is a controlled release pharmaceutical 30 the method comprising administering a therapeutically formulation of a Kftp channel opener selected from the salts effective amount of a solid oral dosage form of a Kamp of the compounds of Formulae I -VIII wherein administra - channel opener selected from the salts of the compounds of tion to an obese , overweight or obesity prone subject results Formulae I -VIII or controlled release pharmaceutical for in at least one of the following : ( a ) inhibition of fasting mulation of a Kate channel opener selected from the salts of insulin secretion , (b ) inhibition of stimulated insulin secre - 35 the compounds of Formulae 1 -VIII . In a preferred embodi tion , ( c ) elevation of energy expenditure , ( d ) elevation of ment, administration is no more than two times per 24 hours , beta oxidation of fat, or ( e ) inhibition of hyperphagia for or once per 24 hours. The daily dosage administered is about 24 hours . preferably between 50 and 180 mg. In certain embodiments , Additionally provided is a controlled release pharmaceu the obese subject has a body mass index greater than 30 tical formulation of a Kamp channel opener selected from the 40 kg/ m² , or greater than 35 kg/ m² , or greater than 40 kg /m² , salts of the compounds of Formulae I - VIII wherein admin - or greater than 50 g /m² , or greater than 60 kg/ m² at the time istration to an obese , overweight or obesity prone subject the method commences. results in at least one of the following : (a ) inhibition of Also provided is a method ofmaintaining a weight loss in fasting insulin secretion , ( b ) inhibition of glucose stimulated an obese overweight, or obesity prone subject, the method insulin secretion , ( c ) elevation of energy expenditure , ( d ) 45 comprising administering a therapeutically effective amount elevation of beta oxidation of fat, or (e ) inhibition of of a solid oral dosage form of a Kamp channel opener hyperphagia for about 18 hours . selected from the salts of the compounds of Formulae I - VIII Still further provided is a controlled release pharmaceu - or controlled release pharmaceutical formulation of a KAT tical formulation of a Kato channel opener selected from the channel opener selected from the salts of the compounds of salts of the compounds of Formulae I - VIII which upon 50 Formulae I - VIII . It is preferable to maintain weight in an administration to an obese , overweight or obesity prone obese subject once some weight loss has occurred when the subject results in at least one of the following : (a ) inhibition alternative is to regain weight. In a preferred embodiment, of fasting insulin secretion , ( b ) inhibition of glucose stimu - administration is no more than two times per 24 hours , or lated insulin secretion , (c ) elevation of energy expenditure , once per 24 hours . ( d ) elevation of beta oxidation of fat, or ( e ) inhibition of 55 Also provided is a method of treating obesity or type 1 or hyperphagia for about 24 hours . type 2 diabetes with a salt of KATP channel opener which Additionally provided is a controlled release pharmaceu - minimizes a range of adverse events including but not tical formulation of a K tp channel opener selected from the limited to headaches, fluid retention , edema, hyperglycemia , salts of the compounds of Formulae 1 -VIII that upon admin - and tachycardia . In accordance with this method , the initial istration to an obese , overweight or obesity prone subject 60 dose is chosen to provide for elevations in supine heart rate results in at least one of the following : ( a ) inhibition of that on average are not greater than 5 beats per minute , fasting insulin secretion , ( b ) inhibition of glucose stimulated followed by tolerization and a return to baseline heart rate by insulin secretion , (c ) elevation of energy expenditure , (d ) the time steady state circulating Kate channel opener levels elevation of beta oxidation of fat , or ( e ) inhibition of are reached . This starting dose is preferably between 10 and hyperphagia for about 18 hours . 65 200 mg of Katp channel opener or the equivalent based on In other embodiments of the invention there are provided relative bioavailability and potency compared to diazoxide . formulation comprising diazoxide choline and about 1 % to Preferably , the Kate channel opener is diazoxide. The start US 9 , 765 ,043 B2 17 18 ing dose is given to the patient daily for days or a few weeks . greater than 20 kg /m² , or greater than 25 kg /m² , or greater In further embodiments , the method includes escalating the than 30 kg /m² , or greater than 35 kg/m² , or greater than 40 dose which is administered when after supine heart rates kg/ m² , or greater than 50 kg /m² , or greater than 60 kg /m2 at return to baseline . An initial escalating dose is established the time the method commences . using the same criteria as the initial dose. The initial 5 Yet further provided is a method of reducing visceral fat escalating dose is given to the patient daily for days or a few in an overweight , obese or obesity prone subject, the method weeks. The increment in dose is preferentially 25 to 150 mg of Karp channel opener or the equivalent based on relative comprising administering an effective amount of a solid oral bioavailability and potency compared to diazoxide. Further dosage form of a Kamp channel opener selected from the rounds of this dose escalation would continue until the 10 salts of the compounds of Formulae I -VIII or controlled therapeutically effective dose is reached . Alternatively, release pharmaceutical formulation of a KATP channel standing heart rate may be utilized where the average opener selected from the salts of the compounds of Formu increase is not greater than 10 beats per minute . lae I- VIII. In a preferred embodiment, administration is no Further provided is a method of treating subjects with more than two times per 24 hours, or once per 24 hours. type 1 or type 2 diabetes suffering from hypoglycemia 15 Still further provided is a method of delaying or prevent associated autonomic failure involving the administration of ing the transition to diabetes of a prediabetic subject com an agent that either stimulates glucagon release from pan - prising administering an effective amount of a Kato channel creatic alpha cells via interaction with Karp channels and /or opener selected from the salts of the compounds of Formu stimulates hypothalamic neurons resulting in an amplifica lae I - VIII or controlled release pharmaceutical formulation tion of or restoration of the counter regulatory hormonal 20 of a Kftp channel opener selected from the salts of the response to hypoglycemia , via activation ofKate channels . compounds of Formulae I- VIII . In a preferred embodiment, In a preferred embodiment, the agent is a therapeutically administration is no more than two times per 24 hours, or effective amount of a formulation selected from the group once per 24 hours . consisting of: Additionally provided is a method of restoring normal i ) a formulation comprising a salt , wherein the salt com - 25 glucose tolerance in a prediabetic subject comprising admin prises an anion of a Kftp channel opener selected from the istering an effective amount of a Kamp channel opener group consisting of Formula I , Formula II, Formula III and selected from the salts of the compounds of Formulae I -VIII Formula IV , and a cation selected from the group consisting or controlled release pharmaceutical formulation of a KTP of an alkali metal and a compound comprising a tertiary channel opener selected from the salts of the compounds of amine or ammonium group ; 30 Formulae I- VIII . In a preferred embodiment, administration ii) a formulation comprising a salt , wherein the salt is no more than two times per 24 hours , or once per 24 hours . comprises an anion of a Kamp channel opener selected from Further provided is a method of restoring normal glucose the group consisting of Formula V , Formula VI, Formula VII tolerance in a diabetic subject comprising administering an and Formula VIII ; and effective amount of a Karp channel opener selected from the iii ) a formulation comprising a salt , wherein the salt 35 salts of the compounds of Formulae I - VIII or controlled comprises an anion of a Kamp channel opener selected from release pharmaceutical formulation of a Kato channel the group consisting of Formula V , Formula VI, Formula VII opener selected from the salts of the compounds of Formu and Formula VIII , wherein at least one substituent of the lae I - VIII . In a preferred embodiment, administration is no compound of Formulae V - VIII includes an amino group . In more than two times per 24 hours, or once per 24 hours. another embodiment, the compound of Formula V -VIII 40 Still further provided is a method of delaying or prevent forms the anion of the salt and a monovalent or divalent ing progression of diabetes in an subject comprising admin metal forms the cation . In other embodiments , the cation istering an effective amount of a KATP channel opener includes a tertiary amino or quaternary ammonium group . selected from the salts of the compounds of Formulae I - VIII Further provided is a method of elevating energy expen - or controlled release pharmaceutical formulation of a KATP diture in an overweight , obese or obesity prone subject, the 45 channel opener selected from the salts of the compounds of method comprising administering an effective amount of a Formulae I - VIII . In a preferred embodiment, administration solid oral dosage form of a Ktp channel opener selected is no more than two times per 24 hours, or once per 24 hours. from the salts of the compounds of Formulae I - VIII or Also provided is a method to prevent or treat weight gain , controlled release pharmaceutical formulation of a KTP impaired glucose tolerance or dyslipidemia associated with channel opener selected from the salts of the compounds of 50 the administration of anti -psychotics to a subject, said Formulae I - VIII . In a preferred embodiment, administration method including the co -administration of an effective is no more than two times per 24 hours , or once per 24 hours . amount of a Karp channel opener selected from the salts of In certain embodiments , the subject has a body mass index the compounds of Formulae I - VIII or controlled release greater than 20 kg /m² , or greater than 25 kg/ m² , or greater pharmaceutical formulation of a KATP channel opener than 30 kg /m² , or greater than 35 kg /m² , or greater than 40 55 selected from the salts of the compounds of Formulae I- VIII . kg / m ” , or greater than 50 kg / m ” , or greater than 60 kg /m² at In a preferred embodiment, administration is no more than the time the method commences . two times per 24 hours, or once per 24 hours Additionally provided is a method of elevating beta Further provided is a method to treat obesity , or hyper oxidation of fat in an overweight, obese or obesity prone phagia in a Prader - Willi Syndrome patient, a Froelich ' s subject, the method comprising administering an effective 60 Syndrome patient, in a Cohen Syndrome patient, in a amount of a solid oral dosage form of a Karp channel opener Summit Syndrome patient, in an Alstrom Syndrome patient, selected from the salts of the compounds of Formulae I - VIII in a Borjeson Syndrome patient or in a Bardet- Biedl Syn or controlled release pharmaceutical formulation of a KATP drome patient comprising the administration of an effective channel opener selected from the salts of the compounds of amount of a Kto channel opener selected from the salts of Formulae I - VIII . In a preferred embodiment, administration 65 the compounds of Formulae I - VIII or controlled release is no more than two times per 24 hours , or once per 24 hours. pharmaceutical formulation of a Kftp channel opener In certain embodiments , the subject has a body mass index selected from the salts of the compounds of Formulae I - VIII . US 9 , 765 ,043 B2 19 20 In a preferred embodiment , administration is no more than Further provided is a method of preventing weight gain , two times per 24 hours, or once per 24 hours. dyslipidemia or impaired glucose tolerance in a subject Still further provided is a method to treat obesity or treated with an anti -psychotic drug , the method comprising elevated triglycerides in a patient suffering hyperlipopro administering a pharmaceutical formulation of a Karp chan teinemia type I, type II, type III or type IV comprising 5 nel opener selected from the salts of the compounds of Formulae I -VIII . administering an effective amount of a Karp channel opener Yet further provided is a method of treating weight gain , selected from the salts of the compounds of Formulae I- VIII dyslipidemia or impaired glucose tolerance in a subject or controlled release pharmaceutical formulation of a KATE treated with an anti - psychotic drug , the method comprising channel opener selected from the salts of the compounds of 10 administering a pharmaceutical formulation of a KATp chan Formulae I - VIII . In a preferred embodiment, administration nel opener selected from the salts of the compounds of is no more than two times per 24 hours , or once per 24 hours. Formulae I - VIII . Also provided is a method of reducing the incidence of Also provided is a method of treating diseases character adverse effects from administration of a KTP channel ized by obesity , hyperphagia , dyslipidemia , or decreased opener selected from the salts of the compounds of Formu 15 energy expenditure including (a ) Prader - Willi Syndrome, (b ) lae I- VIII in the treatment of diseases of a subject achieved Froelich ' s syndrome, ( c ) Cohen syndrome, ( d ) Summit by any of the following : (a ) use of a dosage form that on Syndrome, ( e ) Alstrom Syndrome, ( f ) Borjesen Syndrome, administration reduces Cmax relative to the current Progly - (g ) Bardet - Biedl Syndrome, or (h ) hyperlipoproteinemia cem® oral suspension or capsule products in order to reduce type I, II, III, and IV comprising administering a pharma the incidence of adverse side effects that are associated with 20 ceutical formulation of a Kate channel opener selected from peak drug levels , (b ) use of a dosage form that delays release the salts of the compounds of Formulae I - VIII . until gastric transit is complete in order to reduce the Further provided is a pharmaceutical formulation of a incidence of adverse side effects that are associated with the Kate channel opener selected from the salts of the com release of drug in the stomach , ( c ) initiating dosing at pounds of Formulae I - VIII further comprising a pharmaceu subtherapeutic levels and in a stepwise manner increasing 25 tically active agent other than theKtp channel opener . In dose daily until the therapeutic dose is achieved wherein the this formulation , the other pharmaceutically active agent is number of steps is 2 to 10 to reduce the incidence of adverse an agent useful for the treatment of a condition selected from side effects that occur transiently at the initiation of treat- the group consisting of obesity , prediabetes, diabetes, hyper ment, ( d ) use of the lowest effective dose to achieve the tension , depression , elevated cholesterol, fluid retention , or desired therapeutic effect in order to reduce the incidence of 30 other obesity associated co -morbidities , ischemic and rep adverse side effects that are dose dependent, or ( e ) optimiz - erfusion injury , epilepsy , cognitive impairment, schizophre ing the timing of administration of dose within the day and nia , mania , and other psychotic condition . relative to meals . The formulations containing Kamp channel openers Further provided is a method of reducing the incidence of selected from the salts of the compounds of Formulae I - VIII adverse effects from administration of a KATP channel 35 described herein provide for improved compliance , efficacy opener selected from the salts of the compounds of Formu - and safety , and for co - formulations with other agents . lae I - VIII without substantially impacting the pharmacoki- Included are co - formulations of Kate channel openers netic profile of said administered Karp channel opener, selected from the salts of the compounds of Formulae I - VIII comprising administering to a subject said Karp channel with one or more additional pharmaceutically active agents opener orally in conjunction with a meal which includes 40 that have complementary or similar activities or targets . solid food . As used herein , in administration of the opener in Other pharmaceutically active agents that can be combined conjunction with a meal means that the two are ingested with Kato channel openers selected from the salts of the within 15 minutes of each other. Accordingly , there is compounds of Formulae I - VIII to treat obesity or to main provided a method of reducing the incidence of adverse tain weight loss in an obesity prone subject include , but are effects resulting from orally administering a salt of a KTP 45 not limited to : sibutramine, orlistat, phentermine , rimona channel opener comprising , causing to be orally ingested a bant, a diuretic , an antiepileptic , or other pharmaceutical formulation selected from the group consisting of: active whose therapeutic utility includes weight loss . It is i ) a formulation comprising a salt , said salt comprising an preferable to maintain weight in an obese subject once some anion of a Ktp channel opener selected from the group weight loss has occurred when the alternative is to regain consisting of Formula 1, Formula II, Formula III and For- 50 weight. Other pharmaceutically active agents that may be mula IV , and a cation selected from the group consisting of combined with Ktp channel openers selected from the salts an alkali metal and a compound comprising a tertiary amine of the compounds of Formulae I- VIII to treat type II or ammonium group ; diabetes , or prediabetes include acarbose , miglitol, met ii ) a formulation comprising a salt, said salt comprising an formin , repaglinide , nateglinide , rosiglitazone , proglitazone , anion of a KATP channel opener selected from the group 55 ramipril, metaglidasen , or any other pharmaceutical active consisting of Formula V , Formula VI, Formula VII and that improves insulin sensitivity or glucose utilization or Formula VIII ; and glycemic control where the mode of action is not enhanced iii ) a formulation comprising a salt, said salt comprising insulin secretion . Other pharmaceutical active agent that can an anion of a Karp channel opener selected from the group be combined with Karp channel openers selected from the consisting of Formula V , Formula VI, Formula VII and 60 salts of the compounds of Formulae I - VIII to treat obesity Formula VIII, wherein at least one substituent comprises an associated co -morbidities include a drug active used to amino group ; and , lower cholesterol, a drug active used to lower blood pres a meal containing one or more solid food items sufficient sure , an anti - inflammatory drug that is not a cox - 2 inhibitor, to reduce the incidence of adverse effects resulting from the a drug that is an antidepressant, a drug used to treat urinary orally ingested salt of a Karp channel opener. In a preferred 65 incontinence , or other drug routinely used to treat disease embodiment, the formulation and the meal are taken within conditions the incidence of which is elevated in overweight 15 minutes or less of each other . or obese patients as compared to normal weight subjects US 9 , 765 ,043 B2 21 22 including, but not limited to , drugs to treat atherosclerosis , the methods , the formulation may be administered once , osteoarthritis , disc herniation , degeneration of knees and twice or three times per 24 hours . In certain embodiments , hips , breast, endometrium , cervical, colon , leukemia and the formulation comprises diazoxide choline . prostate cancers , hyperlipidemia , asthma/ reactive airway As noted above , the methods described herein can be used disease , gallstones, GERD , obstructive sleep apnea , obesity 5 to inhibit or prevent the progression of Type I diabetes . In hypoventilation syndrome, recurrent ventral hernias , men some such methods , the rate of beta cell loss is decreased by , strual irregularity and infertility . e . g ., about 5 % to about 95 % compared to the subject prior Also provided herein are methods for treating obesity or to administration of the formulations of the present inven obesity associated co -morbidities or other diseases or con - tion . In other instances , the rate of beta cell loss is decreased ditions involving KATP channels by co - administration to a 10 by at least about 5 % , 10 % , 15 % , 20 % , 25 % , 30 % 40 % , 50 % , subject in need thereof of an effective amount of any of the 60 % , 70 % , 80 % , 90 % , or 95 % compared to the subject prior compounds according to Formulae I - VIII , or a salt of any of to administration of the formulations of the present inven the compounds according to Formulae I - VIII or pharmaceu - tion , or prior to administration of a combination of the tical formulation thereof, and a drug selected from the group formulation as described herein and additional therapeutic consisting of an amphetamine or amphetamine mixture , 15 agent ( s ) . Sibutramine, Orlistat , Rimonabant, a CB - 1 antagonist, a The methods described herein can be used to reduce 5HT2e receptor agonist , a drug used to treat addiction , a beta insulin dosing as described above. In some instance of the adrenergic receptor agonist , an ACC inhibitor, leptin , a methods, the insulin dosing is decreased by about 5 % to leptin analogue, a leptin agonist, a somatostatin agonist , an about 95 % in a subject, compared to the subject' s insulin adiponectin agonist or secretagogue , Amylin , PYY or a PYY 20 dose prior to being administered the formulations of the analogue , a ghrelin antagonist , a drug that inhibits gastro - present invention , or prior to administration of a combina intestinal lipases or other digestive enzymes , a de -novo tion of the formulation as described herein and additional lipogenesis inhibitor, a drug that blocks absorption of dietary therapeutic agent( s ) . In other instances of the methods, the fat , growth hormone or a growth hormone analogue , a insulin dosing is decreased by at least about 5 % , 10 % , 20 % , growth hormone secretagogue , a CCK agonist, an oleoyle - 25 30 % , or 50 % . thanolamine receptor agonist, a fatty acid synthase inhibitor, As described above , the methods described herein can be a thyroid receptor agonist , a selective androgen receptor used to increase glycemic control. “ Glycemic control” refers modulator, a PPAR agonist , a Beta hydroxysteroid Dehy - to attempts to reproduce natural physiological glucose drogenase - 2 inhibitor, oxyntomodulin , oleoylestrone , a homeostasis . Accordingly, glycemic control is increased in a NPY2 receptor antagonist , a NPY5 receptor antagonist, a 30 subject when the natural physiological glucose homeostasis NPY agonist, a monoamine uptake inhibitor, a MTP inhibi- is attained more often in a subject administered the formu tor, a MC4 receptor agonist , a MCH1 receptor antagonist, a lations of the present invention compared to the subject prior 5HT- 6 antagonist, a histamine - 3 antagonist , a glycine ana - to administration of the formulations . log , a fgfl inhibitor, a DGAT- 1 inhibitor, a carboxypeptidase The methods described herein can be used to delay the inhibitor, an appetite suppressant , a non - thiazide diuretic , a 35 loss of residual insulin secretion . Residual insulin secretion drug that lowers cholesterol, a drug that raises HDL cho - refers to the partial preservation of islet beta - cell function , as lesterol, a drug that lowers LDL cholesterol , a drug that demonstrated by preserved insulin production in subjects lowers blood pressure , a drug that is an anti - depressant, a having Type 1 diabetes . Although not sufficient for the needs drug that improves insulin sensitivity , a drug that improves of the individual, residual insulin secretion is important for glucose utilization or uptake, a drug that is an anti - epileptic , 40 metabolic control, for avoidance of hypoglycemic episodes , a drug that is an anti - inflammatory , a drug that is an appetite and for protection against diabetic complications . To retain suppressant, a drug that lowers circulating triglycerides , a residual insulin secretion in type 1 diabetes is highly desir drug that is used to induce weight loss in an overweight or able . As used herein , the term “ residual insulin secretion ” obese individual, and pharmaceutically acceptable salts refers to a level of insulin production by islet beta cells that thereof. 45 is least about 10 % , 15 % , 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , Provided herein are methods of ( a ) inhibiting or prevent- 50 % , or 60 % of the level produced by a subject not ing the progression of type I diabetes, (b ) reducing insulin diagnosed with Type I diabetes. In one instance , the methods dosing , ( c ) increasing glycemic control, or ( d ) delaying the provide that the loss of residual insulin secretion is delayed loss of residual insulin secretion in a subject suffering from by at least about 3 months , 6 months, 12 months , 15 months , type 1 diabetes , comprising administering to said subject a 50 18 months , 21 months , or up to 48 months compared to a therapeutically effective amount of a formulation of a KATP subject not administered the formulations of the present channel opener selected from the salts of the compounds of invention . Formulae I - VIII . For example , the formulation may be further provided herein are methods of increasing insulin selected from the group consisting of: i) a formulation sensitivity in a subject suffering from type II diabetes , comprising a salt , said salt comprising an anion of a KTP 55 comprising administering to said subject a therapeutically channel opener selected from the group consisting of For effective amount of a formulation of a KATP channel opener mula 1 , Formula II , Formula III and Formula IV , and a cation selected from the salts of the compounds of Formulae I - VIII . selected from the group consisting of an alkali metal and a For example , the formulation may be selected from the compound comprising a tertiary amine or ammonium group ; group consisting of: i ) a formulation comprising a salt, said ii ) a formulation comprising a salt , said salt comprising an 60 salt comprising an anion of a KATP channel opener selected anion of a Kate channel opener selected from the group from the group consisting of Formula 1, Formula II , Formula consisting of Formula V , Formula VI, Formula VII and III and Formula IV , and a cation selected from the group Formula VIII ; and iii ) a formulation comprising a salt, said consisting of an alkali metal and a compound comprising a salt comprising an anion of a Ktp channel opener selected tertiary amine or ammonium group ; ii ) a formulation com from the group consisting of Formula V , Formula VI, 65 prising a salt, said salt comprising an anion of a KATP Formula VII and Formula VIII , wherein at least one sub - channel opener selected from the group consisting of For stituent comprises an amino group . In some embodiments of mula V , Formula VI, Formula VII and Formula VIII; and iii ) US 9 , 765 ,043 B2 23 24 a formulation comprising a salt , said salt comprising an the group consisting of a GLP - 1 analog or mimetic , and a anion of a KATP channel opener selected from the group sulfonylurea receptor antagonist such as meglitinides. consisting of Formula V , Formula VI, Formula VII and Suitable sulfonylurea receptor antagonists for use in Formula VIII , wherein at least one substituent comprises an methods described herein include one or more agents amino group . In the methods, the therapeutically effective 5 selected from the group consisting of, but not limited to amount of the formulation may range from about 15 mg/day nateglinide, mitglinide, repaglinide and pharmaceutically to about 500 mg /day . In some embodiments of the methods, acceptable salts thereof. Suitable DPP -IV inhibitors for use in the presentmethods the formulation may be administered once, twice or three include one or more agents selected from the group con times per 24 hours . In certain embodiments , the formulation 10 sisting of, but limited to sitagliptin , saxagliptin , vildagliptin , comprises diazoxide choline . and pharmaceutically acceptable salts thereof. The methods described herein can be used to increase GLP - 1 analogs or mimetics that may be used in the insulin sensitivity in a subject by, e . g . , about 10 % to about present methods include one or more agents selected from 95 % or more . In one instance , the insulin sensitivity is the group consisting of exenatide , liraglutide , albugon , exen increased in a subject by at least about 30 % compared to the 15 dindin - 4 analogs and conjugates, and pharmaceutically accept subject prior to administration of the formulations of the able salts and conjugatesconiugates thereofthereof. . present invention . In other instances , the insulin sensitivity Suitable meglitinides for use in the present methods is increased by at least about 10 % , 15 % , 20 % , 25 % , 30 % , include one or more agents selected from the group con 35 % , 40 % , 45 % , 50 % , 60 % , 70 % , 80 % or 90 % compared to sisting of, but not limited to repaglinide , nateglinide , the subject prior to administration of the formulations of the 20 mitiglinide and pharmaceutically acceptable salts thereof. present invention , or prior to administration of a combina Likewise suitable thiazolidinediones , PPAR agonists or tion of the formulation as described herein and additional partial agonists that may be used in the methods described therapeutic agent( s ) . Insulin sensitivity is indicated , for herein include one or more agents selected from the group example , by reductions in the homeostasis model assess consisting of, but not limited to pioglitazone , rosiglitazone, ment- insulin resistance (HOMA - IR ) index . 25 troglizazone , tesaglitazar, muraglitazar, netoglitazar, Still further provided are methods of treating a subject LY518674 , ragaglitazar, sipoglitazar, and pharmaceutically suffering from type II diabetes , comprising co - administering acceptable salts thereof. to said subject a therapeutically effective amount of a Exemplary disaccharidase inhibitor for use in the present formulation and an anti - diabetic drug that either stimulates methods include one or more agents selected from the group insulin secretion or is a short acting anti - diabetic drug , 30 consisting of, but not limited to acarbose , AO - 128 , and wherein the formulation is selected from the group consist pharmaceutically acceptable salts thereof. ing of : i ) a formulation comprising a KATP channel opener Fructose - 1 , 6 -bisphosphatase inhibitors suitable for use in selected from the group consisting of Formulae I - VIII ; ii ) a the present methods include one or more agents selected formulation comprising a salt, said salt comprising an anion from the group consisting of, but not limited to phenyl of a KATP channel opener selected from the group consist - 35 phosphonates , benzimidazoles , CS -917 , anilinoqiunazolo ing of Formula 1 , Formula II , Formula III and Formula IV , nes , and benzoxaozole benzenesulfonamides, and pharma and a cation selected from the group consisting of an alkali ceutically acceptable salts thereof. metal and a compound comprising a tertiary amine or The formulation and anti - diabetic may be combined in a ammonium group ; iii ) a formulation comprising a salt , said single pharmaceutical composition . For example , the for salt comprising an anion of a KATP channel opener selected 40 mulation and anti - diabetic may be combined in a controlled from the group consisting of Formula V , Formula VI, release pharmaceutical composition comprising 50 to 500 Formula VII and Formula VIII ; and iv ) a formulation mg of diazoxide choline and 20 to 100 mg of sitagliptin . comprising a salt, said salt comprising an anion of a KATP While typically such controlled release pharmaceutical com channel opener selected from the group consisting of For positions are administered once per 24 hours, other dosing mula V , Formula VI, Formula VII and Formula VIII , 45 regimens are contemplated including two or three times a wherein at least one substituent comprises an amino group . day or every other day . In related embodiments of the above method , the anti Exemplary anti -diabetic drug for use in the presentmeth diabetic drug stimulates insulin secretion in a meal depen - ods include one or more agents selected from the group dent fashion or is a short acting anti- diabetic drug with a consisting of, exenatide , nateglinide , mitglinide , repaglin circulating half life less than 5 hours . In the methods, the 50 ide, and pharmaceutically acceptable salts or conjugates formulation and the anti- diabetic drug may be co - adminis - thereof. tered separately , sequentially or simultaneously . Suitable Alternatively, the formulation may comprise 50 to 450 mg anti- diabetic drugs include but are not limited to exenatide, of diazoxide choline and is administered once per 24 hours natiglinide , mitglinide , repaglinide , a DPP -IV inhibitor ( for as a controlled release oral formulation , and the anti- diabetic example vildagliptin , sitagliptin and saxagliptin ), a PPAR 55 is a pharmaceutical composition comprising 5 to 10 ug agonist or partial agonist, a GLP - 1 analog ( e .g ., liraglutide ) exenatide and is administered twice per 24 hours , before or mimetic ( e . g . , modified exendin - 4 analogue ) or agonist , a meals. In such methods, the controlled release oral formu thiazolidinedione, a disaccharidase inhibitor, a fructose -1 ,6 - lation may be a tablet and the exenatide may be administered bisphosphatase inhibitor, a sulfonylurea receptor antagonist by subcutaneous injection . such as meglitinides and pharmaceutically acceptable salts 60 In some embodiments of methods of treating type II thereof. diabetes, the formulation comprises 50 to 500 mg of diaz In some embodiments of the methods, the formulation oxide choline and is administered once per 24 hours as a may be administered once , twice or three times per 24 hours . controlled release oral formulation , and the anti- diabetic is In certain embodiments , the formulation comprises diazox - a pharmaceutical composition comprising the meglitinide ide choline. 65 and is administered three times per 24 hours, before meals . In some embodiments of treating type II diabetes , the Provided herein are methods of treating a dyslipidemia by anti- diabetic drug may be one or more agents selected from ( a ) reducing an abnormally high total cholesterol level in a US 9 , 765 ,043 B2 25 26 subject' s blood , ( b ) reducing an abnormally high LDL lation comprising a salt , said salt comprising an anion of a cholesterol level in a subject ’s blood , ( c ) reducing an abnor KATP channel opener selected from the group consisting of mally high VLDL cholesterol level in a subject' s blood ( d ) Formula V , Formula VI, Formula VII and Formula VIII ; and reducing an abnormally high non -HDL cholesterol level in iii ) a formulation comprising a salt, said salt comprising an a subject ' s blood ( e ) reducing an abnormally high triglyc - 5 anion of a KATP channel opener selected from the group eride level in a subject' s blood and /or ( b ) raising an abnor - consisting of Formula V , Formula VI, Formula VII and mally low HDL cholesterol level in a subject' s blood level, Formula VIII, wherein at least one substituent comprises an comprising administering to said subject a therapeutically amino group . In some embodiments of the methods , the effective amount of a formulation selected from the group formulation may be administered once , twice or three times consisting of: 10 per 24 hours . In certain embodiments , the formulation i) a formulation comprising a Kate channel opener comprises diazoxide choline. selected from the group consisting of Formula 1, Formula II , As noted above, methods described herein can be used to Formula III and Formula IV , Formula V , Formula VI, reduce the circulating androgen levels in a subject by , e. g ., Formula VII , and Formula VIII ; about 5 % to about 95 % of the level of circulating androgen ii ) a formulation comprising a salt , said salt comprising an 15 compared to the subject prior to administration of the anion of a Ktp channel opener selected from the group formulations of the present invention . In other instances , the consisting of Formula I , Formula II, Formula III and For - level of circulating androgen is reduced by at least about 5 % , mula IV , and a cation selected from the group consisting of 10 % , 15 % , 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 50 % , 60 % , an alkali metal and a compound comprising a tertiary amine 70 % or 80 % compared to the subject prior to administration or ammonium group ; 20 of the formulations of the present invention , or prior to iii ) a formulation comprising a salt, said salt comprising administration of a combination of the formulation as an anion of a KATP channel opener selected from the group described herein and additional therapeutic agent( s ) . Circu consisting of Formula V , Formula VI, Formula VII and lating androgen can be measured in a subject using any Formula VIII; and suitable method known in the art . iv ) a formulation comprising a salt , said salt comprising 25 The methods described herein can be used to reestablish an anion of a Kamp channel opener selected from the group normal ovulation cycles in a subject. Ovulation is the time consisting of Formula V , Formula VI, Formula VII and in a female subject ' s menstrual cycle when the ovum , or egg , Formula VIII , wherein at least one substituent comprises an is released . It is when a woman is most fertile and likely to amino group . As used herein , a reduction in the various conceive . Ovulation occurs 12 or 14 days before menstrua specified cholesterol containing lipoproteins in the circula - 30 tion . A menstruation period begins about every 28 days if the tion amounts to a reduction , e . g . , by about 1 % to about 60 % , woman does not become pregnant in a given cycle. In one by about 1 % to about 30 % , by about 2 % to about 20 % . In instance , a normal ovulation cycle of approximately 28 days other embodiments the subject ' s HDL cholesterol levelmay is reestablished in a subject , where the subject experienced be raised , e . g . , by about 1 % to about 60 % , by about 1 % to a cycle of greater than or fewer than 28 days prior to about 50 % , by about 2 % to about 40 % . The subject' s 35 administration of the formulations of the present invention . triglycerides level may also be reduced by the present Ovulation can be measured using any means available , methods by about 5 % to about 95 % , by about 5 % to about including urinary kits , basal body temperature tests , a cer 90 % , by about 5 % to about 85 % , by about 10 % to about vical mucus test and a blood test . 95 % , by about 10 % to about 90 % , or by about 10 % to about Still further provided are methods of treating a subject 85 % . The subject may suffer from or may be at risk for 40 suffering from poly - cystic ovarian syndrome comprising pancreatitis and or may be obese . In some embodiments the co - administering to said subject a therapeutically effective formulation is administered once , twice or three times per 24 amount of a formulation and an anti - androgen therapy, hours . In other embodiments , the formulation comprises wherein the formulation is selected from the group consist diazoxide choline . ing of: i ) a formulation comprising a salt, said salt compris In some embodiments, multiple administrations of the 45 ing an anion of a KATP channel opener selected from the formulation are given over a period of days . In such cases , group consisting of Formula I , Formula II , Formula III and the caloric intake of the subject during the period of days is Formula IV , and a cation selected from the group consisting substantially the same as before the formulation was admin - of an alkali metal and a compound comprising a tertiary istered . As used in this context, “ substantially ” means less amine or ammonium group ; ii ) a formulation comprising a than 15 % change ,more preferably less than 10 % change , or 50 salt, said salt comprising an anion of a KATP channel opener even more preferably at least less than 5 % change . In a most selected from the group consisting of Formula V , Formula preferred embodiment, the caloric intake of the subject is the VI, Formula VII and Formula VIII; and iii ) a formulation same before administration and during the period of days comprising a salt , said salt comprising an anion of a KATP during administration . channel opener selected from the group consisting of For Provided herein are methods of (a ) reducing circulating 55 mula V , Formula VI, Formula VII and Formula VIII , androgen levels , or ( b ) reestablishing normal ovulation wherein at least one substituent comprises an amino group . cycles , in a subject suffering from poly -cystic ovarian syn - In the methods, the formulation and the anti -androgen drome , comprising administering to said subject a therapeu - therapy may be co -administered separately , sequentially or tically effective amount of a formulation of a KATP channel simultaneously . In some embodiments of the methods, the opener selected from the salts of the compounds of Formu - 60 formulation may be administered once , twice or three times lae I - VIII . For example, the formulation may be selected per 24 hours. In certain embodiments , the formulation from the group consisting of: i) a formulation comprising a comprises diazoxide choline . salt , said salt comprising an anion of a KATP channel opener A lso provided are methods of treating a subject suffering selected from the group consisting of Formula I, Formula II , from poly -cystic ovarian syndrome comprising co -adminis Formula III and Formula IV , and a cation selected from the 65 tering to said subject a therapeutically effective amount of a group consisting of an alkali metal and a compound com - formulation and a selective estrogen receptor modulator prising a tertiary amine or ammonium group ; ii ) a formu (SERM ) therapy, wherein the formulation is selected from US 9 ,765 , 043 B2 28 the group consisting of: i) a formulation comprising a salt, simultaneously. In some embodiments of the methods, the said salt comprising an anion of a KATP channel opener formulation may be administered once , twice or three times selected from the group consisting of Formula I, Formula II , per 24 hours . In certain embodiments , the formulation Formula III and Formula IV , and a cation selected from the comprises diazoxide choline. In some embodiments of the group consisting of an alkali metal and a compound com - 5 methods the aromatase inhibitor therapy includes letrozole prising a tertiary amine or ammonium group ; ii ) a formu - or anastrozole . lation comprising a salt, said salt comprising an anion of a Provided herein are methods of treating a subject suffer KATP channel opener selected from the group consisting of ing from hypertension comprising administering to said Formula V , Formula VI , Formula VII and Formula VIII; and subject a therapeutically effective amount of a single oral iii ) a formulation comprising a salt, said salt comprising an 10 agent wherein the oral agent is a formulation of a KATP anion of a KATP channel opener selected from the group channel opener selected from the salts of the compounds of consisting of Formula V , Formula VI, Formula VII and Formulae I -VIII . For example , the formulation may be Formula VIII, wherein at least one substituent comprises an selected from the group consisting of: i ) a formulation amino group . In the methods, the formulation and the comprising a salt, said salt comprising an anion of a KATP selective estrogen receptor modulator (SERM ) therapy may 15 channel opener selected from the group consisting of For be co -administered separately, sequentially or simultane - mula I , Formula II , Formula III and Formula IV , and a cation ously . In some embodiments of themethods , the formulation selected from the group consisting of an alkali metal and a may be administered once , twice or three times per 24 hours . compound comprising a tertiary amine or ammonium group ; In certain embodiments , the formulation comprises diazox - ii ) a formulation comprising a salt , said salt comprising an ide choline . In some embodiments of the methods the SERM 20 anion of a KATP channel opener selected from the group includes clomiphene ( or a salt thereof) or ormeloxifene. consisting of Formula V , Formula VI, Formula VII and Further provided are methods of treating a subject suf Formula VIII ; and iii ) a formulation comprising a salt, said fering from poly - cystic ovarian syndrome comprising co - salt comprising an anion of a KATP channel opener selected administering to said subject a therapeutically effective from the group consisting of Formula V , Formula VI, amount of a formulation and an ovulation inducing therapy, 25 Formula VII and Formula VIII , wherein at least one sub wherein the formulation is selected from the group consist stituent comprises an amino group . In some embodiments of ing of: i ) a formulation comprising a salt , said salt compris - the methods , the formulation may be administered once , ing an anion of a KATP channel opener selected from the twice or three times per 24 hours . In certain embodiments , group consisting of Formula I, Formula II , Formula III and the formulation comprises diazoxide choline . Formula IV , and a cation selected from the group consisting 30 Also provided herein are methods of treating a subject of an alkali metal and a compound comprising a tertiary suffering from hypertension comprising co -administering to amine or ammonium group ; ii ) a formulation comprising a said subject a therapeutically effective amount of a formu salt , said salt comprising an anion of a KATP channel opener lation and an oral anti -hypertensive agent, wherein the selected from the group consisting of Formula V , Formula formulation of a KATP channel opener is selected from the VI, Formula VII and Formula VIII; and iii ) a formulation 35 salts of the compounds of Formulae I- VIII . For example , the comprising a salt, said salt comprising an anion of a KATP formulation may be selected from the group consisting of: i ) channel opener selected from the group consisting of For- a formulation comprising a salt , said salt comprising an mula V , Formula VI, Formula VII and Formula VIII , anion of a KATP channel opener selected from the group wherein at least one substituent comprises an amino group . consisting of Formula 1 , Formula II, Formula III and For In the methods, the formulation and the ovulation inducing 40 mula IV , and a cation selected from the group consisting of therapy may be co -administered separately, sequentially or an alkali metal and a compound comprising a tertiary amine simultaneously . In some embodiments of the methods , the or ammonium group ; ii ) a formulation comprising a salt , formulation may be administered once , twice or three times said salt comprising an anion of a KATP channel opener per 24 hours. In certain embodiments , the formulation selected from the group consisting of Formula V , Formula comprises diazoxide choline . In some embodiments of the 45 VI, Formula VII and Formula VIII; and iii ) a formulation methods the ovulation inducing therapy includes follicle comprising a salt , said salt comprising an anion of a KATP stimulating hormone . channel opener selected from the group consisting of For Still further provided are methods of treating a subject mula V , Formula VI, Formula VII and Formula VIII , suffering from poly -cystic ovarian syndrome comprising wherein at least one substituent comprises an amino group . co - administering to said subject a therapeutically effective 50 In some embodiments of the methods , the formulation may amount of a formulation and an aromatase inhibitor therapy, be administered once , twice or three times per 24 hours . In wherein the formulation is selected from the group consist certain embodiments , the formulation comprises diazoxide ing of: i ) a formulation comprising a salt , said salt compris - choline . ing an anion of a KATP channel opener selected from the Further provided are methods of treating a subject suf group consisting of Formula 1 , Formula II , Formula III and 55 fering from pulmonary hypertension comprising adminis Formula IV , and a cation selected from the group consisting tering to said subject a therapeutically effective amount of a of an alkali metal and a compound comprising a tertiary formulation selected from the group consisting of : amine or ammonium group ; ii ) a formulation comprising a i ) a formulation comprising a salt, said salt comprising an salt, said salt comprising an anion of a KATP channel opener anion of a Ktp channel opener selected from the group selected from the group consisting of Formula V , Formula 60 consisting of Formula I , Formula II , Formula III and For VI, Formula VII and Formula VIII ; and iii ) a formulation mula IV , and a cation selected from the group consisting of comprising a salt, said salt comprising an anion of a KATP an alkali metal and a compound comprising a tertiary amine channel opener selected from the group consisting of For- or ammonium group ; mula V , Formula VI, Formula VII and Formula VIII, ii ) a formulation comprising a salt , said salt comprising an wherein at least one substituent comprises an amino group . 65 anion of a Karp channel opener selected from the group In the methods , the formulation and the aromatase inhibitor consisting of Formula V , Formula VI, Formula VII and therapy may be co - administered separately , sequentially or Formula VIII ; and US 9 , 765 ,043 B2 29 30 iii ) a formulation comprising a salt, said salt comprising remodeling is complete . In some embodiments of the meth an anion of a Ktp channel opener selected from the group ods, the formulation may be administered once , twice or consisting of Formula V , Formula VI, Formula VII and three times per 24 hours. In certain embodiments , the Formula VIII , wherein at least one substituent comprises an formulation comprises diazoxide choline , in the form of, amino group . The amount of the formulation is effective to 5 e . g . , controlled release tablets . As used herein , reference to lower pulmonary arteriolar resistance and pulmonary artery beginning treatment “ immediately ” following the detection pressure and , in some embodiments , to bring pulmonary of myocardial infarction means that the treatment is begun arteriolar resistance and pulmonary artery pressure within within one hour after diagnosis of infarction , and less normal limits ( systolic 15 - 30 mm Hg, diastolic 6 - 12 mm preferably between 1 - 2 hours , 2 - 3 , 3 - 4 hours , 4 - 8 hours and Hg) . Treatment may be continued as long as the subject 10 8 - 24 hours post diagnosis of infarction . continues to suffer from pulmonary hypertension . In some Provided herein are methods of treating a subject at risk embodiments of the methods, the formulation may be for myocardial infarction to prevent infarction , limit infarct administered once , twice or three times per 24 hours . In size , and / or to prevent arrhythmias . The methods include certain embodiments , the formulation comprises diazoxide administering to the subject a therapeutically effective choline , in the form of, e . g ., controlled release tablets . 15 amount of a pharmaceutical formulation selected from the Also provided herein are methods of treatment to prevent group consisting of: late post -myocardial infarction arrhythmias comprising i) a formulation comprising a salt, said salt comprising an administering to a subject that has recently suffered a anion of a Kate channel opener selected from the group myocardial infarction a therapeutically effective amount of consisting of Formula I, Formula II , Formula III and For a pharmaceutical formulation wherein the formulation 20 mula IV , and a cation selected from the group consisting of includes a Kamp channel opener selected from the salts of the an alkali metal and a compound comprising a tertiary amine compounds of Formulae I -VIII . For example, the formula - or ammonium group ; tion may be selected from the group consisting of: ii ) a formulation comprising a salt , said salt comprising an i) a formulation comprising a salt, said salt comprising an anion of a Kate channel opener selected from the group anion of a Katp channel opener selected from the group 25 consisting of Formula V , Formula VI, Formula VII and consisting of Formula 1 , Formula II , Formula III and For - Formula VIII ; and mula IV , and a cation selected from the group consisting of iii ) a formulation comprising a salt, said salt comprising an alkali metal and a compound comprising a tertiary amine an anion of a Kftp channel opener selected from the group or ammonium group ; consisting of Formula V , Formula VI, Formula VII and ii ) a formulation comprising a salt, said salt comprising an 30 Formula VIII, wherein at least one substituent comprises an anion of a KATP channel opener selected from the group amino group . Treatmentmay be continued for as long as the consisting of Formula V , Formula VI, Formula VII and subject is at risk for myocardial infarction . In some embodi Formula VIII; and ments of the methods , the formulation may be administered iii ) a formulation comprising a salt, said salt comprising once, twice or three times per 24 hours . In certain embodi an anion of a Kamp channel opener selected from the group 35 ments , the formulation comprises diazoxide choline, in the consisting of Formula V , Formula VI, Formula VII and form of, e . g . , controlled release tablets . Formula VIII , wherein at least one substituent comprises an In the above methods relating to treating heart disease amino group . By recently suffered a myocardial infarction is such as myocardial infarction ( or its prevention ) or arrhyth meant that the myocardial infarction has occurred within the mias , the administration of the KATP channel opener ( such last 48 hours. The subject is typically treated for a minimum 40 as diazoxide ) may be beneficial by acting as an anti of one year or until the period of late remodeling is com - inflammatory agent. Diazoxide is known to have anti - in plete . In some embodiments of the methods , the formulation flammatory effects ( see Xu et al. , J. Hypertension , 2006 24 : maybe administered once, twice or three times per 24 hours . 915 - 922 ; Wang et al. , Shock 2004 , 22 :23 -28 ). In certain embodiments , the formulation comprises diazox Provided herein are methods of treating a subject suffer ide choline, in the form of, e . g ., controlled release tablets . 45 ing from hypoglycemia - associated autonomic failure com Also provided herein are methods of treating a subject prising administering to said subject a therapeutically effec immediately following the detection of myocardial infarc - tive amount of a formulation of a KATP channel opener tion to limit infarct size and prevent arrhythmias. The selected from the salts of the compounds of Formulae I -VIII . methods include administering to the subject a therapeuti For example , the formulation may be selected from the cally effective amount of a pharmaceutical formulation 50 group consisting of: i ) a formulation comprising a salt , said selected from the group consisting of: salt comprising an anion of a KATP channel opener selected i) a formulation comprising a salt, said salt comprising an from the group consisting of Formula I, Formula II , Formula anion of a KATP channel opener selected from the group III and Formula IV , and a cation selected from the group consisting of Formula I, Formula II, Formula III and For consisting of an alkali metal and a compound comprising a mula IV , and a cation selected from the group consisting of 55 tertiary amine or ammonium group ; ii ) a formulation com an alkali metal and a compound comprising a tertiary amine prising a salt, said salt comprising an anion of a KATP or ammonium group ; channel opener selected from the group consisting of For ii ) a formulation comprising a salt , said salt comprising an mula V , Formula VI, Formula VII and Formula VIII ; iii ) a anion of a Kate channel opener selected from the group formulation comprising a salt, said salt comprising an anion consisting of Formula V , Formula VI, Formula VII and 60 of a KATP channel opener selected from the group consist Formula VIII ; and ing of Formula V , Formula VI, Formula VII and Formula iii ) a formulation comprising a salt , said salt comprising VIII, wherein at least one substituent comprises an amino an anion of a Kftp channel opener selected from the group group ; and iv ) a formulation comprising 7 - chloro - 3 -methyl consisting of Formula V , Formula VI, Formula VII and 2H - 1 , 2 , 4 - benzothiadiazine . In the methods the subject may Formula VIII , wherein at least one substituent comprises an 65 also be suffering from type I diabetes or type II diabetes . In amino group . Treatment may be continued after the infarc - some embodiments of the methods , the formulation may be tion for a minimum of one year or until the period of late administered once , twice or three times per 24 hours . The US 9 , 765 ,043 B2 32 formulation may also be an oral or an intranasal formulation . or ammonium group ; b ) a salt comprising an anion of a In certain embodiments , the formulation comprises diazox - KATP channel opener selected from the group consisting of ide choline . Formula V , Formula VI, Formula VII and Formula VIII; and A method of inducing or increasing beta -cell rest in a c ) a salt comprising a cation of a KATP channel opener subject in need thereof , comprising administering to said 5 selected from the group consisting of Formula V , Formula subject a therapeutically effective amount of a formulation VI, Formula VII and Formula VIII , wherein at least one of a KATP channel opener selected from the salts of the substituent comprises an amino group . compounds of Formulae I- VIII . For example , the formula - In further embodiments , the hypoglycemia is selected tion may be selected from the group consisting of: i ) a from the group consisting of a ) nighttime hypoglycemia , b ) formulation comprising a salt , said salt comprising an anion 10 hypoglycemia attributable to a defect in insulin secretion , c ) of a KATP channel opener selected from the group consist attributable to an insulin secreting tumor, and d ) drug ing of Formula 1, Formula II , Formula III and Formula IV , induced hypoglycemia . and a cation selected from the group consisting of an alkali P rovided herein are methods of treating obesity or type 1 metal and a compound comprising a tertiary amine or or type 2 diabetes in a companion animal. The methods ammonium group ; ii ) a formulation comprising a salt , said 15 include administering to said animal a therapeutically effec salt comprising an anion of a KATP channel opener selected tive amount of a formulation selected from the group from the group consisting of Formula V , Formula VI, consisting of: i) a formulation comprising a KATP channel Formula VII and Formula VIII ; and iii ) a formulation opener selected from the group consisting of Formula I , comprising a salt , said salt comprising an anion of a KATP Formula II , Formula III and Formula IV , Formula V , For channel opener selected from the group consisting of For - 20 mula VI, Formula VII , and Formula VIII; ii ) a formulation mula V , Formula VI, Formula VII and Formula VIII , comprising a salt, said salt comprising an anion of a KATP wherein at least one substituent comprises an amino group . channel opener selected from the group consisting of For In some embodiments of the methods , the formulation may mula 1, Formula II , Formula III and Formula IV , and a cation be administered once , twice or three times per 24 hours . In selected from the group consisting of an alkali metal and a certain embodiments , the formulation comprises diazoxide 25 compound comprising a tertiary amine or ammonium group ; choline. In the methods , the subject may also be obese or iii ) a formulation comprising a salt , said salt comprising an overweight or suffer from type II diabetes . anion of a KATP channel opener selected from the group Also provided herein are polymorphic forms (i . e . , " poly consisting of Formula V , Formula VI, Formula VII and morphs " ) of the compounds of Formulae I - VIII , as exem - Formula VIII ; and iv ) a formulation comprising a salt , said plified by the X - ray Power Diffraction (XRPD ) patterns 30 salt comprising an anion of a KATP channel opener selected shown in any of the figures . from the group consisting of Formula V , Formula VI, Also provided are polymorphs of salts of diazoxide which Formula VII and Formula VIII, wherein at least one sub include diazoxide and a cation selected from the group stituent comprises an amino group . Typically , the animal is consisting of an alkali metal and a compound comprising a a cat , a dog or a horse . The formulation can be suitable for tertiary amine or quaternary ammonium group . 35 oral administration , e . g . , a controlled release tablet or cap Also provided herein are methods for producing a diaz - sule , or a chewable formulation . Alternatively , the formula oxide choline salt , which includes suspending diazoxide in tion may be a granulated controlled release formulation a solvent and mixing with a choline salt , adding a co -solvent which can be applied to food for the animal, e . g . , a powder. to the suspension under conditions sufficient to cause for- In some embodiments , the formulation is administered once mation and precipitation of the diazoxide choline salt, and 40 or twice per 24 hours . In certain embodiments , the formu harvesting the precipitate to provide the diazoxide choline lation comprises diazoxide choline . salt . Provided herein are methods of treating a dyslipidemia in Also provided herein are methods of treating obesity or a subject having a triglyceride level of at least about 500 obesity - related co -morbidity in an obese subject, wherein mg/ dL and an HDL - C level of about 40 mg/ dL or less, the the method comprising administering to a subject in need 45 method comprising administering to the subject a therapeu thereof an effective amount of a compound of Formula tically effective amount of a Kamp channel opener selected V - VIII . from the group consisting of Formula I , Formula II , Formula Also provided herein are methods for treatment of a III and Formula IV , and salts thereof. In some embodiments , subject suffering from or at risk for Alzheimer 's disease the Ktp channel opener comprises an anion Formula I , ( AD ) , which methods include administration to a subject a 50 Formula II, Formula III and Formula IV , and a cation therapeutically effective amount of a pharmaceutical formu - selected from the group consisting of an alkali metal and a lation comprising a compound of any of Formulae I - VIII as compound comprising an ammonium group comprising at provided herein . In some embodiments , the compound is least one tertiary amine group . In some embodiments , the diazoxide . Also provided herein are methods for treatment said Karp channel opener comprises a salt of diazoxide ; such of a subject suffering from or at risk for AD , which methods 55 as diazoxide choline . In some embodiments , the Ktp chan include administration to a subject a therapeutically effective n el opener is formulated as a controlled release formulation amount of a salt of a compound according to any of for oral administration , such as a formulation formulated for Formulae I - VIII. In some embodiments , the compound is a once or twice a day administration . In some embodiments , salt of diazoxide. the subject is administered about 145 to 435 mg per day of In another embodiment, the invention provides a method 60 said Kamp channel opener. In some embodiments, the KTP for treating hypoglycemia by administration of an effective channel opener is co -administered or co - formulated with a amount of a pharmaceutical formulation comprising a salt therapeutically effective amount of a second active com selected from the group consisting of a ) a salt comprising an pound for lowering triglycerides , raising HDL - C , lowering anion of a KATP channel opener selected from the group LDL - C , or any combination thereof. In some related consisting of Formula I , Formula II , Formula III and For- 65 embodiments , the second active compound comprises a mula IV , and a cation selected from the group consisting of statin or a fibrate . In some related embodiments , the second an alkali metal and a compound comprising a tertiary amine active compound comprises a fibrate or a salt thereof; such US 9 , 765 ,043 B2 33 34 as fenofibrate or a salt thereof; such as fenofibrate choline . mula IV , and salts thereof. In some embodiments , the KATP In some further related embodiments , the subject is admin channel opener comprises an anion Formula I , Formula II , istered about 45 to 200 mg per day of fenofibrate choline . In Formula III and Formula IV , and a cation selected from the some embodiments , the subject is a human . group consisting of an alkali metal and a compound com Provided herein are methods for treating dyslipidemia in 5 prising an ammonium group comprising at least one tertiary a subject having a triglyceride level of at least about 1000 amine group . In some embodiments , the said Karp channel mg/ dL , themethods comprising administering to the subject opener comprises a salt of diazoxide ; such as diazoxide a therapeutically effective amount of a fibrate or a salt choline . In some embodiments , the Ktp channel opener is thereof and a therapeutically effective amount of a KTP formulated as a controlled release formulation for oral channel opener selected from the group consisting of For - 10 administration , such as a formulation formulated for once or mula I, Formula II , Formula III and Formula IV , and salts twice a day administration . In some embodiments, the thereof. In some embodiments , the Ktp channel opener subject is administered about 145 to 435 mg per day of said comprises an anion Formula I, Formula II, Formula III and Kate channel opener . In some embodiments , the KATP Formula IV , and a cation selected from the group consisting channel opener is co -administered or co - formulated with a of an alkali metal and a compound comprising an ammo- 15 therapeutically effective amount of a second active com nium group comprising at least one tertiary amine group . In pound . In some related embodiments , the second active some embodiments , the said Karp channel opener comprises compound comprises a fibrate or a salt thereof; such as a salt of diazoxide; such as diazoxide choline . In some fenofibrate or a salt thereof; such as fenofibrate choline . In embodiments , the Ktp channel opener is formulated as a some further related embodiments , the subject is adminis controlled release formulation for oral administration , such 20 tered about 45 to 200 mg per day of fenofibrate choline . In as a formulation formulated for once or twice a day admin some related embodiments , the second active compound istration . In some embodiments , the subject is administered comprises a statin . In some related embodiments , the second about 145 to 435 mg per day of said KATP channel opener. active compound and the Ktp channel opener are co In some embodiments , the fibrate or a salt thereof; such as formulated , such as a controlled release formulation for oral fenofibrate or a salt thereof; such as fenofibrate choline . In 25 administration , such as for once or twice a day administra some related embodiments , the subject is administered about tion . In some related embodiments , the subject is human . 45 to 200 mg per day of fenofibrate choline. In some Also provided herein are pharmaceutical formulations embodiments , the fibrate or a salt thereof and the KTP comprising diazoxide choline , wherein oral administration channel opener are co - formulated , such as a controlled of a 290 mg dose of diazoxide choline in the formulations release formulation for oral administration , such as formu- 30 once daily to a subject results in steady state AUC0- 24 > 500 lated for once or twice a day administration . In some ug * hr/ mL . In some embodiments , oral administration of a embodiments , the subject is human . 290 mg dose of diazoxide choline in the formulations once Provided herein are methods for reducing elevated tri - daily to a subject further results in steady state % Peak - to glycerides in a subject undergoing statin therapy , the meth Trough Fluctuation of less than 30 % . In some embodiments , ods comprising administering to the subject a therapeutically 35 oral administration of a 290 mg dose of diazoxide choline in effective amount of a Kamp channel opener selected from the the formulations once daily to a subject results in steady group consisting of Formula 1 , Formula II , Formula III and state average circulating drug level (Caviss ) between 14 and Formula IV , and salts thereof. In some embodiments , the 31 ug /mL . In some embodiments , the pharmaceutical for KATP channel opener comprises an anion Formula I, For- mulations are compressed tablet formulations. mula II , Formula III and Formula IV , and a cation selected 40 Also provided herein are pharmaceutical formulations from the group consisting of an alkali metal and a compound comprising a salt of diazoxide formulated for oral adminis comprising an ammonium group comprising at least one tration , wherein bioavailability of diazoxide is at least about tertiary amine group . In some embodiments, the said KTP 50 % ; such as at least about 75 % ; such as at least about 90 % . channel opener comprises a salt of diazoxide ; such as In some related embodiments , the salt of diazoxide is diazoxide choline . In some embodiments , the Katp channel 45 diazoxide choline . In some further related embodiments , opener is formulated as a controlled release formulation for diazoxide choline is of polymorph form B . In some embodi oral administration , such as a formulation formulated for ments, the pharmaceutical formulations are compressed once or twice a day administration . In some embodiments , tablet formulations . the subject is administered about 145 to 435 mg per day of Also provided herein are methods for treating a dyslipi said Karp channel opener. In some embodiments , the KATP 50 demia in a subject, the method comprising administering to channel opener is co -administered or co - formulated with a the subject : a ) a formulation comprising one or more therapeutically effective amount of a third active compound omega - 3 fatty acids, and b ) a formulation comprising a for lowering triglycerides . In some related embodiments, the therapeutically effective amount of a Ktp channel opener third active compound comprises a fibrate or a salt thereof; selected from the group consisting of Formula 1, Formula II , such as fenofibrate or a salt thereof; such as fenofibrate 55 Formula III and Formula IV , and salts thereof. In some choline. In some further related embodiments , the subject is embodiments , the Ktp channel opener comprises an anion administered about 45 to 200 mg per day of fenofibrate Formula I, Formula II , Formula III and Formula IV , and a choline . In some related embodiments , the fibrate or a salt cation selected from the group consisting of an alkali metal thereof and theKtp channel opener are co - formulated , such and a compound comprising an ammonium group compris as a controlled release formulation for oral administration , 60 ing at least one tertiary amine group . In some embodiments , such as for once or twice a day administration . In some the dyslipidemia is selected from the group consisting of related embodiments , the subject is human . abnormally high total cholesterol level in a subject ' s blood , Provided herein are methods for treating a subject with abnormally high LDL cholesterol, abnormally high VLDL nonalcoholic steatohepatitis (NASH ) , the methods compris cholesterol, abnormally high non - HDL cholesterol, abnor ing administering to the subject a therapeutically effective 65 mally high triglycerides, abnormally low HDL cholesterol, amount of a Kato channel opener selected from the group or any combination thereof . In some embodiments , the consisting of Formula I, Formula II, Formula III and For- dyslipidemia comprises abnormally high triglycerides, such US 9 , 765 ,043 B2 35 36 as a triglyceride level of at least about 500 mg/ dL ; such as lation comprising either a Kate channel opener or a fibrate a triglyceride level of at least about 1000 mg/ dL . In some or a salt thereof. In some embodiments , each of the plurality embodiments , the said Karp channel opener comprises a salt of blister cavities contains two or more pharmaceutical of diazoxide ; such as diazoxide choline. In some embodi- formulations, wherein at least one of said pharmaceutical ments , the Karp Channel opener is formulated as a controlled 5 formulations comprises a Karp channel opener , and at least release formulation for oral administration , such as a for one other of said pharmaceutical formulations comprises a mulation formulated for once or twice a day administration . In some embodiments , the subject is administered about 145 fibrate or a salt thereof. In some embodiments , the KATP to 435 mg per day of said Kto channel opener . In some channel opener and said fibrate are co - formulated in a single embodiments, the omega - 3 fatty acid formulation is sub - 10 pharmaceutical formulation . In some related embodiments , stantially free of DHA . each of the plurality of blister cavities contains the co Also provided herein are methods for initiating treatment formulated pharmaceutical formulation . In some embodi for a dyslipidemia in a subject, the methods comprising ments , theK TP channel opener is selected from the group administering a fibrate or a salt thereof and a Kato channel consisting of Formula I , Formula II , Formula III and For opener selected from the group consisting of Formula I , is15 mulamu. IV , and salts thereof. In some embodiments , the KATP Formula II , Formula III and Formula IV , and salts thereof; channel opener comprises an anion Formula 1 , Formula II , wherein the fibrate or a salt thereof and the Karp channel Formula III and Formula IV , and a cation selected from the opener are both initially administered at sub - optimal titra - group consisting of an alkali metal and a compound com tion doses , and the doses of both are increased to mainte - prising an ammonium group comprising at least one tertiary nance doses over 7 to 28 days . In some embodiments , the 20 amine group . In some embodiments , the Karp channel KATP channel opener comprises an anion Formula 1, For opener comprises a salt of diazoxide ; such as diazoxide mula II , Formula III and Formula IV , and a cation selected choline. In some embodiments, the fibrate or a salt thereof from the group consisting of an alkali metal and a compound comprises fenofibrate or a salt thereof; such as fenofibrate comprising an ammonium group comprising at least one choline . tertiary amine group . In some embodiments, the dyslipi- 25 Also provided herein are methods for treating a subject demia comprises a triglyceride level of at least about 500 with acute pancreatitis , the method comprising intrave mg/ dL . In some related embodiments, the dyslipidemia nously administering a bolus dose of a Kamp channel opener further comprises a HDL - C level of less than about 40 of between about 0 .5 to 5 mg/ kg over 5 to 10 minutes ; mg/ dL . In some embodiments , the dyslipidemia comprises a wherein the Kate channel opener is selected from the group triglyceride level of at least about 1000 mg/ dL . In some 30 consisting of Formula 1 , Formula II, Formula III and For embodiments , the titration doses of the fibrate or a salt mula IV , and wherein the Ktp channel opener is formulated thereof and the Kato channel opener are about between for intravenous administration . In some embodiments , the about one third to about one half of the corresponding dose of Kto channel opener administered as a bolus is maintenance doses. In some embodiments , the Karp channel between about 50 to 200 mg. In some embodiments , the opener is formulated as a controlled release formulation for 35 methods further comprise additional administration of the oral administration for oral administration , such as for once Ktp channel opener after completion of the bolus at or twice daily administration . In some embodiments , the between about 0 .02 to 0 .2 mg/ kg /hr , along with administra Kate channel opener comprises a salt of diazoxide ; such as tion of insulin on a recurring basis at a level and rate diazoxide choline . In some embodiments, the Kate channel sufficient to maintain fasting glucose between about 70 opener titration dose is about 70 mg to 220 mg. In some 40 mg/ dL and 125 mg/ dL and peak post prandial glucose less embodiments , the Ktp channel opener maintenance dose is than 200 mg /dL . In some related embodiments , the insulin about 145 mg to 435 mg. In some embodiments, the fibrate comprises a basal insulin , a fast - acting prandial insulin , or a or a salt thereof is formulated as a controlled release mixture thereof. In some embodiments , the Kate channel formulation for oral administration , such as for once or opener comprises diazoxide or an ion thereof. In some twice daily administration . In some embodiments , the fibrate 45 embodiments , the methods further comprise co -administra fibrate or a salt thereof comprises fenofibrate or a salt tion of nicorandil . In some embodiments , the methods thereof; such as fenofibrate choline . In some embodiments , further comprise treating the subject using plasmapheresis . the titration dose of the fibrate or a salt thereof is about 35 In some embodiments , the subject is a human . mg to 100 mg. In some embodiments, the maintenance dose In the present context, the term “ therapeutically effective ” of the fibrate or a salt thereof is about 100 mg to about 200 50 or " effective amount” indicates that thematerials or amount mg . In some embodiments, the titration doses of the fibrate of material is effective to prevent, alleviate , or ameliorate or a salt thereof and the Ktp channel opener are co - one or more symptoms of a disease or medical condition , formulated ; such as co - formulated as a controlled release and / or to prolong the survival of the subject being treated . formulation for oral administration , such as for once or The term “ pharmaceutically acceptable ” indicates that the twice daily administration . In some embodiments , themain - 55 identified material does not have properties that would cause tenance doses of the fibrate or a salt thereof and the KTP a reasonably prudent medical practitioner to avoid admin channel opener are co - formulated ; such as co - formulated as istration of the material to a patient , taking into consider a controlled release formulation for oral administration , such ation the disease or conditions to be treated and the respec as for once or twice daily administration . tive route of administration . For example , it is commonly Also provided herein are kits comprising: a pharmaceu - 60 required that such a material be essentially sterile , e . g ., for tical treatment blister card with a plurality ofblister cavities; injectibles . seven to twenty eight daily dosages of a Ktp channel As used herein , the term " composition ” refers to a for opener ; and seven to twenty eight daily dosages of a fibrate mulation suitable for administration to an intended animal or a salt thereof. In these kits , the daily dosages of theKTP subject for therapeutic purposes that contains at least one channel opener and the fibrate or a salt thereof are sub - 65 pharmaceutically active compound and at least one pharma optimal titration dosages. In some embodiments , each of the ceutically acceptable carrier or excipient. Other terms as plurality of blister cavities contain a pharmaceutical formu - used herein are defined below . US 9 , 765 , 043 B2 37 38 As used herein , the term “ co -administer ” or “ co -admin - as the area under the blood or plasma drug concentration istration ” refers to administration of two or more pharma- time curve ( AUC ) and the peak blood or plasma concentra ceutically active materials to a subject at the same time. For tion ( C max ) of the drug . example , two compositions, each in tablet form , can be Bioequivalent: Two formulations of the same active sub co - administered by oral ingestion at the same time or within 5 stance are bioequivalent when there is no significant differ minutes of each other. Co - administration also encompasses e nce in the rate and extent to which the active substance administration of two active materials co - formulated in a becomes available at the site of drug action when adminis single delivery form . That is , two compositions can be tered at the same molar dose under similar conditions. combined in a single formulation ( co - formulated ) for admin “ Formulation ” in this definition may include the free base of istration to a subject so that the compositions are co - " the active substance or different salts of the active substance . administered , e . g . in a single tablet, capsule , oral suspension , Bioequivalence may be demonstrated through several in injectible liquid , etc . vivo and in vitro methods. These methods, in descending Adipocyte : An animal connective tissue cell specialized order of preference , include pharmacokinetic , pharmacody for the synthesis and storage of fat . namic , clinical and in vitro studies . In particular , bioequiva Agonist : A chemical compound that has affinity for and 15 lence is demonstrated using pharmacokinetic measures such stimulates physiological activity at cell receptors normally as the area under the blood or plasma drug concentration stimulated by naturally occurring substances , triggering a time curve ( AUC ) and the peak blood or plasma concentra biochemical response . An agonist of a receptor can also be tion (Cmax ) of the drug , using statistical criteria . considered an activator of the receptor. 20 Cannabinoid Receptor : Receptors in the endocannabinoid About: is used herein to mean in quantitative terms plus (EC ) system associated with the intake of food and tobacco or minus 10 % . dependency . Blocking the cannabinoid receptor may reduce Adipose tissue: Tissue comprised principally of adipo - dependence on tobacco and the craving for food . cytes . Capsule : refers to a softgel, caplet, or any other encap Adolescent: A person between 10 and 19 years of age . 25 sulated dosage form known to practitioners in the art , or a Adiponectin : A protein hormone produced and secreted portion thereof. Softgel refers a soft gelatin capsule, in exclusively by adipocytes that regulates the metabolism of agreement with the accepted nomenclature adopted by the lipids and glucose . Adiponectin influences the body 's SoftGel Association . A softgel is a one -piece , sealed , soft response to insulin . Adiponectin also has anti- inflammatory gelatin ( or other film - forming material) shell that contains a 30 solution , a suspension , or a semi- solid paste . effects on the cells lining the walls of blood vessels . Combination : Refers to any association between or Alkalimetal : refers to elements included in Group I of the among two or more items. The combination can be two or periodic table , such as , lithium , sodium , potassium , more separate items, such as two compositions or two rubidium , cesium and francium . collections . It can be a mixture thereof, such as a single Amelioration of the symptoms of a particular disorderorder by 35 mixture of the two or more items, or any variation thereof. administration of a particular pharmaceutical composition : Combined hyperlipidemia : Refers to a commonly occur refers to any lessening , whether permanent or temporary, ring form of hypercholesterolemia (elevated cholesterol lasting or transient that can be attributed to or associated level ) characterized by increased LDL cholesterol and tri with administration of the composition . glyceride concentrations, often accompanied by decreased Analog : a compound that resembles another in structure 40 HDL cholesterol. but differs by at least one atom . Companion animal . Animals kept for the purpose of Antagonist : A substance that tends to nullify the action of providing companionship to humans, e . g ., house pets , another , as a drug that binds to a cell receptor without including cats and dogs and horses . eliciting a biological response when confronted with an Compression tablet : Tablet formed by the exertion of agonist for the receptor. 45 pressure to a volume of tablet matrix in a die . Anti- androgen therapy : a therapy using medications to Compression coated tablet : A tablet formed by the addi block production of or interfere with the action of male sex tion of a coating by compression to a compressed core hormones , e . g . testosterone . Anti - androgen therapies suit - containing the pharmaceutical active . As used herein the able for use in the methods described herein include but are term “ tablet ” is intended to mean the same as a compression not limited to Progestin , cyproterone , ethinylestradiol, 50 tablet unless indicated otherwise . cyproterone , and androgen receptor protein inhibitors . Derivative : A chemical substance derived from another Atherosclerotic Plaque : A buildup of cholesterol and fatty substance by modification or substitution . material within a blood vessel due to the effects of athero - Daily dosage: The total amount of a drug taken in a 24 sclerosis hour period whether taken as a single dose or taken in Bariatric Surgery : A range of surgical procedures which 55 multiple doses . are designed to aid in the management or treatment of DPP -IV inhibitor : A class of anti - diabetic drugs which obesity and allied diseases. inhibit the enzyme dipeptidylpeptidase -IV , also known as Beta cell rest : Temporarily placing beta cells in a condi DPP - IV . The DPP - IV enzyme cleaves the N - terminal dipep tion in which there is reduced metabolic stress due to tide from GLP - 1 , inactivating it. DPP - IV inhibitors thus suppressed secretion of insulin . 60 increase the potency of GLP - 1 biological effects . Bilaminate : A component of a pharmaceutical dosage Disaccharidase inhibitor: A class of anti -diabetic drugs form that consists of the lamination of two distinct materials . which act by inhibiting disaccharidase enzymes . Disaccha Bioavailability : Refers to the amount or extent of thera - ridases break down disaccharides into monosaccharides and peutically active substance that is released from the drug include , e . g . , lactase , sucrase , trehalase , and maltase . Inhi product and becomes available in the body at the intended 65 bition of disaccharidases delays and decreases absorption of site of drug action . The amount or extent of drug released monosaccharides by the body, decreasing post- meal glucose can be established by the pharmacokinetic - parameters , such peaks. US 9 , 765 ,043 B2 39 40 Diazoxide: 7 - chloro - 3 -methyl - 2H - 1 , 2 , 4 - benzothiadiazine sphatase , a key enzyme in the gluconeogenesis pathway . 1 ,1 dioxide (shown below with its tautomer ) with the Inhibition of this enzyme lowers elevated glucose levels empirical formula C8H7CIN2O2S and a molecular weight etes of 230 .7 . Gastric Lipase : An enzyme secreted into the gastrointes 5 tinal tract that catalyzes the hydrolysis of dietary triglycer ides . Glidant: An inactive component of a pharmaceutical formulation that prevents caking of the matrix during pro cessing steps . NH 10 h GLP - 1 : Glucagon like peptide 1 is a peptide produced by O= intestinal endocrine cells in two principle forms, GLP - 107 or 36 amide ) and GLP - 1 ( 7 -37 ) , upon the ingestion of food . It is involved in stimulation of glucose - dependent insulin Dyslipidemia : A disorder of lipoprotein metabolism , 16 secretion and insulin biosynthesis , inhibition of glucagon including lipoprotein overproduction or deficiency. Dyslipi secretion and gastric emptying, and inhibition of food demias may be manifested by elevation of the total choles - intake. terol, low -density lipoprotein (LDL ) cholesterol and triglyc HDL cholesterol: The cholesterol found in high density eride , and a decrease in high -density lipoprotein (HDL ) lipoprotein particles. HDL particles are believed to transport cholesterol concentration in the blood . Optimal LDL cho - 20 cholesterol from tissues in the body to the liver . lesterol level for adults is less than 100 mg/ dL (2 .60 mmol/ HMG - CoA reductase inhibitors (or statins) form a class of L ) , optimal HDL cholesterol level is equal to or greater than hypolipidemic agents , used as pharmaceutical agents to 40 mg/dL ( 1. 02 mmol/ L ), and optimal triglyceride level is lower cholesterol levels in people with or at risk of cardio less than 150 mg/ dL ( 1 . 7 mmol/ L ). As used herein , a vascular disease . They lower cholesterol by inhibiting the dyslipidemia is defined as an abnormal level which is at least 25 enzyme HMG - CoA reductase , which is the rate - limiting 5 % greater (or lower ) than the normal level ,more preferably enzyme of the mevalonate pathway of cholesterol synthesis . at least 10 % greater (or lower ) than the normal level, more Hypercholesterolemia : A condition characterized by preferably at least 20 % greater or lower than the normal elevated cholesterol. level. Dyslipidemia is a risk factor for cardiovascular dis Hyperinsulinemia : Excessively high blood insulin levels , ease, predisposing affected individuals to atherosclerosis . 30 which is differentiated from hyperinsulinism , excessive Obese and obese diabetic patients experience higher rates of secretion of insulin by the pancreatic islets . Hyperinsuline mia may be the result of a variety of conditions, such as dyslipidemia . Although diazoxide administration has been obesity and pregnancy. reported to reduce circulating triglyceride levels in treated Hyperinsulinism : Excessive secretion of insulin by the obese patients (Alemzadeh et al. 1998, J Clin Endocrinol 35 pancreatic islets . Metab 83 : 1911- 1915 ) no statistically significant reduction Hyperlipidemia : A general term for elevated concentra in cholesterol has been shown . In animal models of obesity tions of any or all of the lipids in the plasma, such as and obese diabetes, reductions in both total cholesterol and cholesterol, triglycerides and lipoproteins. circulating triglycerides have been reported (Alemzadeh et Hyperphagia : Ingestion of a greater than optimal quantity al. European Journal of Endocrinology (2002 ) 146 871 - 879; 40 of food . Alemzadeh and Tushaus Med Sci Monit, 2005 ; 11 ( 12 ) : Hypertension : Chronic high blood pressure , typically BR439 -444 ). In these models , diazoxide was administered above 140 ( systolic ) over 90 (diastolic ) mm Hg. Chronically when the treated animals transitioned from a normal phe - elevated blood pressure can cause blood vessel changes in notype to either obese or obese diabetic disease states. the back of the eye , thickening of the heart muscle , kidney Encapsulation system : A structural feature that contains 45 failure , and brain damage . drug within such as a pharmaceutical capsule . A gel into Hypertriglyceridemia ( or hypertriglyceridaemia ) denotes which drug is incorporated also is considered an encapsu - high ( hyper - ) blood levels ( - emia ) of triglycerides without lation system . elevated cholesterol, the most abundant fatty molecule in Endogenous hyperlipidemia : characterized primarily by most organisms. It has been associated with atherosclerosis , elevated VLDL (both triglycerides and cholesterol associ- 50 even in the absence of hypercholesterolemia (high choles ated with VLDL may also be elevated ) . Endogenous hyper - terol levels ) . It can also lead to pancreatitis in excessive lipidemia results from an endogenous metabolic source of concentrations . the increased lipids rather than from a dietary source of the Hypoglycemia - associated autonomic failure: A condition increased lipids . where hypoglycemic patients , e . g . , patients with type I - 55 diabetes or advanced type II diabetes , become unable to Equivalent amount: An amount of a derivative of a drug » recognize the symptoms ofhypoglycemia , and /or lose coun that in assays or upon administration to a subject produces ter- regulatory hormonal responses, primarily glucagon and an equal effect to a defined amount of the non -derivatized epiepherine extending periods of hypoglycemia with their drug. associated sequelae . Fatty acid synthase: The central enzyme of a multienzymetienzyme 60 Ingredient of a pharmaceutical composition : Refers to one complex that catalyses the formation of palmitate from or more materials used in the manufacture of a pharmaceu acetylcoenzyme A , malonylcoenzyme A , and NADPH . tical composition . Ingredient can refer to an active ingredi Fibrates: A class of amphipathic carboxylic acids primar - ent (an agent ) or to other materials in the compositions . ily used for decreasing serum triglycerides, while increasing Ingredients can include water and other solvents , salts , high density lipoprotein (HDL ). 65 buffers , surfactants , non - aqueous solvents , and flavorings . Fructose - 1 ,6 -bisphosphatase inhibitor: A class of anti - Insulin dosing: The administration of exogenous insulin diabetic drugs which act by inhibiting fructose - 1 , 6 -bispho - to a subject . US 9 , 765, 043 B2 41 Insulin resistance : A condition in which the tissues of the Obesity : An increase in body weight beyond the limitation body are diminished in their ability to respond to insulin . of skeletal and physical requirement, as the result of an Ischemic injury : Injury to tissue that results from a low excessive accumulation of fat in the body . Formally defined oxygen state usually due to obstruction of the arterial blood as having a body mass index greater than 30 kg/m2 . supply or inadequate blood flow leading to hypoxia in the 5 Obesity Prone : Subjects who because of genetic predis tissue . position or prior history of obesity are at above average risk Ketoacidosis : Acidosis accompanied by the accumulation of becoming obese . Obesity related co -morbidities : Any disease or condition of ketone bodies (ketosis ) in the body tissue and fluids, as in of animals or humans that are increased incidence in obese diabetic acidosis . 10 or overweight subjects . Examples of such conditions include Kit: Refers to a packaged combination . A packaged com hypertension , prediabetes, type 2 diabetes, osteoarthritis and bination can optionally include a label or labels , instructions cardiovascular conditions . and / or reagents for use with the combination . Oral anti -hypertensive agent: An orally administered Kir : Pore forming subunit of the KATP channel . Also therapeutic agent which is used to treat high blood pressure. known as the inwardly rectifying subunit of thele KAIPKATP 15 Oral antihypertensive agents suitable for use in methods channel . Typically existing as Kir6 . x and infrequently as described herein include but are not limited to diuretics , Kir2 .x subspecies. beta - blockers , calcium channel blockers , ACE inhibitors , KATP channel: An ATP sensitive potassium ion channel rennin inhibitors , angiotensin II antagonists , and alpha - 1 across the cell membrane formed by the association of 4 blockers . copies of a sulfonylurea receptor and 4 copies of a pore 20 Osmotically controlled release: A pharmaceutical dosage forming subunit Kir . Agonizing the channel can lead to form in which the release of the active drug is principally membrane hyperpolarization . achieved by the hydration of a swellable component of the KATP channel opener : As used herein refers to a com - formulation . pound of any of Formulae I - VIII , or a derivative , salt or Overweight: An subject whose weight is above that which prodrug thereof, having one or more or preferably all of the 25 is ideal for their height but who fails to meet the criteria for following three properties : ( 1 ) opening SURx /Kirb . y potas - classification as obese . In humans using Body Mass Index sium channels , where x = 1 , 2A or 2B and y = 1 or 2 ; ( 2 ) (kg / m2 ) an overweight subjects has a BMIbetween 25 and binding to the SURx subunit of KATP channels ; and ( 3 ) 30 . inhibiting glucose induced release of insulin following Oxidation of Fat : A series of reactions involving acyl administration of the compound in vivo . 30 coenzyme A compounds , whereby these undergo beta oxi Late myocardial remodeling : myocardial infarction dation and thioclastic cleavage , with the formation of acetyl induced alterations of left ventricular ( LV ) architecture with coenzyme A ; the major pathway of fatty acid catabolism in scar formation , ventricular dilatation , and hypertrophy of the living tissue . noninfarcted ( remote ) myocardium . Pharmaceutical composition : Refers to a composition that Leptin : Product ( 16 kD ) of the ob ( obesity ) locus . It is 35 contains an agent and one or more other ingredients that is found in plasma of mammals and exerts a hormonal action , formulated for administration to a subject. An agent refers to which reduces food uptake and increases energy expendi- an active ingredient of a pharmaceutical composition . Typi ture . cally active ingredients are active for treatment of a disease Lipogenesis : The generation of new lipids, primarily or condition . For example , agents that can be included in triacylglycerides. It is dependent on the action of multiple 40 pharmaceutical compositions include agents for treating distinct enzymes and transport molecules. obesity or diabetes. The pharmaceutically active agent can Lipolysis : The breakdown of fat by the coordinated action be referred to as “ a pharmaceutical active ." of multiple enzymes . Pharmaceutical effect : Refers to an effect observed upon Lipoprotein lipase: An enzyme of the hydrolase class that administration of an agent intended for treatment of a catalyses the reaction of triacyglycerol and water to yield 45 disease or disorder or for amelioration of the symptoms diacylglycerol and a fatty acid anion . The enzyme hydroly . thereof . ses triacylglycerols in chylomicrons, very - low - density lipo - Pharmacodynamic : An effect mediated by drug action . proteins, low - density lipoproteins, and diacylglycerols. Pharmacokinetic : Relating to the absorption , distribution , Lubricant: An inactive component of a pharmaceutical metabolism and elimination of the drug in the body . formulation that provides for the flow ofmaterials in various 50 Poly -cystic ovarian syndrome: A disorder where the ovary processing steps, particularly tableting . secretes abnormally high levels of testosterone and estro Meglitinide: A class of anti- diabetic drugs which block gens , which results in irregular or no menses , excess body potassium channels by antagonism of sulfonylurea receptor hair growth , occasionally baldness, and often obesity , dia component of the channel in beta cells , resulting in increased betes and hypertension . insulin secretion . 55 PEO : An abbreviation for polyoxyethylene . As used Microparticle: A small particulate formed in the process herein , and except as otherwise indicated , polyoxyethylene of developing pharmaceutical formulations that may be is a polyether polymer of ethylene glycol having an average coated prior to producing the final dosage from . molecular weight of greater than 20 , 000 g /mol . In some MTP ( microsomal triglyceride transfer protein ) inhibi- embodiments , the average molecular weight of PEO is from tors : A class of pharmaceutical compounds that inhibit MTP 60 greater than 20 ,000 up to 300 ,000 g /mol . PEO may be used activity to lower cholesterol and triglycerides . in the form of copolymers with other polymers or as a Nonalcoholic steatohepatitis (NASH ) : Nonalcoholic ste - mixture of a combination of grades. Preferred concentra atohepatitis or NASH is a common , silent liver disease . It tions of PEO include 3 % to 40 % either as a single grade or resembles alcoholic liver disease , but occurs in people who as a mixture of grades (molecular weights ) . drink little or no alcohol. The major features in NASH are 65 Polymorph : A crystalline form of a compound that exists fat in the liver, inflammation and liver damage . The disease in at least two crystalline forms. Polymorphic forms of any may progress to cirrhosis. given compound are defined by the same chemical formula US 9 , 765, 043 B2 43 44 and /or composition and are as distinct in chemical structure Salt : The neutral, basic or acid compound formed by the as crystalline structures of two different chemical com union of an acid or an acid radical and a base or basic radical. pounds. Such compounds may differ in packing or geometri- Used generally to describe any ionic compound not con cal arrangement of respective crystalline lattices. The taining an oxide or hydroxide ion . chemical and /or physical properties or characteristics of the 5 A " short- acting anti - diabetic drug ” refers to an agent that various polymorphs may vary with each distinct polymor anti - diabetic drug is taken with meals to boost the insulin phic form , and may include , but are not limited to , variations response to each meal. Short acting anti - diabetic drugs in solubility , melting point, density , hardness , crystal shape, typically have rapid onset of effects with maximal effects optical and electrical properties , vapor pressure , and stabil 10 typically realized between 30 minutes and 3 hours after ity. administration and with circulating half- lives less than 5 Preadipocyte : A progenitor cell to adipocytes. hours . PPAR agonist : Peroxisome proliferator - activated receptor Solid oral dosage form : Pharmaceutical formulations agonists include compounds that activate , e . g . the PPARy dedesigned for oral administration including capsules and receptor, leading to , e . g ., a decrease in insulin resistancene FPARY , 15 tablets modification of adipocyte differentiation , and a decrease in Squalene synthase: squalene synthase is an enzyme at a leptin levels . Thiazolidinediones target PPARY. branch point in the isoprenoid biosynthetic pathway capable PPAR partial agonist : Peroxisome proliferator -activated of diverting carbon flow to the biosynthesis of sterols. receptor partial agonists are PPAR agonists that can only Squalene Synthase inhibitor : an inhibitor of squalene incompletely agonize the receptor. 20 synthase . Prediabetic : A condition that precedes diagnosis of type II Subject : Refers to animals , including mammals , such as diabetes. Type II diabetes is a form of diabetes mellitus human beings , domesticated animals , and animals of com which is characterized by insulin insensitivity or resistance . mercial value . Prodrug : Refers to a compound which , when metabolized , Sulfonylurea receptor: Acomponent of the KATP channel yields the desired active compound . Typically , the prodrug 25 responsible for interaction with sulfonylurea , other KATP is inactive, or less active than the active compound, but may channel antagonists , diazoxide and other KATP channel provide advantageous handling , administration , or meta - agonists . bolic properties. For example , some prodrugs are esters of Sulfonylurea receptor antagonist: a molecule which upon the active compound ; during metabolysis , the ester group is interaction with the sulfonylurea receptor acts to block the cleaved to yield the active drug . Also , some prodrugs are 30 KATP channel. activated enzymatically to yield the active compound , or a Tablet : Pharmaceutical dosage form that is produced by compound which , upon further chemical reaction , yields the forming a volume of a matrix containing pharmaceutical active compound . active and excipients into a size and shape suitable for oral Prolonged Administration (prolonged basis ) : Administra - administration . tion of a pharmaceutically acceptable formulation of a drug 35 Thermogenesis : The physiological process of heat pro for 7 or more days . Typically , prolonged administration is duction in the body. for at least two weeks , preferably at least one month , and Thiazolidinedione : A class of anti - diabetic drugs compris even more preferably at least two months ( i . e . at least 8 ing a thiazolidine ring having 2 oxo groups attached . Thi weeks ) . azolidinediones bind to and activate the PPARy receptor. Quick dissolving formulation : A pharmaceutical formu - 40 Threshold Concentration : The minimum circulating con lation which upon oral administration may release substan - centration of a drug required to exert a specific metabolic , tially all of the drug active from the formulation within 10 physiological or compositional change in the body of a minutes . treated human or animal. QD , BID and TID : QD ( quaque die ) means once per day Thyroid receptor: The thyroid (hormone ) receptor regu administration of a pharmaceutical substance or formula - 45 lates a diverse set of genes that control processes from tion ; BID (bis in die ) means twice per day ; and TID ( Ter In embryonic development to adult homeostasis. Receptors for Die ) means three time per day . thyroid hormones are members of a large family of nuclear Release formulation (sustained ) , (or " sustained release receptors that include those of the steroid hormones . Upon formulation ” ) : A formulation of pharmaceutical product binding of thyroid hormone, the thyroid receptor releases that, upon administration to animals , provides for release of 50 corepressor proteins and undergoes a conformational change the active pharmaceutical over an extended period of time that allows for the interaction of coactivating proteins nec than provided by formulations of the same pharmaceutical essary for gene transcription . active that result in rapid uptake. Similar terms are extended - Thyroid receptor activator : A molecule which upon inter release , prolonged -release , and slow -release . In all cases , the action with the thyroid hormone receptor acts to increase preparation , by definition , has a reduced rate of release of 55 activity of the thyroid hormone receptor. active substance . Treatment: Any manner in which the symptoms of a Release formulation (delayed ), (or " delayed release for- condition , disorder or disease or other indication , are ame mulation ” ) : Delayed - release products are modified -release , liorated or otherwise beneficially altered . but are not extended -release . They involve the release of Triglyceride : Storage fats of animal and human adipose discrete amount( s ) of drug some time after drug adminis - 60 tissue principally consisting of glycerol esters of saturated tration , e . g . enteric - coated products , and exhibit a lag time fatty acids . during which little or no absorption occurs . Type I diabetes: A chronic condition in which the pancreas Release formulation (controlled ), (or “ controlled release makes little or no insulin because the beta cells have been formulation ” ) : A formulation of pharmaceutical product that destroyed . may include both delay of release of pharmaceutical active 65 Type II diabetes : A chronic condition that is primarily upon administration and control of release in the manner characterized by insulin resistance , relative insulin defi described for sustained release . ciency , and hyperglycemia . US 9 , 765 ,043 B2 45 46 Uncoupling protein : A family of proteins that allow product of potassium methoxide reaction with diazoxide in oxidation in mitochondria to proceed without the usual methanol, product of sodium methoxide reaction with diaz concomitant phosphorylation to produce ATP . oxide in methanol, and freeform diazoxide, respectively . Visceral fat: Human adipose tissues principally found FIG . 16A and FIG . 16B show XRPD patterns of ( a ) below the subcutaneous fat and muscle layer in the body. polymorphic Form A of the choline salt of diazoxide , and (b ) a mixture of polymorphic forms A and B of the choline salt BRIEF DESCRIPTION OF THE FIGURES of diazoxide , respectively . FIG . 17A and FIG . 17B show the NMR spectra (DMSO FIG . 1 shows UV spectra of the free form diazoxide and d6 solvent) for (a ) polymorphic Form A of the choline salt the sodium and potassium salts of diazoxide in acetonitrile . 10 of diazoxide, and ( b ) polymorphic Form B of the choline salt FIG . 2 shows UV spectra of the free form diazoxide at of diazoxide , respectively. varying pH . FIG . 18A , FIG . 18B and FIG . 18C show XRPD patterns FIG . 3 shows UV spectra of the free form diazoxide and of ( a ) polymorphic Form A of the potassium salt of diaz sodium and potassium salts of diazoxide in methanol. oxide , ( b ) polymorphic Form B of the potassium salt of FIG . 4A , FIG . 4B , FIG . 4C and FIG . 4D show X - Ray 15 diazoxide , and ( c ) polymorphic Form C of the potassium salt Powder Diffraction patterns for (a ) free form diazoxide, (b ) of diazoxide, respectively . potassium salt of diazoxide from THF, ( c ) lysine salt of FIG . 19A , FIG . 19B , FIG . 19C and FIG . 19D show XRPD diazoxide from MEK , and (d ) sodium salt of diazoxide from patterns of ( a ) polymorphic Form D of the potassium salt of acetonitrile , respectively . diazoxide , ( b ) polymorphic Form E of the potassium salt of FIG . 5A , FIG . 5B and FIG . 5C show NMR spectra 20 diazoxide , (c ) polymorphic Form F of the potassium salt of (DMSO -d6 solvent) for ( a ) free form diazoxide , ( b ) potas - diazoxide, and ( d ) polymorphic Form G of the potassium sium salt , and ( c ) sodium salt , respectively . salt of diazoxide, respectively . FIG . 6A , FIG . 6B and FIG . 6C show X - Ray Powder FIG . 20 shows the DSC spectra of diazoxide choline salt Diffraction patterns for ( a ) sodium salt of diazoxide , (b ) Form A . Description : “ a ” (Extrap . Peak = 120 .44° C . ; Peak sodium salt of diazoxide after slurrying in water , and ( c ) free 25 Value = - 1 . 02 mW ; normalized = - 0 . 20 Wg- 1; Peak = 118 .63° form diazoxide , respectively . C . ) ; “ b ” (Extrap . Peak = 167 . 94° C . ; Peak Value = - 19 . 39mW : FIG . 7 shows DSC spectra for the free form diazoxide normalized = - 3 . 79 Wg- 1 ; Peak = 167 . 27° C . ) . ( top ) and potassium salt of diazoxide (bottom ). Description : FIG . 21 shows the DSC spectra of diazoxide choline salt " a " ( Integral = - 317 .56 m ) ; normalized = - 84 . 82 Jg 1 ; Form B . Description : “ a ” ( Extrap . Peak = 165 .05° C .; Peak Onset= 120 .81° C . ; Peak = 121. 29° C . ); “ b ” ( Integral = - 30 Value = - 3 .85 mW ; normalized = - 0 . 86 Wg- 1; Peak = 162 .66° 1170 . 43 m ) ; normalized = 154 .64 Jg - 1 ; Onset = 329 . 54° C . ; C . ). Peak = 329. 21° C .) ; “ C ” (Extrap . Peak = 355 .01° C . ; Peak FIG . 22 provides systolic blood pressure (SBP ) and Value = - 4 .58 mW ; normalized = - 1 .22 Wg- 1 ; Peak = 353 . 530 diastolic blood pressure (DBP ) for Proglycem Oral Suspen C . ) . sion (Proglycem ) and Diazoxide Choline Controlled - Re FIG . 8 shows TGA spectra for the free form diazoxide 35 lease Tablets (DCCRT ) at various times following dose ( top ) and potassium salt of diazoxide ( bottom ). administration (mean : SEM ) . FIG . 9A , FIG . 9B and FIG . 9C show X -Ray Powder FIG . 23 provides pulse rate for Proglycem Oral Suspen Diffraction patterns for ( a ) potassium salt of diazoxide, (b ) sion (Proglycem ) and Diazoxide Choline Controlled -Re potassium salt of diazoxide after slurrying in toluene , and ( c ) lease Tablets (DCCRT ) at various times following dose potassium salt of diazoxide after slurrying in toluene for 14 40 administration (mean _ SEM ) . days , respectively . FIG . 24 provides mean plasma diazoxide ( SD ) concen FIG . 10A , FIG . 10B and FIG . 10C show X - Ray Powder trations after a 200 mg dose of diazoxide ( linear coordi Diffraction patterns for (a ) free form diazoxide, ( b ) choline nates ). salt of diazoxide, and (c ) hexamethyl hexamethylene diam FIG . 25 provides mean plasma diazoxide ( USD ) concen monium hydroxide salt of diazoxide , respectively. 45 trations after a 200 mg dose of diazoxide ( semilog coordi FIG . 11 shows DSC spectra for the free form diazoxide nates ). ( top ) and choline salt of diazoxide (bottom ) . Description : FIG . 26 provides simulations to steady- state of once daily “ a” ( Integral = - 41 .24 m ) ; normalized = - 8 .05 Jg 1 ; dosing with 200 mg diazoxide. Onset= 101. 23° C .; Peak = 119. 29° C .) ; “ b ” (Integral = FIG . 27 provides a bar graph comparing the median 497 .37 m ) ; normalized = 97 . 10 Jg - 1 ; Onset = 166 .03° C .; 50 percentage change in levels of different lipid measurements Peak = 167 . 27° C . ) ; “ c ” ( Integral = - 1167. 83 m ); normal for patients that were treated with DCCR for 12 weeks ized = 154 . 29 Jg - 1 ; Onset = 329 .54° C . ; Peak = 329 .21° C . ) . followed by co - administration of DCCR with fenofibrate FIG . 12 shows TGA spectra for the free form diazoxide choline for 6 weeks, and patients that received placebo for ( top ) and choline salt of diazoxide (bottom ) . 12 weeks followed by co - administration of placebo with FIG . 13A , FIG . 13B and FIG . 13C show X -Ray Powder 55 fenofibrate choline for 6 weeks . Lipids measured for these Diffraction patterns for ( a ) choline salt of diazoxide , (b ) studies were triglycerides ( TG ) , total cholesterol ( TC ) , non choline salt of diazoxide after slurrying in dichloromethane HDL - C , VLDL - C , LDL - C , and HDL - C . Details are for 7 days , and ( c ) choline salt of diazoxide after moisture described in Example sections 15 . 1 and 15. 2 . sorption analysis , respectively . FIG . 28 provides a bar graph comparing the median FIG . 14A , FIG . 14B and FIG . 14C show NMR spectra 60 percentage change in levels of different lipid measurements ( DMSO - d6 solvent) for ( a ) free form diazoxide , ( b ) choline for patients that were treated with DCCR for 12 weeks salt, and ( c ) hexamethyl hexamethylene diammonium followed by co -administration of DCCR with fenofibrate hydroxide salt of diazoxide, respectively . choline for 6 weeks, and patients that only received feno FIG . 15A shows overlay XRPD patterns of free form fibrate choline for 6 weeks. Lipids measured for these diazoxide , the product of potassium methoxide in methanol, 65 studies were triglycerides ( TG ) , total cholesterol ( TC ) , non and the product of sodium methoxide in methanol. FIG . HDL - C , VLDL - C , LDL - C , and HDL - C . Details are 15B , FIG . 15C and FIG . 15D show the XRPD patterns for described in Example section 15 . 1 and 15 . 3 . US 9 , 765 ,043 B2 47 48 FIG . 29 provides a bar graph comparing the median from salts of the compounds defined by Formulae I- VIII that percentage change in levels of different lipid measurements achieve therapeutic outcomes while reducing the incidence for patients that were treated with DCCR for 12 weeks of adverse effects . followed by co -administration of DCCR with fenofibrate Still further provided are pharmaceutical formulations of choline for 6 weeks, patients that received omega - 3 fatty 5 particular KATP channel openers of salts of compounds of acids and fenofibrate for 8 weeks ( FIG . 2 of Roth et al. J Formulae I - VIII that may be administered to subjects once Cardiovasc Pharmacol. 2009 September ; 54 ( 3 ) : 196 - 203 ), per day ( QD ), twice per day (BID ) or three time per day and their respective controls . Lipids measured in these ( TID ) . The skilled artisan would realize each dosage per day studies were triglycerides ( TG ) , total cholesterol ( TC ) , non per time may comprise one or more tablets administered to HDL - C , VLDL - C , LDL - C , and HDL - C . JCP = Data from a subject . In preferred embodiments, the total effective dose Roth et al . ( J Cardiovasc Pharmacol. 2009 September ; per day can be 100 , 200 , 300 , 400 , 500 or 600 mg of KATP 54 (3 ): 196 - 203 ) . Details are described in section 15 . 1 and channel openers as active agent ( administered as control 15 .4 . release formulations ) . Such doses can be effective in achiev ing weight loss or reduction in total cholesterol, reduction in DETAILED DESCRIPTION OF THE LDL cholesterol, reduction in non -HDL cholesterol, reduc INVENTION tion in VLDL cholesterol, increase in HDL cholesterol, and reduction in triglyceride without substantial caloric reduc The present invention provides salts of compounds of tion ,more preferably with no caloric reduction . Such control Formulae I- VIII and methods for their preparation . Salts of 20 release formulations comprise particular KATP channel compounds of Formulae I -IV may be prepared using mon openers of salts of compounds of formulae I - VIII formula ovalent alkali metal cations and compounds which include tion that require once per day dosing with or without caloric one or more of a tertiary amine or quaternary ammonium restricted diet . In addition , with control release formulations , moiety . In such salts , the compounds of Formulae I- IV exist the dosing required per day to reach clinical efficacy is much in their anionic form . Furthermore , it has been discovered 25 less compared to immediate release formulations . that the selection of a solvent for the preparation of these In particular, pharmaceutical formulations selected from salts plays an important role in salt formation . Also salts of compounds defined by Formulae I - VIII and formu described herein is the failure to obtain a salt of diazoxide lated for oral administration exhibit advantageous properties from an alkali metal alkoxide using the method described in including : facilitating consistency of absorption , pharma U . S . Pat . No . 2 , 986 , 573 . 30 cokinetic and pharmacodynamic responses across treated Compounds of Formulae V - VIII can form both anions and patients, contributing to patient compliance and improving cations, and thus salts can be prepared using a variety of the safety profile of the product , such as by reducing the counter ions, including both anions and cations. Cations of frequency of serious adverse effects .Method of treatment of the compounds of Formulae V - VIII can be formed at an metabolic and other diseases of humans and animals by amino group , and anions of the compounds of Formulae 35 administering the formulations are also provided . V - VIII can be formed at either an amino group or at the As shown below , diazoxide and derivatives thereof can sulfonyl group . The formation of salts based on compounds exist as proton tautomers . Proton tautomers are isomers that of Formulae V - VIII can be done in a variety of solvents , differ from each other only in the location of a hydrogen preferably organic solvents . atom and a double bond . The hydrogen atom and double As discussed herein , two polymorphic forms ( i. e .. Forms 40 bond switch locations between a carbon atom and a het A and B ) of the choline salt of diazoxide have been identi eroatom , such as for example N . Thus , when the substituent fied. In summary, both Forms Aand B are anhydrous crystals on the nitrogen is hydrogen , the twotwo isomericisomer chemical of diazoxide choline salt . Diazoxide choline salt Form Acan structures may be used interchangeably . be formed using fast cooling procedures as provided herein , whereas slow cooling procedures generally favor formation 45 of Form B . Slurry studies shows that Form A readily converts to Form B . Without wishing to be bound by theory , the slurry studies indicate that Form B of diazoxide choline salt is the thermodynamically more stable form . Regarding the potassium salt of diazoxide, seven poly - 50 morphic forms have been identified ( i . e . , Forms A - G ) . Diazoxide potassium salt Forms C , D , and F were observed be an acetone solvent, a hemihydrate , and a dioxane solvent, The particular KATP channel openers that can be used in respectively. Forms A , B , E , and G were not commonly the invention formulations include salts of any of the com observed during screening, and elemental analysis suggests 55 pounds within Formulae I to VIII . Exemplary compounds that Forms A , B , E and G may be mixtures , have residual which have been previously reported include diazoxide , solvent present, and /or not be a potassium salt, at least in BPDZ 62 , BPDZ 73 , NN414 and BPDZ 154 ( see , for part . Without wishing to be bound by theory, slurry studies example , Schou et al. , Bioorg . Med . Chem ., 13, 141- 155 suggest that Form D is the thermodynamically most stable (2005 ) ) . Compound BPDZ 154 also is an effective KATP polymorph of the diazoxide potassium salt polymorphs . 60 channel activator in patients with hyperinsulinism and in Further provided are pharmaceutical formulations of par - patients with pancreatic insulinoma. The synthesis of BPDZ ticular KATP channel openers of salts of compounds of compound is provided in Cosgrove et al ., J . Clin . Endocri Formulae I - VIII that when administered to subjects achieve nol. Metab . , 87 , 4860 -4868 ( 2002 ). novel pharmacodynamic , pharmacokinetic , therapeutic , Channel openers demonstrating decreased activity in the physiological, and metabolic outcomes . Yet further provided 65 inhibition of insulin release and increased activity in vas are pharmaceutical formulations, methods of administration cular smooth muscle tissue have been previously reported and dosing of particular KATP channel openers selected and include analogs of diazoxide such as, for example , US 9 , 765 ,043 B2 49 50 3 - isopropylamino - 7 -methoxy - 4H - 1 , 2 ,4 , -benzothiadiazine from incubated rat pancreatic islets can be performed as 1 ,1 -dioxide , (a selective Kir6 . 2 /SUR1 channel opener; see described by Ouedraogo et al. , Biol. Chem ., 383 , 1759 - 1768 Dabrowski et al ., Diabetes , 51 , 1896 - 1906 ( 2002 ) , and (2002 ) . 2 - alkyl substituted diazoxides ( see, for example , Ouedraogo Activation of recombinant KATP channels by KATP et al. , Biol. Chem . , 383 , 1759 - 1768 ( 2002 ) ). The 2 - alkyl 5 channel openers can be examined by monitoring macro substituted diazoxides generally do not function as tradi scopic currents of inside -out membrane patches from Xeno tional potassium channel activators, but instead show poten - pus oocytes co -expressing Kir6 .2 and either SUR1 , SUR2A tial as Ca2 + blockers . or SUR2B . SUR expressing membranes can be prepared by Other diazoxide analogs which have been previously known methods . See , for example , Dabrowski et al. , Dia reported include described in Schou et al. , Bioorg. Med . 10 betes, 51 , 1896 -1906 ( 2002 ) . Chem ., 13 , 141- 155 (2005 ) , are shown below . Binding experiments can be used to determine the ability of KATP channel openers to bind SUR1, SUR2A and SUR2B . See , for example , Schwanstecher et al. , EMBO J ., PR3 17 , 5529 - 5535 ( 1998 ) . Preparation of SUR1 and SUR2A chimeras, as described by Babenko et al. , allows for comparison of pharmacologic P2 profiles ( i . e . sulfonyl sensitivity and responsiveness to diaz oxide or other potassium channel openers ) of the SUR1/ 20 Kir6 . 2 and SUR2A / Kir6 . 2 potassium channels . See Babenko et al. , J . Biol. Chem ., 275 ( 2 ) , 717 - 720 ( 2000 ) . The R1, R2 and R3 are: cloning of a sulfonylurea receptor and an inwardly rectifying a ) H , C1, NHCH( CH3 ) 2 K + channel is described by Isomoto et al. , J. Biol. Chem . , b ) CF , H , NHCH( CH3) 2 271 ( 40 ) , 24321- 24324 ( 1996 ) ; D ’ hahan et al. , PNAS, c ) H , CI, NHCH2CH2CH (CH3 ) 2 25 96 ( 21 ) , 12162 - 12167 ( 1999 ) . d ) H , Cl, NH- cyclobutyl Differences between the human SUR1 and human SUR2 Diazoxide analogs having different alkyl substituents at genes are described and shown in Aguilar -Bryan et al ., the 3 position of themolecule (identified as R shown below ) Physiological Review , 78 ( 1 ) : 227 - 245 ( 1998 ) . are described in Bertolino et al. , Receptors and Channels , 1, “ Halo ” and “ halogen ” refer to all halogens , that is , chloro 267- 278 ( 1993 ) . 30 ( Cl) , fluoro ( F ) , bromo (Br ), or iodo ( I ) . “ Hydroxyl” and “ hydroxy ” refer to the group OH . “ Substituted oxy ” refers to the group - ORaa , where Raa R6 N can be alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, 35 substituted aralkyl , cycloalkyl, substituted cycloalkyl, het R erocyclyl, or substituted heterocyclyl. “ Substituted thiol” refers to the group - SRbb , where Rbb can be alkyl , substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, R3, R and R7 are: 40 substituted aralkyl, cycloalkyl, substituted cycloalkyl, het a ) H , H , CH2 erocyclyl, or substituted heterocyclyl . b ) H , H , C1 “ Alkyl ” refers to an alkane - derived radical containing c ) CH -, Cl , H from 1 to 10 , preferably 1 to 6 , more preferably 1 -4 , yet d ) CH , C1, H , C1 more preferably 1 - 2 , carbon atoms. Alkyl includes straight e ) NH2, H , H 45 chain alkyl, branched alkyl and cycloalkyl, such as methyl, f) CH ,CH , C1, H , C1 ethyl, propyl , isopropyl, butyl , t- butyl , and the like. The g ) nC4H , H , CI alkyl group can be attached at any available point to produce h ) nC3H11, H , C1 a stable compound . An " alkylene ” is a divalent alkyl. i ) nC , H , , H , C1 A “ substituted alkyl ” is an alkyl group independently j) nCzH7, C1, H 50 substituted with 1 or more , e . g . , 1 , 2 , or 3 , groups or k ) nC H9, C1, H substituents such as halo , hydroxy , optionally substituted 1) nC3H11, C1, H alkoxy , optionally substituted alkylthio , alkylsulfinyl, alkyl m ) nC ,H15 , C1, H sulfonyl, optionally substituted amino , optionally substi n ) nCzH , , C1, C1 tuted amido , amidino , urea optionally substituted with alkyl, o) nC2H2, C1, C1 55 aminosulfonyl optionally N -mono - or N , N -di - substituted p ) nCzH11 , C1, C1 with alkyl, alkylsulfonylamino , carboxyl, heterocycle , sub q ) nC H15 , C1, C1 stituted heterocycle , nitro , cyano , thiol, sulfonylamino or the r ) H , CL , H like attached at any available point to produce a stable KATP channel activity of salts of the compounds of compound . In particular, “ fluoro substituted ” refers to sub Formulae 1 -VIII and related compounds can be measured by 60 stitution by 1 or more , e . g . , 1 , 2 , or 3 fluorine atoms. membrane potential studies as described in Schou et al. , " Optionally fluoro substituted ” means that substitution , if Bioorg . Med . Chem ., 13 , 141 - 155 ( 2005 ) and Dabrowski, et present, is fluoro . The term “ optionally substituted ” as used al. , Diabetes, 51, 1896 - 1906 (2002 ) . herein means that substitution may , but need not, be present. Measurement of the inhibition of glucose - stimulated insu - “ Lower alkyl” refers to an alkyl group having 1 - 6 carbon lin release from BTC6 cells is described in Schou et al ., 65 atoms. Bioorg . Med . Chem . , 13 , 141- 155 (2005 ) . The ability of “ substituted lower alkyl” is a lower alkyl which is particular KATP channel openers to inhibit release of insulin substituted with 1 or more , e. g. , 1 , 2, or 3, groups or US 9 , 765 ,043 B2 51 52 substituents , as defined above, attached at any available substituted aryl , heteroaryl, substituted heteroaryl, het point to produce a stable compound . eroaralkyl, substituted heteroaralkyl, aralkyl or substituted " Cycloalkyl” refers to saturated or unsaturated , non aralkyl. aromatic monocyclic , bicyclic or tricyclic carbon ring sys “ Amino ” or “ amine” denotes the group - NH2. A " diva tems of 3 - 8 , more preferably 3 - 6 , ring members per ring, 5 lent amine ” denotes the group — NH — A " substituted such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, divalent amine” denotes the group — NRkk - wherein Rkk is and the like . “ Cycloalkylene” is a divalent cycloalkyl. alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, “ Substituted cycloalkyl” refers to saturated or unsatu - substituted heteroaryl, acyl, substituted acyl, sulfonyl or rated , non - aromatic monocyclic , bicyclic or tricyclic carbon substituted sulfonyl. ring systems of 3 - 8 , more preferably 3 - 6 , ring members per 10 “ Substituted amino " or " substituted amine ” denotes the ring , such as cyclopropyl, cyclopentyl, cyclohexyl, adaman - group — NRmmRnn , wherein Rmm and Rnn are indepen tyl, and the like independently substituted with 1 or more , dently hydrogen , alkyl, substituted alkyl, aryl, substituted e . g . , 1 , 2 , or 3 , groups or substituents such as halo , hydroxy , aryl, heteroaryl, substituted heteroaryl, acyl, substituted optionally substituted alkoxy, optionally substituted alkyl acyl, sulfonyl, substituted sulfonyl, or cycloalkyl provided , thio , alkylsulfinyl, alkylsulfonyl, optionally substituted 15 however, that at least one of Rmm and Rnn is not hydrogen . amino , optionally substituted amido , amidino , urea option - RmmRnn in combination with the nitrogen may form an ally substituted with alkyl, aminosulfonyl optionally optionally substituted heterocyclic or heteroaryl ring . N -mono - or N , N -di - substituted with alkyl, alkylsulfo - “ Alkylsulfinyl” denotes the group - S (O )Roo , wherein nylamino , carboxyl, heterocycle, substituted heterocycle , Roo is optionally substituted alkyl. nitro , cyano , thiol, sulfonylamino or the like attached at any 20 “ Alkylsulfonyl ” denotes the group - S (O ) 2Rpp , wherein available point to produce a stable compound . Rpp is optionally substituted alkyl. “ Aryl” alone or in combination means phenyl or naphthyl “ Alkylsulfonylamino ” denotes the group — NRqqs (0 ) optionally carbocyclic fused with a cycloalkyl of preferably 2Rrr, wherein Rrr is optionally substituted alkyl, and Rqq is 5 - 7 , more preferably 5 - 6 , ring members . hydrogen or alkyl. “ Substituted aryl” refers to an aryl group as defined above 25 A “ primary amino substituent” denotes the group — NH2 . independently substituted with 1 or more , e . g ., 1 , 2 , or 3 , A " secondary amino substituent” denotes the group groups or substituents such as halo , hydroxy , optionally — NHRss, wherein Rss is alkyl, substituted alkyl, aryl, substituted alkoxy, optionally substituted alkylthio , alkyl- substituted aryl, heteroaryl, substituted heteroaryl , acyl, sub sulfinyl, alkylsulfonyl, optionally substituted amino , option - stituted acyl, sulfonyl, substituted sulfonyl, or cycloalkyl. ally substituted amido , amidino , urea optionally substituted 30 A " tertiary amino substituent ” denotes the group — NRss with alkyl, aminosulfonyl optionally N -mono - or N , N - di- Rtt , wherein Rss and Rtt are independently alkyl, substituted substituted with alkyl, alkylsulfonylamino , carboxyl, hetero - alkyl, aryl, substituted aryl, heteroaryl, substituted het cycle , substituted heterocycle , nitro , cyano , thiol, sulfo eroaryl, acyl, substituted acyl, sulfonyl, substituted sulfonyl , nylamino or the like attached at any available point to or cycloalkyl. produce a stable compound . 35 " Quaternary ammonium substituent” denotes the group “ Alkoxy ” denotes the group ORcc , where Rcc is alkyl . — N +RssRttRuu , wherein Rss , Rtt and Ruu are indepen “ Lower alkoxy ” denotes the group — ORccc , where Rccc is dently alkyl, substituted alkyl, aryl, substituted aryl, het lower alkyl eroaryeroaryl , substituted heteroaryl, acyl, substituted acyl , sulfo “ Substituted alkoxy ” denotes the group — ORdd , where nyl, substituted sulfonyl, or cycloalkyl . Rdd is substituted alkyl. “ Substituted lower alkoxy ” denotes 40 “Heteroaryl ” means a monocyclic aromatic ring structure the group — ORddd , where Rddd is substituted lower alkyl . containing 5 or 6 ring atoms, or a bicyclic aromatic group “ Alkylthio ” or “ thioalkoxy ” refers to the group — S having 8 to 10 atoms, containing one or more , preferably Ree , where Ree is alkyl. 1 - 4 , more preferably 1 - 3 , even more preferably 1 - 2 , het " Substituted alkylthio " or " substituted thioalkoxy ” refers e roatoms independently selected from the group consisting to the group — S - R , where R is substituted alkyl. 45 of O , S , and N . Heteroaryl is also intended to include “ Sulfinyl ” denotes the group - S ( O ) - , oxidized S or N , such as sulfinyl, sulfonyl and N -oxide of a “ Sulfonyl” denotes the group - S ( O ) - , tertiary ring nitrogen . Acarbon or nitrogen atom is the point “ Substituted sulfinyl” denotes the group - S ( O ) - Rff, of attachment of the heteroaryl ring structure such that a where Rff is alkyl , substituted alkyl , cycloalkyl , substituted stable aromatic ring is retained . Examples of heteroaryl cycloalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, het - 50 groups are pyridinyl, pyridazinyl, pyrazinyl, quinaoxalyl, erocyclyl , substituted heterocyclyl, heterocyclylalkyl, sub indolizinyl, benzo [ b ] thienyl, quinazolinyl, purinyl, indolyl, stituted hetereocyclylalkyl, aryl, substituted aryl, heteroaryl, quinolinyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thie substituted heteroaryl, heteroaralkyl, substituted het nyl, isoxazolyl, oxathiadiazolyl , isothiazolyl, tetrazolyl, imi eroaralkyl , aralkyl or substituted aralkyl. dazolyl, triazinyl , furanyl, benzofuryl, indolyl, and the like . “ Substituted sulfonyl” denotes the group - S ( O ) Rgg , 55 “ Heteroarylene” means a divalent heteroaryl. where Rgg is alkyl, substituted alkyl, cycloalkyl, substituted “ Heterocycle ” or “ heterocyclyl ” means a saturated or cycloalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, het unsaturated , non - aromatic carbocyclic group having a single erocyclyl, substituted heterocyclyl, heterocyclylalkyl , sub ring or multiple condensed rings, e. g . a cycloalkyl group stituted hetereocyclylalkyl, aryl, substituted aryl, heteroaryl, having from 5 to 10 atoms in which from 1 to 3 carbon atoms substituted heteroaryl, heteroaralkyl, substituted het- 60 in a ring are replaced by heteroatoms, such as O , S , N , and ereroaralkyl , aralkyl or substituted aralkyl. are optionally fused with benzo or heteroaryl of 5 - 6 ring “ Sulfonylamino ” denotes the group - S (O )2NRhh - where members and /or are optionally substituted . Heterocyclyl is Rhh is hydrogen or alkyl. intended to include oxidized S or N , such as sulfinyl, “ Substituted sulfonylamino ” denotes the group - S ( O ) sulfonyl and N -oxide of a tertiary ring nitrogen . Examples of 2NRii -Rjj , where Rii is hydrogen or optionally substituted 65 heterocycle or heterocyclyl groups are morpholino , tetrahy alkyl, and Rjj is alkyl, substituted alkyl, cycloalkyl, substi drofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, pip tuted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, erazinyl, dihydrobenzofuryl, dihydroindolyl, and the like . US 9 , 765 ,043 B2 53 54 " Heterocyclylalkyl” refers to the group - R -Het where readily dissolved and absorbed , (6 ) provide, when incorpo Het is a heterocycle group and R is an alkylene group . rated into a pharmaceutical formulation , for absorption of A “ substituted heteroaryl, ” “ substituted heterocyclyl, ” or greater than 80 % of the administered dose, ( 7 ) present no “ substituted heterocyclylalkyl” is a heteroaryl, heterocyclyl, elevated toxicological risk as compared to the free base of or heterocyclylalkyl, respectively, independently substituted 5 the KATP channel opener, ( 8 ) can be formulated into accept with 1 or more , e . g . , 1 , 2 , or 3 , groups or substituents such able pharmaceutical formulations to treat obesity and other as halogen , hydroxy , optionally substituted alkoxy , option diseases of humans, ( 9 ) are acceptable to the FDA as the ally substituted alkylthio , alkylsulfinyl, alkylsulfonyl, acy - basis of a drug product, ( 10 ) can be recrystallized to improve loxy , optionally substituted aryl, optionally substituted ary - purity , ( 11 ) can be used to form co -crystals of two or more loxy, optionally substituted heteroaryloxy , optionally 10 salts of the KATP channel opener , ( 12 ) have limited hygro substituted amino , optionally substituted amido , amidino, scopicity to improve stability, ( 13 ) synthetic and crystalli urea optionally substituted with alkyl, aryl, heteroaryl or z ation conditions under which the salt is formed can be heterocyclyl groups , aminosulfonyl optionally N -mono - or varied resulting in different crystal structures ( polymorphs ) N , N - di- substituted with alkyl, aryl or heteroaryl groups, can be controlled in the synthesis of the salt , or (14 ) have alkylsulfonylamino , arylsulfonylamino , heteroarylsulfo - 15 improved solubility as compared to the free base in aqueous nylamino , alkylcarbonylamino , arylcarbonylamino , het systems at physiological pH values . eroarylcarbonylamino , carboxyl, heterocycle , substituted The KATP channel openers provided in Formulae I - VIII heterocycle , heteroaryl, substituted heteroaryl, nitro , cyano , are preferably formulated as pharmaceutically acceptable thiol, sulfonylamino , optionally substituted alkyl, optionally salts . Pharmaceutically acceptable salts are non - toxic salts in substituted alkenyl, or optionally substituted alkynyl, 20 the amounts and concentrations at which they are adminis attached at any available point to produce a stable com tered . The preparation of such salts can facilitate the phar pound . macological use by altering the physical characteristics of a “ Amido ” denotes the group _ C ( O )NH2 . “ Substituted compound without preventing it from exerting its physi amido ” denotes the group C ( O )NRKR1 , wherein Rk and ological effect. Useful alterations in physical properties R1 are independently hydrogen , lower alkyl, substituted 25 include lowering the melting point to facilitate transmucosal lower alkyl, aryl, substituted aryl, heteroaryl, or substituted administration and increasing the solubility to facilitate heteroaryl, provided , however, that at least one of Rk and R1 administering lower effective doses of the drug . is not hydrogen . RkRl in combination with the nitrogen may Salts of the compounds of Formulae I - IV can include form an optionally substituted heterocyclic or heteroaryl metal cations, preferably alkali metal cations, such as for ring. 30 example , sodium or potassium . Cations can be selected from “ Amidino ” denotes the group _ C ( = NRm )NRnRo , any group I alkali metal . Divalent metals cations, such as wherein Rm , Rn , and Ro are independently hydrogen or alkaline earth metals (e . g ., magnesium , calcium and the optionally substituted lower alkyl. like ) , have not been found to be useful for salt formation “ Acyloxy ” denotes the group OC ( O ) Rh , where Rh is with the compounds of Formulae I - IV . hydrogen , alkyl, substituted alkyl, cycloalkyl, substituted 35 Salts of the compounds of Formulae I- IV which include cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, sub - alkali metal cations can be prepared by reacting the com stituted aryl, heteroaryl , substituted heteroaryl and the like . pounds of Formulae I - IV with an alkali metal hydroxide or “ Aryloxy ” denotes the group — OAr, where Ar is an aryl , alkali metal alkoxide, such as for example , NaOH , KOH or or substituted aryl, group . “ Heteroaryloxy ” denotes groups NaOCH3, in a variety of solvents which may be selected — OHet , wherein Het is an optionally substituted heteroaryl 40 from low molecular weight ketones ( e . g . , acetone, methyl group . ethyl ketone ) , tetrahydrofuran ( THF ) , dimethylformamide “ Arylsulfonylamino ” denotes the group - NRqS ( O ) 2Rs, ( DMF) , and n -methylpyrrolidinone , and the like . Surpris wherein Rs is optionally substituted aryl , and Rq is hydrogen ingly , salt formation with an alkali metal hydroxide or or lower alkyl. alkoxide is not observed when an alcohol, particularly a “ Heteroarylsulfonylamino ” denotes the group — NRqS 45 lower alcohol such as for example methanol or ethanol, is ( 0 )2Rt , wherein Rt is optionally substituted heteroaryl, and used as the solvent. This result was confirmed by both Rq is hydrogen or lower alkyl . X - Ray Powder Diffraction and NMR , and is contrary to the " Alkylcarbonylamino ” denotes the group - NRqC ( O )Rp , disclosure of U . S . Pat . No . 2 ,986 ,573 , which purports to wherein Rp is optionally substituted alkyl, and Rq is hydro - describe formation of diazoxide salts in alcohol. gen or lower alkyl. 50 The compounds of Formulae I -IV can also form salts with “ Arylcarbonylamino ” denotes the group — NRqC ( O ) Rs, organic cations that include at least one tertiary amine or wherein Rs is optionally substituted aryl, and Rq is hydrogen ammonium cation . Organic cation compounds can be mon or lower alkyl. ovalent, divalent, trivalent and tetravalent by inclusion of “ Heteroarylcarbonylamino ” denotes the group — NRqC one , two , three or four tertiary amine or ammonium ions ( O )Rt , wherein Rt is optionally substituted aryl, and Rq is 55 within the compound , respectively. When a multivalent hydrogen or lower alkyl. compound is used , the tertiary amine or quaternary ammo Pharmaceutical formulations containing KATP channel nium moieties are preferably separated by a chain of at least openers can include the free base of a compound defined by 4 atoms, more preferably by a chain of at least 6 atoms, such any of Formulae I - VIII , or a salt thereof. Salts of the as for example , hexamethyl hexamethylene diammonium compounds of Formulae I - VIII as provided herein may have 60 dihydroxide , wherein the quaternary ammonium moieties one or more of the following characteristics : ( 1 ) stability in are separated by — (CH2 ) 6 - . Primary and secondary amines solution during synthesis and formulation , ( 2 ) stability in a do not to effectively form salts with the compounds of solid state , ( 3 ) compatibility with excipients used in the Formulae I - IV . manufacture of tablet formulations, ( 4 ) quantitatively yield Salts of the compounds of Formulae I - IV can be prepared the KATP channel opener upon exposure to simulated or 65 by reacting the compounds of Formulae I- IV with com actual gastric and duodenal conditions, ( 5 ) release KATP pounds that include at least one tertiary amine or quaternary channel opener from sufficiently small particles that are ammonium ion (e .g . , choline hydroxide, hexamethylhexam US 9 , 765 ,043 B2 55 56 ethylene diammonium dihydroxide ) in a solvent selected nate , probutate , propionate , saccharate , sodium glycinate , from low molecular weight ketones ( e . g . , acetone , methyl sodium phosphate , sodium succinate, stearate , succinate , ethyl ketone ) , tetrahydrofuran , dimethylformamide, and sulfate , sulfonate , sulfosalicylate, tartrate , tebutate , terepha n -methyl pyrrolidinone. As with the preparation of salts late , terephthalate , tosylate , triflutate , trihydrate , trisilicate , from alkali metal hydroxides , amine and ammonium con - 5 tromethamine , valerate , or xinafoate . Preferred organic cat taining compounds do not form salts when the solvent is an ions include compounds having tertiary amines or quater alcohol. nary ammonium groups Pharmaceutically acceptable salts of the compounds of Other, pharmaceutically acceptable salts of the com Formulae I - IV can also include basic addition salts such as pounds of Formulae V - VIII include acid addition salts such those containing benzathine , chloroprocaine, choline, dieth - 10 as those containing sulfate , chloride , hydrochloride , fumar ylamino - ethanol, hydroxyethyl pyrrolidine , ammonium , tet- ate , maleate , phosphate , sulfamate , acetate , citrate, lactate , rapropylammonium , tetrabutylphosphonium , hexamethyl tartrate , methanesulfonate , ethanesulfonate , benzenesul diammonium , methyldiethanamine , triethylamine, meglu - fonate , p - toluene sulfonate , cyclohexylsulfamate and qui mine , and procaine, and can be prepared using the appro nate . Pharmaceutically acceptable salts of the compounds of priate corresponding bases . 15 Formulae V - VIII can be obtained from acids such as hydro Preferred basic addition salts of the compounds of For chloric acid , maleic acid , sulfuric acid , phosphoric acid , mulae I -IV can include those containing hexamethyl hex sulfamic acid , acetic acid , citric acid , lactic acid , tartaric amethylene diammonium , choline, sodium , potassium , acid , malonic acid , methanesulfonic acid , ethanesulfonic methyldiethyl amine , triethylamine , diethylamino - ethanol, acid , benzenesulfonic acid , p -toluenesulfonic acid , cyclo hydroxyethyl pyrrolidine, tetrapropylammonium and tetra - 20 hexylsulfamic acid , fumaric acid , and quinic acid . butylphosphonium ions . Pharmaceutically acceptable salts of the compounds of Preferred basic addition salts of the compounds of For - Formulae V -VIII also include basic addition salts such as mulae I - IV can be prepared using hexamethyl hexamethyl- those containing benzathine , chloroprocaine, choline , ene diammonium dihydroxide , choline hydroxide , sodium diethanolamine , ethylenediamine , meglumine , procaine , hydroxide , sodium methoxide, potassium hydroxide , potas - 25 aluminum , calcium , lithium , magnesium , potassium , sium methoxide , ammonium hydroxide , tetrapropylammo- sodium , ammonium , alkylamine , and zinc , when acidic nium hydroxide , and tetrabutylphosphonium hydroxide . The functional groups, such as carboxylic acid or phenol are basic addition salts can be separated into inorganic salts present. For example , see Remington ' s Pharmaceutical Sci ( e . g . , sodium , potassium and the like ) and organic salts ( e . g ., ences , 19th ed . , Mack Publishing Co . , Easton , Pa . , Vol. 2 , p . choline , hexamethyl hexamethylene diammonium hydrox - 30 1457 , 1995 . Such salts of the compounds of Formulae ide , and the like ) . V -VIII can be prepared using the appropriate corresponding The compounds of Formulae V -VIII have the unique bases . property of being able to form both anions and cations. In Salts of the compounds of Formulae V - VIII can be basic media , the compounds of Formulae V - VIII typically prepared , for example , by dissolving the free -base form of a form anions . Anions can be formed at either an amino or 35 compound in a suitable solvent, such as an aqueous or substituted amino substituent, or at the sulfonyl group . In aqueous -alcohol in solution containing the appropriate acid acidic media , the compounds of Formulae V - VIII generally and then isolated by evaporating the solution . In another form cations by protonation of an amino group , thereby example , a salt is prepared by reacting the free base and acid forming an ammonium moiety . in an organic solvent. Salts of the anions of compounds of Formulae V - VIII can 40 The salts of the compounds of Formulae V - VIII may be include metal cations, including monovalent metal cations present as a complex . Examples of complexes include of any group I alkali metal ( e . g . , sodium , potassium , and the 8 - chlorotheophylline complex ( analogous to , e . g . , dimenhy like) , divalent metal cations of any group II alkaline earth drinate : diphenhydramine 8 - chlorotheophylline ( 1 : 1 ) com metal ( e . g ., calcium , magnesium , and the like ), and alumi plex ; Dramamine ) and various cyclodextrin inclusion com num cations . 45 plexes . Salts of the compounds of Formulae V -VIII which include Solvents useful in the preparation of pharmaceutically metal cations can be prepared by reacting the compounds of acceptable salts of the compounds of Formulae V - VIII Formulae V -VIII with a alkali or alkaline earth metal include organic solvents , such as for example , acetonitrile , hydroxides or alkoxides , such as for example , sodium acetone , alcohols ( e . g ., methanol, ethanol and isopropanol) , hydroxide or sodium methoxide , in an organic solvent, such 50 tetrahydrofuran , methyl ethyl ketone (MEK ), ethers ( e. g ., as for example lower alcohols , low molecular weight diethyl ether ) , benzene , toluene , xylenes, dimethylforma ketones ( e . g . , acetone , methyl ethyl ketone , and the like ), mide (DMF ) , and N -methylpyrrolidinone (NMP ), and the tetrahydrofuran , dimethylformamide , and n -methylpyrroli - like. Preferably, the solvents are selected from acetonitrile dinone , and the like . and MEK . Salts of the compounds of Formulae V - VIII , may include 55 The salts of compounds of Formulae V - VIII may be organic or inorganic counter ions , including but not limited present as a complex . Examples of complexes include to , acetate , acetonide , acetyl, adipate , aspartate , besylate, 8 -chlorotheophylline complex (analogous to , e . g . , dimenhy biacetate , bitartrate , bromide , butoxide, butyrate , calcium , drinate : diphenhydramine 8 - chlorotheophylline ( 1 : 1 ) com camsylate , caproate , carbonate , citrate , cypionate , decano - plex ; Dramamine ) and various cyclodextrin inclusion com ate , diacetate , dimegulumine , dinitrate , dipotassium , dipro - 60 plexes . pionate, disodium , disulfide, edisylate , enanthate , estolate , Formulations of salts of the compounds of Formulae etabonate , ethylsuccinate , fumarate , furoate , gluceptate , glu - I- VIII provided herein exhibit at least one , or preferably conate , hexacetonide, hippurate , hyclate , hydrobromide , some or even more preferably , all the following character hydrochloride , isethionate , lactobionate , malate , maleate , istics : ( 1 ) they are stable at ambient temperatures for a meglumine, methylbromide , methylsulfate , metrizoate , 65 minimum of one year ; ( 2 ) they provide for ease of oral nafate , napsylate , nitrate , oleate , palmitate , pamoate , phen - administration ; ( 3 ) they facilitate patient compliance with propionate , phosphate , pivalate , polistirex , polygalacturo dosing ; (4 ) upon administration , they consistently facilitate US 9 , 765 ,043 B2 57 58 high levels of absorption of the pharmaceutical active ; (5 ) polymer coated pellets , granules , or microparticles which upon once or twice daily oral administration they allow can be further encapsulated or compressed into a tablet, ( 6 ) release of the KATP channel opener over a sustained time the use of an osmotic pump system , ( 7 ) the use of a frame such that the circulating concentration of the KATP compression coated tablet , or ( 8 ) combinations of these channel opener or its metabolically active metabolites does 5 approaches . not fall below a therapeutically effective concentration ; ( 6 ) Delay of release of KATP channel openers selected from they achieve these results independent of the pH of the the salts of the compounds of Formulae I -VIII from the gastrointestinal tract of treated subjects , and ( 7 ) they delay formulation until gastric transit is complete can be achieved release until gastric transit is complete or nearly complete . in the formulations provided herein by any of several Formulations designed for oral administration of the salts 10 mechanisms. For example , pH sensitive polymer or co of the compounds of Formulae I - VIII can be provided , for polymer can be used which when applied around the drug example, as capsules , tablets, or as quick dissolve tablets or matrix functions as an effective barrier to release of active at films. Capsule or tablet formulations include a number of pH 3 . 0 or lower and is unstable at pH 5 . 5 and above . This distinguishing components. One is a component to improve provides for control of release of the active compound in the absorption of the KATP channel opener . Another sustains 15 stomach but rapidly allows release once the dosage form has release of the drug over more than 2 hours . A third delays passed into the small intestine . An alternative to a pH substantial release of the drug until gastric transit is com sensitive polymer or co -polymer is a polymer or co -polymer pleted . that is non -aqueous -soluble . The extent of resistance to Oral administration formulations of the salts of the com - release in the gastric environment can be controlled by pounds of Formulae I - VIII can also be provided , for 20 coating with a blend of the non - aqueous - soluble and a example, as oral suspensions, oral solutions, encapsulated aqueous soluble polymer. In this approach neither of the oral suspensions, and encapsulated oral solutions . Formula - blended polymers or co - polyers are pH sensitive . One tions can be designed for immediate release or controlled example of a pH sensitive co -polymer is the Eudragit® release . Preferably , such oral formulations are not produced methacrylic co - polymers , including Eudragit® L 100 , S 100 from a liquid form of the sodium salt of diazoxide . 25 or L 100 - 55 solids, L 30 D -55 or FS 30D dispersions, or the Formulations of the salts of the compounds of Formulae L 12 , 5 or S 12 , 5 organic solutions. I -VIII can also be prepared for transdermal , intranasal and Polymers that delay release can be applied to a tablet intravenous ( I . V . ) administration , provided that when the either by spray coating ( as a thin film ) or by compression anion is diazoxide and the cation is sodium , the formulation coating . If a capsule is used , then the polymer ( s ) may be is not for intravenous use . 30 applied over the surface of the capsule or applied to In another embodiment, formulations of the salts of the microparticles of the drug , which may then be encapsulated compounds of Formulae I - VIII are prepared for transdermal such as in a capsule or gel. If the capsule is coated , then it or intranasal, administration , provided that when the anion is will resist disintegration until after gastric transit . If diazoxide and the cation is sodium , the formulation is not microparticles are coated , then the capsule may disintegrate produced using a liquid form of the salt of the compounds 35 in the stomach but little to no drug will be released until after of Formulae I - VIII . the free microparticles complete gastric transit. Finally , an In another embodiment, formulations of the salts of the osmotic pump system that uses e . g . , a swellable hydrogel compounds of Formulae I - VIII are prepared for transdermal, can be used to delay drug release in the stomach . The intranasal and intravenous ( I. V . ) administration excluding swellable hydrogel takes up moisture after administration . the sodium salt of diazoxide . 40 Swelling of the gel results in displacement of the drug from Formulations of KATP channel openers prepared using the system for absorption . The timing and rate of release of salts of the compounds selected from Formulae I - VIII the drug depend on the gel used , and the rate at which exhibit improved solubility and absorption compared to moisture reaches the gel, which can be controlled by the size previous formulations of these drugs . These advantageous of the opening in the system through which fluid enters. See properties are achieved by any one or more of the following 45 Drug Delivery Technologies online article Dong et al. , approaches : ( 1 ) reducing particle size of the formulation by “ L - OROS® SOFTCAPTM for Controlled Release of Non comminution , spray drying , or other micronising techniques, Aqueous Liquid Formulations . " ( 2 ) using an ion exchange resin in the formulation , ( 3 ) using Accordingly, delay of release of formulations of KATP inclusion complexes, for example using a cyclodextrin , ( 4 ) channel openers prepared as salts of the compounds of compaction of the salt of KATP channel opener with a 50 Formulae I - VIII until after gastric transit is complete can be solubilizing agent including low viscosity hypromellose , achieved by any of several mechanisms, including , but not low viscosity methylcellulose or similarly functioning limited to : ( a ) a pH sensitive polymer or co - polymer applied excipient and combinations thereof, ( 5 ) associating the salt as a compression coating on a tablet ; ( b ) a pH sensitive of the KATP channel opener with a distinct salt prior to polymer or co -polymer applied as a thin film on a tablet ; ( c ) formulation , (6 ) using a solid dispersion of the salt of the 55 a pH sensitive polymer or co - polymer applied as a thin film KATP channel opener , ( 7 ) using a self emulsifying system , to an encapsulation system ; ( d ) a pH sensitive polymer or ( 8 ) adding one or more surfactants to the formulation , ( 9 ) co - polymer applied to encapsulated microparticles, ( e ) a using nanoparticles in the formulation , or ( 10 ) combinations non - aqueous - soluble polymer or copolymer applied as a of these approaches . compression coating on a tablet; (f ) a non -aqueous - soluble Release of KATP channel opener selected from salts of 60 polymer or co -polymer applied as a thin film on a tablet; ( g ) the compounds of Formulae I - VIII over a sustained period a non -aqueous soluble polymer applied as a thin film to an of time ( e . g . , 2 - 30 hours ) can be achieved by the use of one encapsulation system ; ( h ) a non -aqueous soluble polymer or more approaches including , but not limited to : ( 1) the use applied to microparticles ; (i ) incorporation of the formula of pH sensitive polymeric coatings, ( 2 ) the use of a hydrogel , tion in an osmotic pump system , or ( i ) use of systems ( 3 ) the use of a film coating that controls the rate of diffusion 65 controlled by ion exchange resins , or ( k ) combinations of of the drug from a coated matrix , ( 4 ) the use of an erodable these approaches , wherein the pH sensitive polymer or matrix that controls rate of drug release , (5 ) the use of co - polymer is resistant to degradation under acid conditions. US 9 , 765 ,043 B2 59 60 Formulations are provided that are designed for admin - include a matrix , thus, providing a primary and a secondary istration once daily (i . e. , once per 24 hours ). These formu - matrix as described in U . S . Pat. No . 4 ,880 , 830 to Rhodes . lations can contain between 25 and 500 mg ofKATP channel The gelling agent preferably is a polymeric material, openers selected from salts of the compounds of Formulae which can include , for example , any pharmaceutically I -VIII . Formulations intended for administration twice daily 5 acceptable water soluble or water insoluble slow releasing (per 24 hours ) may also be provided . These can contain polymer such as xantham gum , gelatin , cellulose ethers , between 25 and 250 mg of KATP channel openers . gum arabic , locust bean gum , guar gum , carboxyvinyl The formulations provided herein exhibit improved safety polymer, agar, acacia gum , tragacanth , veegum , sodium of the administered drug product. This improvement in alginate or alginic acid , polyvinylpyrrolidone, polyvinyl safety occurs by at least two mechanisms. First , delay of alcohol, or film forming polymers such as methyl cellulose release of active drug until gastric transit is complete can (MC ) , carboxymethyl cellulose (CMC ) , hydroxypropyl reduce the incidence of a range of gastrointestinal adverse methylcellulose , hyroxypropyl methyl cellulose (HPMC ), side effects including nausea , vomiting, dyspepsia , abdomi- hydroxypropyl cellulose (HPC ) , hydroxyethyl cellulose nal pain , diarrhea and ileus . Second , by sustaining release of 16 (HEC ) , ethylcellulose (EC ) , acrylic resins or mixtures of the the active drug over 2 or more hours up to as long as 24 a bove ( see e. g ., U .S . Pat. No. 5, 415 ,871 ) . hours, peak drug levels are reduced relative to the peak drug The gelling agent of the matrix also can be a heterodis levels observed for the same administered dose using any perse gum comprising a heteropolysaccharide component oral formulation that does not have sustained or controlled and a homopolysaccharide component which produces a release . This reduction in peak drug levels can contribute to 20 fast - forming and rigid gel as described in U . S . Pat. No. reductions in adverse effects that are partially or completely 5 ,399 , 359 . The matrix also can include a cross - linking agent determined by peak drug levels. These adverse effects such as a monovalent or multivalentmetal cations to further include : fluid retention with the associated reduced rates of add rigidity and decrease dissolution of the matrix , thus excretion of sodium , chloride and uric acid , edema, hyper- further slowing release of drug. The amount of crosslinking glycemia and the associated potential for progression to 25 agent to add can be determined using methods routine to the ketoacidosis , cataracts and non -ketotic hyperosmolar coma , ordinary skilled artisan . headaches, tachycardia and palpitations . The matrix of the controlled release composition also can include one or more pharmaceutically acceptable excipients Also provided herein are controlled release formulations recognized by those skilled in the art , i . e . formulation ofKATP channel openers prepared from salts of compoundseach of 30 excipients . Such excipients include , for example , binders : of Formulae I -VIII , which have one feature from each of 30 polyvinylpyrrolidone , gelatin , starch paste, microcrystalline A - D as shown in Table 1 . cellulose ; diluents (or fillers ): starch , sucrose , dextrose, lactose , fructose , xylitol, sorbitol, sodium chloride, dextrins , TABLE 1 calcium phosphate , calcium sulphate ; and lubricants : stearic Controlled Release Formulation Characteristics and Properties 35 acid , magnesium stearate , calcium stearate , Precirol® and flow aids for example talc or colloidal silicon dioxide . A . Unit Form : Tablet or Capsule B . Dosage /unit : 10 - 100 mg The matrix of the controlled release composition can 100 - 200 mg further include a hydrophobic material which slows the 200 - 300 mg hydration of the gelling agent without disrupting the hydro 300 - 500 mg 40 philic nature of the matrix , as described in U . S . Pat. No . 500 - 2000 mg C . Dosing Once daily (24 hours ) 5 ,399 , 359 . The hydrophobic polymer can include , for Twice daily ( 24 hours ) example , alkylcellulose such as ethylcellulose , other hydro D . Release time: 2 - 4 hrs phobic cellulosic materials , polymers or copolymers derived 4 - 8 hrs from acrylic or methacrylic acid esters, copolymers of 8 - 24 hours 45 acrylic and methacrylic acid esters , zein , waxes, shellac , hydrogenated vegetable oils , waxes and waxy substances For example , a controlled release composition can be a such as carnauba wax , spermaceti wax , candellila wax , tablet containing 25 - 100 mg of a salt of a compound of cocoa butter, cetosteryl alcohol, beeswax , ceresin , paraffin , Formulae I - VIII , wherein such tablet administered once myristyl alcohol, stearyl alcohol, cetylalcohol and stearic daily to achieve a controlled release time of 2 - 4 hours . All 50 acid , and any other pharmaceutically acceptable hydropho of these formulations can further include the feature of bic material known to those skilled in the art . substantially delaying pharmaceutical active release until The amount of hydrophobic material incorporated into the after gastric transit is complete . controlled release composition is that which is effective to In addition , any of the above formulations from Table 1 slow the hydration of the gelling agent without disrupting can include at least one feature that improves the solubility 55 the hydrophilic matrix formed upon exposure to an envi or absorption of the KATP channel opener . ronmental fluid . In certain preferred embodiments , the Exemplary controlled release formulations provided hydrophobic material is included in the matrix in an amount herein include the active compound ( I . e ., a KATP channel from about 1 to about 20 percent by weight and replaces a opener selected from a salt of a compound of any of corresponding amount of the formulation excipient. A sol Formulae I - VIII) and a matrix which includes a gelling 60 vent for the hydrophobic material may be an aqueous or agent that swells upon contact with aqueous fluid . The active organic solvent, or mixtures thereof. compound entrapped within the gel is slowly released into Examples of commercially available alkylcelluloses are the body upon dissolution of the gel. The active compound Aquacoat® (aqueous dispersion of ethylcellulose available can be evenly dispersed within the matrix or can be present from FMC ) and Surelease® (aqueous dispersion of ethyl as pockets of drug in the matrix . For example , the drug can 65 cellulose available from Colorcon ). Examples of commer be formulated into small granules which are dispersed cially available acrylic polymers suitable for use as the within the matrix . In addition , the granules of drug also can hydrophobic material include Eudragit® RS and RL (copo US 9 ,765 ,043 B2 62 lymers of acrylic and methacrylic acid esters having a low hols , petrolatum and lanolin alcohols , phthalic acid esters , content ( e .g ., 1 :20 or 1: 40 ) of quaternary ammonium com - polyethylene glycols , propylene glycol, rape oil, sesame oil, pounds ). triacetin , tributyl citrate , triethyl citrate , and triethyl acetyl The controlled release composition also can be coated to citrate , or a mixture of any two or more of the foregoing . retard access of liquids to the active compound and/ or retard 5 Plasticizers which can be used for aqueous coatings include , release of the active compound through the film -coating for example , propylene glycol, polyethylene glycol ( PEG The film - coating can provide characteristics of gastroresis - 400 ), triacetin , polysorbate 80 , triethyl citrate , and diethyl tance and enterosolubility by resisting rapid dissolution of d - tartrate . the composition in the digestive tract. The film -coating A coating solution comprising a mixture of hydroxypro generally represents about 5 - 15 % by weight of the con - 10 pylmethylcellulose and aqueous ethylcellulose ( e . g . Aqua trolled release composition . Preferably , the core by weight coat brand ) as the polymer and dibutyl sebacate as plasti represents about 90 % of the composition with the remaining cizer can be used for coating microparticles . (Aquacoat is an 10 % provided by the coating . Such coating can be a film - aqueous polymeric dispersion of ethylcellulose and contains coating as is well known in the art and include gels , waxes, sodium lauryl sulfate and cetyl alcohol) . Preferably , the fats , emulsifiers , combination of fats and emulsifiers , poly - 15 plasticizer represents about 1 - 2 % of the composition . mers , starch , and the like . In addition to the polymers, the coating layer can include Polymers and co -polymers are useful as thin film coat- an excipient to assist in formulation of the coating solution . ings . Solution coatings and dispersion coatings can be used Such excipients may include a lubricant or a wetting agent. to coat the active compound , either alone or combined with Suitable lubricants as excipients for the film coating include , a matrix . The coating is preferably applied to the drug or 20 for example , talc , calcium stearate , colloidal silicon dioxide , drug and matrix combination as a solid core of material as glycerin , magnesium stearate , mineral oil, polyethylene gly is well known in the art . col , and zinc stearate , aluminum stearate or a mixture of any A solution for coating can include polymers in both two or more of the foregoing . Suitable wetting agents organic solvent and aqueous solvent systems, and typically include, for example , sodium lauryl sulfate , acacia , ben further including one or more compounds that act as a 25 zalkonium chloride , cetomacrogol emulsifying wax , ceto plasticizer . Polymers useful for coating compositions stearyl alcohol, cetyl alcohol, cholesterol, diethanolamine , include , for example , methylcellulose (Methocel® A ; Dow docusate sodium , sodium stearate , emulsifying wax , glyc Chemical Co .) , hydroxypropylmethylcellulose with a eryl monostearate , hydroxypropyl cellulose , lanolin alco molecular weight between 1 ,000 and 4 ,000 ,000 (Methocel® hols , lecithin , mineral oil , monoethanolamine , poloxamer, E ; Dow Chemical Co . or Pharmacoat® ; Shin Etsu ), 30 polyoxyethylene alkyl ethers , polyoxyethylene castor oil hydroxypropyl cellulose with a molecular weight between derivatives , polyoxyethylene sorbitan fatty acid esters , poly 2 , 000 and 2 , 000 , 000 , ethyl cellulose , cellulose acetate , cel oxyethylene stearates, propylene glycol alginate , sorbitan lulose triacetate , cellulose acetate butyrate , cellulose acetate esters , stearyl alcohol and triethanolamine, or a mixture of phthalate , cellulose acetate trimellitate (Eastman Kodak ) , any two or more of the foregoing . carboxymethylethyl cellulose (Duodcel® ), hydroxypropyl 35 The specified tablet or capsule formulations of Table 1 methylcellulose phthalate , ethylcellulose, methylcellulose may include co - formulation with an obesity treating drug ( in and , in general, cellulosic derivatives , polymethacrylic acid addition to a KATP channel opener selected from a salt of a methacrylic acid copolymer ( Type A 1 : 1 Eudragit L100 ; compound of Formulae I - VIII ) . Obesity treating drugs that Type B 1 : 2 Eudragit S100 ; and Type C 1 : 1 Eudragit L100 - may be used include , but are not limited to , sibutramine 55 , aqueous dispersion 30 % solids, Eudragit L30D ) , poly 40 hydrochloride ( 5 - 30 mg/ unit ), orlistat ( 50 - 360 mg/ unit ), (meth ) acryl ester : poly ( ethyl acrylate , methyl methacrylate phentermine hydrochloride or resin complex ( 15 to 40 2 : 1 ) , Eudragit NE30D aqueous dispersion 30 % solids, mg/ unit ) , zonisamide ( 100 to 600 mg/ unit ) , topiramate (64 polyaminomethacrylate Eudragit E100 , poly (trimethylam - to 400 mg/ unit ) , naltrexone hydrochloride (50 to 600 monioethyl methacrylate chloride ) ammoniomethacrylate mg/ unit) , rimonabant (5 to 20 mg/ unit ) , ADP356 ( 5 to 25 copolymer , Eudragit RL30D and Eudragit RS30D , car - 45 mg/ unit ) , ATL962 (20 to 400 mg/ unit ) , or AOD9604 ( 1 to 10 boxyvinyl polymers , polyvinylalcohols , glucans scleroglu - mg/ unit ) . These formulations are preferably used once daily . cans, mannans , and xanthans. For a twice daily dosing , the amount of KATP channel Aqueous polymeric dispersions include Eudragit L30D opener selected from a salt of a compound of Formulae and RS /RL30D , and NE30D , Aquacoat® brand ethyl cellu - I - VIII is one half the amount included in the once daily lose , Surelease brand ethyl cellulose , EC brand N - 10F ethyl 50 formulation and the co - formulated obesity treating drug is cellulose , Aquateric brand cellulose acetate phthalate , Coa - half of the amount specified . Alternative obesity treating teric brand Poly ( vinyl acetate phthalate ), and Aqacoat brand drugs may include , but are not limited to : selective serotonin hydroxypropyl methylcellulose acetate succinate . Most of 2c receptor agonists , dopamine antagonists , cannabinoid - 1 these dispersions are latex , pseudolatex powder or micron receptor antagonists , leptin analogues, leptin transport and / ized powder mediums. 55 or leptin receptor promoters , neuropeptide Y and agouti A plasticizing agent may be included in the coating to related peptide antagonists , proopiomelanocortin and improve the elasticity and the stability of the polymer film cocaine and amphetamine regulated transcript promoters, and to prevent changes in the polymer permeability over melanocyte -stimulating hormone analogues, melanocortin - 4 prolonged storage. Such changes may affect the drug release receptor agonists , and agents that affect insulin metabolism / rate . Suitable conventional plasticizing agents include , for 60 activity , which can include protein -tyrosine phosphatase - 1B exexample , diethyl phthalate , glycerol triacetate , acetylated inhibitors , peroxisome proliferator activated receptor monoglycerides , acetyltributylcitrate , acetyltriethyl citrate , antagonists , short - acting bromocriptine (ergoset ) , soma castor oil, citric acid esters , dibutyl phthalate , dibutyl seba - tostatin agonists (octreotide ) , and adiponectin , gastrointes cate , diethyloxalate , diethyl malate , diethylfumarate , dieth tinal- neural pathway agents , including those that increase ylphthalate , diethylsuccinate , diethylmalonate , diethyltart - 65 cholecystokinin activity , increase glucagon - like peptide - 1 arate , dimethylphthalate , glycerin , glycerol, glyceryl activity ( e . g . , exendin 4 , liraglutide, dipeptidyl peptidase IV triacetate , glyceryltributyrate , mineral oil and lanolin alco - inhibitors) , and increase protein YY3 -36 activity and those US 9 , 765 ,043 B2 63 64 that decrease ghrelin activity , as well as amylin analogues , captopril ( 2 . 5 to 150 mg/ unit ), lisinopril ( 10 to 40 mg/ unit) , agents that may increase resting metabolic rate ( selective” benzaepril hydrochloride ( 10 to 80 mg/ unit ) , quinapril B - 3 stimulators /agonist , uncoupling protein homologues , hydrochloride ( 10 to 80 mg/ unit ) , peridopril erbumine ( 4 to and thyroid receptor agonists ) , melanin concentrating hor - 8 mg/ unit ) , ramipril ( 1 .25 to 20 mg/ unit ) , trandolapril ( 1 to mone antagonists , phytostanol analogues, amylase inhibi- 5 8 mg/ unit ) , fosinopril sodium ( 10 to 80 mg/ unit ), moexipril tors , growth hormone fragments , synthetic analogues of hydrochloride ( 5 to 20 mg/ unit ) , losartan potassium (25 to dehydroepiandrosterone sulfate , antagonists of adipocyte 200 mg/ unit ) , irbesartan (75 to 600 mg/ unit ), valsartan ( 40 11B hydroxysteroid dehydrogenase type 1 activity , corti - to 600 mg/ unit ), candesartan cilexetil (4 to 64 mg /unit ), cotropin releasing hormone agonists , inhibitors of fatty acid olmesartan medoxamil ( 5 to 80 mg /unit ) , telmisartan ( 20 to synthesis , carboxypeptidase inhibitors , indanones / indanols , 10 160 mg/ unit ) , eprosartan mesylate ( 75 to 600 mg /unit ) , aminosterols , and other gastrointestinal lipase inhibitors . atenolol (25 to 200 mg/ unit ) , propranolol hydrochloride ( 10 The specified tablet or capsule formulations of Table 1 to 180 mg/ unit ), metoprolol tartrate, succinate or fumarate may include co - formulation with a diabetes treating drug ( in (each at 25 to 400 mg/ unit ), nadolol (20 to 160 mg/ unit ) , addition to a KATP channel opener selected from a salt of a betaxolol hydrochloride ( 10 to 40 mg/ unit ) , acebutolol compound of Formulae I - VIII ). Diabetes treating drugs that 15 hydrochloride ( 200 to 800 mg/ unit ) , pindolol ( 5 to 20 may be used include , but are not limited to , acarbose (50 to mg/ unit ) , bisoprolol fumarate (5 to 20 mg/ unit ) , nifedipine 300 mg/ unit ) , miglitol ( 25 to 300 mg/ unit ) , metformin ( 15 to 100 mg/ unit ), felodipine ( 2 . 5 to 20 mg/ unit ), amlo hydrochloride (300 to 2000 mg/ unit ), repaglinide ( 1 - 16 dipine besylate ( 2 .5 to 20 mg/ unit ), nicardipine (10 to 40 mg/ unit) , nateglinide (200 to 400 mg/ unit) , rosiglitazone ( 5 mg/ unit) , nisoldipine ( 10 to 80 mg/ unit ), terazosin hydro to 50 mg/ unit ), metaglidasen ( 100 to 400 mg/ unit ) or any 20 chloride (1 to 20 mg/ unit ), doxaxosin mesylate (4 to 16 drug that improves insulin sensitivity , or improves glucose mg/ unit ) , prazosin hydrochloride ( 2 . 5 to 10 mg/ unit ) , or utilization and uptake. These formulations are preferably alfuzosin hydrochloride ( 10 to 20 mg/ unit ) . These formula used once daily . For a twice daily dosing , the amount of the tions are preferably used once daily. For a twice daily KATP channel opener selected from a salt of a compound of dosing , the amount of KATP channel opener is preferably Formulae I - VIII is half the amount included in the once daily 25 half the amount included in the once daily formulation and formulation and the co - formulated diabetes treating drug is the co - formulated hypertension treating drug is half of the half of the amount specified . amount specified . The specified tablet or capsule formulations of Table 1 The specified tablet or capsule formulations of Table 1 may include co - formulation with a cholesterol lowering may include co - formulation with a diuretic to treat edema. drug . Cholesterol lowering drugs that may be used include , 30 Diuretics that may be used include , but are not limited to but are not limited to , pravastatin , simvastatin , atorvastatin , amiloride hydrochloride ( 1 to 10 mg/ unit ) , spironolactone fluvastatin , rosuvastatin , or lovastatin (all at 10 to 80 ( 10 to 100 mg /unit ) , triamterene ( 25 to 200 mg/ unit ) , mg /unit ) , fibrates (50 to 300 mg /unit ) , niacin (500 to 2000 bumetanide ( 0 . 5 to 4 mg/ unit ) , furosemide ( 10 to 160 mg/ unit ), thyroid receptor activators ( 0 .5 to 100 mg/ unit ), mg/ unit ), ethacrynic acid or ethacrynate sodium ( each at 10 MTP inhibitors ( 20 to 1000 mg/ unit ) , PPAR delta agonists 35 to 50 mg/ unit ) , torsemide ( 5 to 100 mg / unit ) , chlorthalidone and modulators ( 5 to 400 mg /unit ) , and squalene synthase ( 10 to 200 mg/ unit ), indapamide ( 1 to 5 mg /unit ), hydro inhibitor ( 10 to 1000 mg/ unit ) . These formulations are chlorothiazide ( 10 to 100 mg/ unit ) , chlorothiazide ( 50 to 500 preferably used once daily. Each of these classes of active mg/ unit ) , bendroflumethiazide ( 5 to 25 mg/ unit ), hydroflu may also be used to raise HDL cholesterol. For a twice daily m ethiazide (10 to 50 mg/ unit ) , mythyclothiazide ( 1 to 5 dosing , the amount of KATP channel opener selected from 40 mg/ unit ), or polythiazide ( 1 to 10 mg/ unit ) . These formula a salt of a compound of Formulae I - VIII is preferably 25 to tions are preferably used once daily . For a twice daily 200 mg/ unit and the co - formulated cholesterol lowering dosing , the amount of KATP channel opener selected from drug is half of the amount specified . a salt of a compound of Formulae I- VIII is preferably half The specified tablet or capsule formulations of Table 1 the amount included in the once daily formulation and the may include co - formulation with a depression treating drug . 45 co - formulated diuretic is half of the amount specified . Depression treating drugs that may be used include , but are The specified tablet or capsule formulations of Table 1 not limited to , citalopram hydrobromide ( 10 to 80 mg/ unit ) , may include co - formulation with a drug to treat inflamma escitalopram hydrobromide ( 5 to 40 mg/ unit ) , fluvoxamine tion or pain . Drugs for treating inflammation or pain that maleate ( 25 to 300 mg/ unit ) , paroxetine hydrochloride ( 12 . 5 may be used include , but are not limited to aspirin ( 100 to to 75 mg/ unit ) , fluoxetine hydrochloride ( 30 to 100 mg /unit ) , 50 1000 mg/ unit ) , tramadol hydrochloride ( 25 to 150 mg/ unit ) , setraline hydrochloride ( 25 to 200 mg/ unit ) , amitriptyline gabapentin ( 100 to 800 mg/ unit ) , acetaminophen ( 100 to hydrochloride ( 10 to 200 mg/ unit ) , desipramine hydrochlo - 1000 mg/ unit ) , carbamazepine ( 100 to 400 mg/ unit ) , ibu ride ( 10 to 300 mg/ unit ), nortriptyline hydrochloride ( 10 to profen ( 100 to 1600 mg/ unit ), ketoprofen (12 to 200 150 mg /unit ) , duloxetine hydrochloride ( 20 to 210 mg /unit ) , mg/ unit ) , fenprofen sodium ( 100 to 600 mg/ unit ) , flurbipro venlafaxine hydrochloride (37 . 5 to 150 mg/ unit ) , phenelzine 55 fen sodium or flurbiprofen (both at 50 to 200 mg/ unit) , or sulfate ( 10 to 30 mg/ unit ), bupropion hydrochloride ( 200 to combinations of any of these with a steroid or aspirin . These 400 mg/ unit ), or mirtazapine (7 .5 to 90 mg/ unit ). These formulations are preferably used once daily . For a twice formulations are preferably used once daily . For a twice daily dosing, the amount of KATP channel opener selected daily dosing , the amount of KATP channel opener selected from a salt of a compound of Formulae I - VIII is preferably from a salt of a compound of Formulae I - VIII is preferably 60 half the amount included in the once daily formulation and half the amount included in the once daily formulation and the co - formulated diuretic is half of the amount specified . the co - formulated depression treating drug is half of the The specified tablet or capsule formulations of Table 1 amount specified . may include co - formulation with a drug to treat obesity The specified tablet or capsule formulations of Table 1 associated co -morbidities include those specified above for may include co - formulation with a hypertension treating 65 treating diabetes, cholesterol, depression , hypertension and drug . Hypertension treating drugs that may be used include , edema, or drugs to treat atherosclerosis , osteoarthritis , disc but are not limited , to enalapril maleate (2 .5 to 40 mg/ unit ) , herniation , degeneration of knees and hips , breast, endome US 9 , 765 ,043 B2 65 66 trial, cervical, colon , leukemia and prostate cancers , hyper - Provided are formulations suitable for continuous admin lipidemia , asthma/ reactive airway disease , gallstones, istration once or twice daily (per 24 hours ) to a subject , GERD , obstructive sleep apnea , obesity hypoventilation resulting in a circulating concentration of KATP channel syndrome, recurrent ventral hernias, menstrual irregularity openers selected from a salt of a compound of Formulae and infertility . 5 I- VIII sufficient to induce either beta - cell rest or improved The specified tablet or capsule formulations of Table 1 insulin sensitivity or both . Such beta - cell rest and improve may include co - formulation with an anti -psychotic drug . ments in insulin sensitivity can contribute to effective treat The combination used to treat the psychotic condition and to ment of type 1 diabetes , type II diabetes and prediabetes . treat or prevent weight gain , dyslipidemia or impaired Such beta - cell rest and improvements in insulin sensitivity glucose tolerance in the treated subject. Drugs for treating 10 can contribute to effective restoration of normal glucose various psychotic conditions that may be used include , but tolerance in type II diabetic and prediabetic subjects . are not limited to , lithium or a salt thereof ( 250 to 2500 The various pharmaceutical KATP channel opener for mg/ unit ), carbamazepine or a salt thereof (50 to 1200 mulations selected from a salt of a compound of Formulae mg/ unit ), valproate , valproic acid , or divalproex ( 125 to I - VIII have a variety of applications, including, but not 2500 mg/ unit ), lamotrigine ( 12. 5 to 200 mg/ unit ), olanzap - 15 limited to : ( 1 ) treatment of obesity ; ( 2 ) prevention of weight ine ( 5 to 20 mg/ unit ), clozapine (12 . 5 to 450 mg/ unit ), or gain in subjects who are predisposed to obesity ; ( 3 ) treat risperidone (0 . 25 to 4 mg/ unit ). These coformulations are ment of hyperinsulinemia or hyperinsulinism ; (4 ) treatment preferably intended for once per day administration . For a of hypoglycemia ; (5 ) treatment of hyperlipidemia , (6 ) treat twice daily dosing, the amount of KATP channel opener ment of type II diabetes , ( 7 ) preservation of pancreatic selected from a salt of a compound of Formulae I - VIII is 20 function in type 1 diabetics ; ( 8 ) treatment of metabolic preferably half the amount included in the once daily syndrome (or syndrome X ) ; ( 9 ) prevention of the transition formulation and the co - formulated anti- psychotic is half of from prediabetes to diabetes, (10 ) correction of the defects the amount specified . in insulin secretion and insulin sensitivity contributing to The specified tablet or capsule formulations of Table 1 prediabetes and type II diabetes, ( 11) treatment of polycystic may include co - formulation with a drug to treat or prevent 25 Ovary syndrome, ( 12 ) prevention of ischemic or reperfusion ischemic or reperfusion injury . Drugs for treating or pre - injury , ( 13 ) treat weight gain , dyslipidemia , or impairment of venting ischemic or reperfusion injury that may be used glucose tolerance in subjects treated with antipsychotics include, but are not limited to : low molecular weight hepa - drugs, ( 14 ) prevent weight gain , dyslipidemia , or impair rins ( e . g ., dalteparin , enoxaparin , nadroparin , tinzaparin or ment of glucose tolerance in subjects treated with antipsy danaparoid ) , ancrod , pentoxifylline , nimodipine, flunarizine , 30 chotics drugs and ( 15 ) treatment of any disease where ebselen , tirilazad , clomethiazole , an AMPA agonist ( e . g . , hyperlipidemia , hyperinsulinemia , hyperinsulinism , hyper GYKI 52466 , NBQX , YM9OK , zonampanel , or MPQX ), lipidemia , hyperphagia or obesity are contributing factors to SYM 2081 , selfotel, Cerestat, CP - 101, 606 , dextrophan , dex - the severity or progression of the disease, including but not tromethorphan , MK -801 , NPS1502 , remacemide, ACEA limited to , Prader Willi Syndrome, Froelich ' s syndrome, 1021 , GV150526 , eliprodil ifenprodil , lubeluzole , naloxone , 35 Cohen syndrome, Summit Syndrome, Alstrom Syndrome, nalmefene citicoline , acetyl- 1 - carnitine , nifedipine , resvera - Borjesen Syndrome, Bardet- Biedl Syndrome, or hyperlipo trol, a nitrone derivative, clopidogrel, dabigatram , prasugrel, proteinemia type I , II , III , and IV . troxoprodil, AGY- 94806 , or KAI- 9803 . In one embodiment, a KATP channel opener selected Provided are formulations administered once or twice from a salt of a compound of Formulae I - VIII is adminis daily to an obese or overweight subject continuously result 40 tered to an overweight or obese subject as an oral dosage in a circulating concentration of KATP channel opener once per 24 hours to induce weight loss . In further embodi selected from a salt of a compound of Formulae I - VIII ments , the subject ( a ) is not a type 1 diabetic , (b ) is not a type sufficient to induce weight loss . Weight loss occurs by the II diabetic , ( c ) is not experiencing chronic , recurrent or preferential loss of body fat . Additional weight loss can drug - induced hypoglycemia , ( d ) does not have metabolic occur when the formulation is administered in combination 45 syndrome, or ( e ) is not experiencing malignant hyperten with a reduced calorie diet. sion . Provided are formulations of KATP channel openers In one embodiment, a KATP channel opener selected selected from a salt of a compound of Formulae I - VIII from a salt of a compound of Formulae I - VIII is adminis administered as a single dose to an obese , overweight or tered to an overweight or obese subject as an oral dosage obesity - prone subject that result in the inhibition of fasting 50 twice per 24 hours to induce weight loss . This treatment can or glucose stimulated insulin secretion for about 24 hours or be the sole treatment to induce weight loss . In further for about 18 hours . embodiments , the overweight or obese subject ( a ) does not Provided are formulations of KATP channel openers have an insulin secreting tumor, ( b ) is not suffering from selected from a salt of a compound of Formulae I - VIII Poly Cystic Ovary Syndrome, ( c ) is not a type 1 diabetic , ( d ) administered as a single dose to an obese , overweight or 55 is not a type II diabetic , ( e ) does not have metabolic obesity -prone subject that result in the elevation of energy syndrome, ( f ) is not experiencing chronic recurrent or drug expenditure for about 24 hours or for about 18 hours . induced hypoglycemia , ( g ) has not been treated for schizo Provided are formulations of KATP channel openers phrenia with haloperidol, or ( h ) is not experiencing malig selected from a salt of a compound of Formulae I - VIII nant hypertension . In further embodiments , the overweight administered as a single dose to an obese , overweight or 60 or obese adolescent ( a ) has not been diagnosed as being type obesity -prone subject that result in the elevation of beta I or type II diabetic , ( b ) is not experiencing chronic , recur oxidation of fat for about 24 hours or for about 18 hours . rent or drug -induced hypoglycemia , or ( c ) has not been Provided are formulations of KATP channel openers diagnosed as having metabolic syndrome. selected from a salt of a compound of Formulae I - VIII In another embodiment , a KATP channel opener selected administered as a single dose to an obese , overweight or 65 from a salt of a compound of Formulae I - VIII is adminis obesity - prone hyperphagic subject that result in the inhibi- tered to an overweight or obese subject as an oral dosage tion of hyperphagia for about 24 hours or for about 18 hours . form three times per 24 hours to induce weight loss. This US 9 , 765 ,043 B2 68 treatment can be the sole treatment to induce weight loss . In I- VIII is administered to an subject in need thereof to induce further embodiments , the overweight or obese subject ( a ) (a ) the preferential loss of body fat or (b ) the preferential loss does not have an insulin -secreting tumor, ( b ) is not suffering of visceral body fat. from Poly Cystic Ovary Syndrome, ( c ) is not a type I In additional embodiments , an oral dosage of a KATP diabetic , ( d ) is not a type II diabetic , ( e ) does not have 5 channel opener selected from a salt of a compound of metabolic syndrome, or ( f ) is not experiencing chronic , Formulae I -VIII is administered one , two or three times per recurrent or drug - induced hypoglycemia . 24 hours at daily doses of 50 to 700 mg to an subject to ( a ) In another embodiment, a KATP channel opener selected induce the loss of 25 % , 50 % or 75 % of initial body fat, ( b ) from a salt of a compound of Formulae I -VIII is adminis - induce the preferential loss of body fat, or ( c ) induce the tered to an overweight or obese adolescent as an oral dosage 10 preferential loss of visceral fat. form three times per 24 hours to induce weight loss . This In another embodiment, an oral dosage of a KATP channel treatment can be the sole treatment to induce weight loss. In opener selected from a salt of a compound of Formulae further embodiments , the overweight or obese adolescent is I - VIII is administered to an subject to induce the preferential ( a ) is not a type I or type II diabetic , ( b ) is not experiencing loss of body fat and to induce reduction in circulating chronic , recurrent or drug - induced hypoglycemia or ( c ) does 15 triglycerides . not have metabolic syndrome. In another embodiment, an oral dosage of a KATP channel In another embodiment , a KATP channel opener selected opener selected from a salt of a compound of Formulae from a salt of a compound of Formulae I - VIII is adminis - I - VIII is co -administered with sibutramine , orlistat, rimona tered as an oral dosage form three times per 24 hours to bant, an appetite suppressant, an anti -depressant , an anti induce weight loss to an overweight or obese adult who ( a ) 20 epileptic , a diuretic , a drug that induces weight loss by a is not simultaneously receiving glucagon injections, triiodo mechanism that is distinct from a KATP channel opener, or thyroxin or furosemide , ( b ) is not being treated for schizo - a drug that lowers blood pressure , to induce weight loss phrenia with haloperidol, or ( c ) is not experiencing malig and / or treat obesity associated co -morbidities in an over nant hypertension . weight, obese , or obesity prone subject. In further embodi In another embodiment, a KATP channel opener selected 25 ments , the overweight, obese , or obesity prone subject ( a ) is from a salt of a compound of Formulae I - VIII is adminis - a type 1 diabetic , (b ) is not a type II diabetic , ( c ) is not tered to an overweight or obese subject as an oral dosage suffering from chronic , recurrent or drug - induced hypogly form four times per 24 hours to induce weight loss. cemia , or ( d ) does not have metabolic syndrome . In another embodiment, a KATP channel opener selected In another embodiment an oral dosage of a KATP channel from a salt of a compound of Formulae I -VIII is adminis - 30 opener selected from a salt of a compound of Formulae tered to an overweight or obese subject as an oral dosage I - VIII is co - administered with an anti - depressant , a drug that form administered from one , two , three or four times per 24 lowers blood pressure , a drug that lowers cholesterol, a drug hours to induce weight loss at a daily dose of 50 to 700 mg. that raises HDL , an anti- inflammatory that is not a Cox - 2 In a further embodiment, the overweight or obese subject ( a ) inhibitor, a drug that lowers circulating triglycerides, to an is not type 1 diabetic , ( b ) is not type II diabetic , ( c ) is not 35 overweight, obese , or obesity prone subject to induce weight suffering chronic , recurrent or drug - induced hypoglycemia , loss and /or treat obesity associated co -morbidities . In further or ( d ) does not have metabolic syndrome . embodiments , the overweight, obese, or obesity prone sub In another embodiment, a KATP channel opener selected ject ( a ) is not a type 1 diabetic , ( b ) is not a type II diabetic , from a salt of a compound of Formulae I - VIII is adminis ( c ) is not suffering from chronic , recurrent or drug - induced tered to an overweight or obese subject as an oral dosage 40 hypoglycemia , or ( d ) does not have metabolic syndrome. form administered from one , two, three or four times per 24 In another embodiment, an oral dosage of a KATP channel hours to induce weight loss at a daily dose of 130 to 400 mg. opener selected from a salt of a compound of Formulae In a further embodiment, the overweight or obese subject ( a ) I- VIII is co -administered with a drug that lowers blood is not type 1 diabetic , (b ) is not type II diabetic , ( c ) is not pressure , a drug that lowers cholesterol, a drug that raises suffering chronic , recurrent or drug - induced hypoglycemia , 45 HDL , an anti- inflammatory that is not a Cox - 2 inhibitor, a or ( d ) does not have metabolic syndrome. drug that lowers circulating triglycerides , to maintain weight In other embodiments , a KATP channel opener selected and /or treat obesity associated co -morbidities in an over from a salt of a compound of Formulae I - VIII is adminis weight, obese , or obesity prone subject , as it is preferable to tered to an overweight or obesity prone subject as an oral maintain weight in an obese subject once some weight loss dosage form one , two , three or four times per 24 hours to 50 has occurred when the alternative is to regain weight. In maintain a weight loss , as it is preferable to maintain weight further embodiments , the overweight, obese , or obesity in an obese subject once some weight loss has occurred prone subject ( a ) is not a type I diabetic, ( b ) is not a type II when the alternative is to regain weight. In a further embodi - diabetic , ( c ) is not suffering from chronic , recurrent or ment, the administered daily dose of the KATP channel drug - induced hypoglycemia , or ( d ) does not have metabolic opener is 50 to 275 mg. 55 syndrome. In other embodiments , a KATP channel opener selected In additional embodiments , an oral dosage form of a from a salt of a compound of Formulae I - VIII is adminis - KATP channel opener selected from a salt of a compound of tered as an oral dosage form to an overweight, obese, or Formulae I - VIII is used to administer a therapeutically obesity prone subject to ( a ) elevate energy expenditure , (b ) effective dose of a KATP channel opener to an obese , elevate beta oxidation of fat, or ( c ) reduce circulating 60 overweight or obesity prone subject in need thereof to treat triglyceride concentrations. obesity , to ( a ) provide beta cell rest , (b ) treat type I or type In other embodiments , an oral dosage of a KATP channel II diabetes , or ( c ) prevent the occurrence of diabetes. opener selected from a salt of a compound of Formulae In additional embodiments, an oral dosage form of a I - VIII is administered to an subject in need thereof to induce KATP channel opener selected from a salt of a compound of the loss of 25 % , 50 % , or 75 % of initial body fat. 65 Formulae I - VIII is co - administered with Phentermine or a In another embodiment, an oral dosage of a KATP channel derivative thereof to an obese adult or adolescent to induce opener selected from a salt of a compound of Formulae weight loss and /or treat obesity and obesity - associated co US 9 ,765 , 043 B2 69 70 morbidities. In further embodiments , a solid oral dosage centrations; ( 25 ) reduced circulating triglyceride concentra form or tablet formulation of a KATP channel opener is tions; ( 26 ) enhancement of beta- cell rest . co - administered with Phentermine or a derivative thereof to Threshold concentrations of the current invention include an obese adult or adolescent to treat metabolic syndrome in those circulating concentrations of KATP channel openers a patient in need thereof. 5 resulting from the administration of salts of compounds of In further embodiments , a pharmaceutically acceptable Formulae I - VIII as an i . v . formulation , an immediate release formulation of a KATP channel opener selected from a salt oral formulation , a controlled release formulation , a trans of a compound of Formulae I - VIII at doses of 50 to 700 dermal formulation , or an intranasal formulation to an mg/ day is co -administered with Phentermine or a derivative overweight or obese subject which results in ( 1 ) measurable thereof at daily doses of 15 to 37 . 5 mg to an overweight or 10 suppression of fasting insulin levels, ( 2 ) suppression of obese subject to induce weight loss , to treat metabolic fasting insulin levels by at least 20 % from the baseline syndrome, or to induce weight loss and treat obesity - asso - measurement in the same subject prior to treatment with a ciated co -morbidities . KATP channel opener selected from a salt of a compound of In another embodiment, a quick dissolving formulation of Formulae I - VIII , ( 3 ) suppression of fasting insulin levels by a KATP channel opener selected from a salt of a compound 15 at least 30 % from the baseline measurement in the same of Formulae I - VIII is used to provide a therapeutically subject prior to treatment with a Kamp channel opener effective dose to a patient in need thereof. selected from a salt of a compound of Formulae I -VIII , ( 4 ) In further embodiments , a KATP channel opener selected suppression of fasting insulin levels by at least 40 % from the from a salt of a compound of Formulae I - VIII is adminis - baseline measurement in the same subject prior to treatment tered once per 24 hours at doses of 50 mg to 700 mg to an 20 with a KATP channel opener selected from a salt of a overweight or obese subject. compound of Formulae I - VIII , ( 5 ) suppression of fasting In further embodiments, a KATP channel opener selected insulin levels by at least 50 % from the baseline measure from a salt of a compound of Formulae I -VIII is formulated ment in the same subject prior to treatment with a KATP as a tablet or capsule for oral administration . The tablet or channel opener selected from a salt of a compound of capsule may be co - formulated with metformin . In another 25 Formulae I - VIII , ( 6 ) suppression of fasting insulin levels by embodiment, a KATP channel opener selected from a salt of at least 60 % from the baseline measurement in the same a compound of Formulae I - VIII is formulated as an oral subject prior to treatment with a Kftp channel opener suspension or solution , and the oral suspension or solution selected from a salt of a compound of Formulae I -VIII , ( 7 ) may be further encapsulated in another embodiment. suppression of fasting insulin levels by at least 70 % from the In another embodiment, a pharmaceutical salt of a KATP 30 baseline measurement in the same subject prior to treatment channel opener selected from a salt of a compound of with a KTP channel opener selected from a salt of a Formulae I - VIII is formulated as a tablet or capsule for oral compound of Formulae I - VIII , ( 8 ) suppression of fasting administration , or as an oral suspension or as an oral insulin levels by at least 80 % from the baseline measure solution , or as an oral suspension or solution that is encap ment in the same subject prior to treatment with a KATP sulated . 35 channel opener selected from a salt of a compound of In another embodiment a KATP channel opener selected Formulae I - VIII , ( 9 ) loss of weight, ( 10 ) elevation of resting from a salt of a compound of Formulae I - VIII is co - energy expenditure , or ( 11 ) elevation of the oxidation of fat formulated with hydro - chlorothiazide, chlorothiazide , or fatty acids. Threshold effects of the current invention cyclothiazide , benzthiazide , metyclothiazide , bendro - flume - include those circulating concentrations of Kamp channel thiazide , hydroflumethiazide , trichlormethiazide , or polythi- 40 openers selected from salts of compounds of Formulae azide in a pharmaceutical formulation suitable for oral I - VIII resulting from the administration of an i . v . formula administration . tion of the drug , or an immediate release oral formulation of Upon administration of formulations which include a salt the drug, or a controlled release formulation of the drug, or of a compound of Formulae I - VIII provided herein to a sustained release formulation , or a transdermal formula humans or animals , some or all of the following effects are 45 tion , or an intranasal formulation of the drug to an obesity observed : ( 1) the production of lipoprotein lipase by adipo - prone subject which result in ( 1) the loss of weight, and ( 2 ) cytes is reduced ; ( 2 ) enhanced lipolysis by adipocytes; ( 3 ) the maintenance of weight. Threshold effects of the current expression of fatty acid synthase by adipocytes is reduced ; invention include those circulating concentrations ofKTP ( 4 ) glyceraldehydes phosphate dehydrogenase activity of channel openers selected from salts of compounds of For adipocytes is reduced ; ( 5 ) little or no new triglycerides are 50 mulae I - VIII resulting from the administration of an i . v . synthesized and stored by adipocytes; (6 ) enhanced expres - formulation of the drug, or an immediate release oral for sion of B3 Adrenergic Receptor ( B3AR ) an improvement in mulation of the drug , or a controlled release formulation of the adrenergic function in adipocytes ; ( 7 ) reduced glucose the drug, or a sustained release formulation , or a transdermal stimulated secretion of insulin by pancreatic B - cells ; ( 8 ) formulation , or an intranasal formulation of the drug to a decreased insulinemia ; ( 9 ) enhanced blood glucose levels ; 55 prediabetic subject which result in prevention of the transi ( 10 ) increased expression of Uncoupling Protein 1 in adi - tion to diabetes. Threshold effects of the current invention pocytes ; ( 11 ) enhanced thermogenesis in white and brown include those circulating concentrations of KATP channel adipose tissue ; ( 12 ) reduction of plasma triglyceride con - openers resulting from the administration of salts of com centration ; ( 13 ) decrease in circulating leptin concentra - pounds of Formulae I -VIII as an i .v . formulation , or an tions ; ( 14 ) up -regulation of insulin receptors ; ( 15 ) enhanced 60 immediate release oral formulation , or a controlled release glucose uptake; ( 16 ) reduced adipocyte hyperplasia ; ( 17 ) formulation , or a sustained release formulation , or a trans reduced adipocyte hypertrophy ; ( 18 ) reduced rates of con - dermal formulation , or an intranasal formulation to a subject version of preadipocytes to adipocytes ; (19 ) reduced rates of with type 1 diabetes which result in beta cell rest. hyperphagia ; (20 ) increased protection of CNS, cardiac and The mode of action by which weight is maintained or lost other tissues from ischemic or reperfusion injury ; (21 ) 65 resulting from the prolonged administration ofKarp channel improved insulin sensitivity ; (22 ) elevated CSF insulin openers selected from salts of compounds of Formulae concentrations; (23 ) elevated circulating adiponectin con - I - VIII to overweight, obese or obesity prone subjects as US 9 , 765 ,043 B2 71 72 provided herein includes, but is not limited to , one or more tion of insulin receptors ; ( 18 ) enhanced glucose uptake ; (19 ) of ( 1 ) enhanced energy expenditure, ( 2 ) enhanced oxidation reduced adipocyte hyperplasia ; ( 20 ) reduced adipocyte of fat and fatty acids , ( 3 ) enhancement of lipolysis in adipose hypertrophy ; (21 ) reduced rates of conversion of preadipo tissue , ( 4 ) enhanced glucose uptake by tissues and enhanced cytes to adipocytes; (22 ) reduced rates of hyperphagia ; (23 ) insulin sensitivity , and ( 5 ) improved beta adrenergic 5 elevated circulating adiponectin concentration ; ( 24 ) elevated response . The mode of action by which weight is maintained cerebrospinal fluid insulin levels ; (25 ) enhanced islet insulin or lost resulting from the prolonged administration ofKTP mRNA and insulin content; or ( 26 ) enhanced metabolic channel openers selected from salts of compounds of For efficiency of insulin . mulae I - VIII to obese or obesity prone subjects as provided Immediate or prolonged administration of formulations of herein may also include the suppression of appetite . 10 KATP channel openers selected from salts of compounds of Prolonged administration of pharmaceutical formulations Formulae I - VIII to prediabetic or type I diabetic humans or of KATP channel openers selected from salts of compounds animals results in the prevention of beta cell failure , of Formulae I- VIII to overweight or obese humans or improved glycemic control, and prevention of the transition animals results in substantial and sustained weight loss from prediabetes to diabetes including some or all of the including some or all of the following effects : ( 1 ) preferen - 15 following effects : ( 1 ) increase in resting energy expenditure ; tial loss of body fat ; ( 2 ) loss of greater than 25 % of initial ( 2 ) increase in the oxidation of fat and fatty acids; ( 3 ) body fat mass ; (3 ) loss of greater than 50 % of initial body reduction in blood pressure ; ( 4 ) production of lipoprotein fat mass ; ( 4 ) loss of greater than 75 % of initial body fat lipase by adipocytes is reduced ; (5 ) enhanced lipolysis by mass; ( 5 ) significant increase in resting energy expenditure; adipocytes ; ( 6 ) expression of fatty acid synthase by adipo ( 6 ) increase in the oxidation of fat and fatty acids; ( 7 ) 20 cytes is reduced ; (7 ) glyceraldehyde phosphate dehydroge reduction in blood pressure ; ( 8 ) production of lipoprotein nase activity of adipocytes is reduced ; ( 8 ) little or no new lipase by adipocytes is reduced ; ( 9 ) enhanced lipolysis by triglycerides are synthesized and stored by adipocytes ; ( 9 ) adipocytes; ( 10 ) expression of fatty acid synthase by adipo enhanced expression of B3 Adrenergic Receptor (B3AR ) and cytes is reduced ; (11 ) glyceraldehydes phosphate dehydro an improvement in the adrenergic function in adipocytes; genase activity of adipocytes is reduced ; ( 12 ) little or no new 25 ( 10 ) reduced glucose stimulated secretion of insulin by triglycerides are synthesized and stored by adipocytes ; ( 13 ) pancreatic B - cells ; (11 ) decreased insulinemia ; ( 12 ) enhanced expression of ß3 Adrenergic Receptor (B3AR ) and enhanced blood glucose levels ; ( 13 ) increased expression of an improvement in the adrenergic function in adipocytes ; Uncoupling Protein 1 in adipocytes ; ( 14 ) enhanced thermo ( 14 ) reduced glucose stimulated secretion of insulin by genesis in white and brown adipose tissue ; ( 15 ) reduction of pancreatic B - cells ; (15 ) decreased insulinemia ; (16 ) 30 plasma triglyceride concentration ; ( 16 ) decreased circulat enhanced blood glucose levels ; ( 17 ) increased expression of ing leptin concentrations; ( 17) up - regulation of insulin Uncoupling Protein 1 in adipocytes; ( 18 ) enhanced thermo- receptors; ( 18 ) enhanced glucose uptake ; ( 19 ) reduced adi genesis in white and brown adipose tissue ; ( 19 ) reduction of pocyte hyperplasia ; (20 ) reduced adipocyte hypertrophy ; plasma triglyceride concentration ; ( 20 ) decrease in circulat- (21 ) reduced rates of conversion of preadipocytes to adipo ing leptin concentrations; ( 21) up -regulation of insulin 35 cytes ; ( 22 ) reduced rates of hyperphagia ; ( 23 ) elevated receptors ; ( 22 ) enhanced glucose uptake; (23 ) reduced adi- circulating adiponectin concentrations ; ( 24 ) elevated cere pocyte hyperplasia ; ( 24 ) reduced adipocyte hypertrophy ; brospinal fluid insulin levels ; (25 ) enhanced islet insulin ( 25 ) reduced rates of conversion of preadipocytes to adipo - mRNA and insulin content; or ( 26 ) enhanced metabolic cytes ; (26 ) reduced rates of hyperphagia ; (27 ) the sequential efficiency of insulin . loss first of the metabolically most active adipose tissue 40 Immediate or prolonged administration of formulations of (visceral ) , followed by the loss of less metabolically active KATP channel openers selected from salts of compounds of adipose tissue; ( 28 ) elevation of circulating adiponectin Formulae I- VIII to humans or animals that are at risk for concentrations ; (29 ) elevation of cerebrospinal fluid insulin myocardial infarct , or stroke, or undergoing surgical proce levels ; ( 30 ) enhanced islet insulin mRNA and insulin con - dure that restores blood flow to heart or brain results in tent ; or (31 ) enhanced metabolic efficiency of insulin . 45 improved therapeutic outcomes post- surgically , or following Prolonged administration of formulations of KATP chan the occurrence of myocardial infarct or stroke by improving nel openers selected from salts of compounds of Formulae the survival of tissue after blood flow is restored , reduced I -VIII to obesity prone humans or animals , including sub - stunning of tissue , and altering the nature of the inflamma jects who have undergone various types of bariatric surgery, tory responses . results in sustained maintenance of weight including some 50 Pharmaceutical formulations as provided herein are or all of the following effects : ( 1 ) increased resting energy designed to be used in the treatment of obesity , hyperlipi expenditure ; ( 2 ) increase in the oxidation of fat and fatty demia , hypertension , weight maintenance , type I diabetes , acids ; ( 3 ) reduction in blood pressure ; ( 4 ) production of prediabetes , type II diabetes , metabolic syndrome or any lipoprotein lipase by adipocytes is reduced ; ( 5 ) enhanced condition where weight loss , reduction in circulating triglyc lipolysis by adipocytes ; ( 6 ) expression of fatty acid synthase 55 erides or beta cell rest contributes to therapeutic outcomes by adipocytes is reduced ; ( 7 ) glyceraldehyde phosphate provide for a range of critical changes in pharmacodynamic dehydrogenase activity of adipocytes is reduced ; (8 ) little or and pharmacokinetic responses to administered doses of no new triglycerides are synthesized and stored by adipo - KATP channel openers selected from salts of compounds of cytes ; ( 9 ) enhanced expression of B3 Adrenergic Receptor Formulae I - VIII which changes include one or more of the ( B3AR ) and improvement in the adrenergic function in 60 following : ( 1 ) extending the pharmacodynamic effect of an adipocytes ; ( 10 ) reduced glucose stimulated secretion of administered dose to 24 hours or longer as measured by the insulin by pancreatic B -cells ; ( 11) decreased insulinemia ; suppression of insulin secretion ; (2 ) providing for substan ( 12 ) enhanced blood glucose levels ; ( 13 ) increased expres tial uptake of the active pharmaceutical ingredient in the sion of Uncoupling Protein 1 in adipocytes ; ( 14 ) enhanced small intestine ; ( 3 ) providing for substantial uptake of the thermogenesis in white and brown adipose tissue; ( 15 ) 65 active pharmaceutical ingredient in the large intestine ; ( 4 ) reduction of plasma triglyceride concentration ; ( 16 ) result in lowered Cmax versus current oral suspension or decreased circulating leptin concentration ; ( 17 ) up - regula capsule products for the same administered dose of active US 9 , 765 ,043 B2 73 74 pharmaceutical ingredient ; ( 5 ) provide for circulating con of progression of diabetes , ( 4 ) improvements in glucose centrations of unbound active pharmaceutical ingredient tolerance , ( 5 ) reduced hypertension , and (6 ) reduced rates of above threshold concentrations for 24 or more hours from a single administered dose ; and (6 ) provide for more consis - Co - administration of drugs with formulations of KATP tent drug absorption by treated subjects as compared to 5 channel openers selected from salts of compounds of For existing capsule formulations . mulae I- VIII in the treatment of diseases of overweight , Pharmaceutical co -formulations of the current invention designed to treat a range of conditions in humans and obese or obesity prone human and animal subjects involves animals include the combination of KATP channel openers the co - administration of a pharmaceutically acceptable for selected from salts of compounds of Formulae I - VIII with : 10 mulation of KATP channel openers with an acceptable ( 1 ) a diuretic , ( 2 ) a drug that lowers blood pressure , ( 3 ) a formulation of: ( 1 ) sibutramine, ( 2 ) orlistat, ( 3 ) rimonabant, drug that suppresses appetite , (4 ) a cannabinoid receptor ( 4 ) a drug that is an appetite suppressant, (5 ) any drug used antagonist , ( 5 ) a drug that suppresses that action of gastric to induce weight loss in an obese or overweight subject, (6 ) lipases , ( 6 ) any drug that is used to induce weight loss , ( 7 ) a non - thiazide diuretic , ( 7 ) a drug that lowers cholesterol , ( 8 ) a drug that lowers cholesterol. ( 8 ) a drug that lowers LDL 15 a drug that raises HDL cholesterol, ( 9 ) a drug that lowers bound cholesterol, (9 ) a drug that improves insulin sensi LDL cholesterol, ( 10 ) a drug that lowers blood pressure , ( 11) tivity , ( 10 ) a drug that improves glucose utilization or a drug that is an antidepressant , (12 ) a drug that improves uptake , ( 11 ) a drug that reduces incidence of atherosclerotic insulin sensitivity , ( 13 ) a drug that improves glucose utili plaque , ( 12 ) a drug that reduces inflammation , ( 13 ) a drug zation and uptake ( 14 ) a drug that is an antiepileptic , ( 15 ) that is antidepressant , (14 ) a drug that is an antiepileptic , or 20 a drug that is an anti- inflammatory , or ( 16 ) a drug that lowers ( 15 ) a drug that is an anti- psychotic . circulating triglycerides. Treatment of humans or animals using pharmaceutical Co -administration of drugs with formulations of KATP formulations (which include KATP channel openers selected channel openers selected from salts of compounds of For from salts of compounds of Formulae I - VIII ) result in mulae I -VIII in the treatment or prevention of weight gain , reduced incidence of adverse side effects including but not 25 dyslipidemia , impaired glucose tolerance or diabetes in limited to edema , fluid retention , reduced rates of excretion subjects treated with antipsychotics drugs involve the co of sodium , chloride, and uric acid , hyperglycemia , ketoaci- administration of a pharmaceutically acceptable formulation dosis , nausea , vomiting , dyspepsia , ileus and headaches. ofKATP channel openers with an acceptable formulation of: These reductions in frequency of adverse side effects are lithium , carbamazepine , valproic acid and divalproex , and achieved by : ( 1 ) initiating dosing of subjects at subthera - 30 lamotrigine ; antidepressants generally classified as mono peutic doses and in a step wise manner increasing the dose amine oxidase inhibitors including isocarboxazid , phenel daily until the therapeutic dose is achieved where the zine sulfate and tranylcypromine sulfate ; tricyclic antide number of days over which the step up in dose is effected is pressants including doxepin , clomipramine , amitriptyline , 2 to 10 , ( 2 ) use of the lowest effective dose to achieve the maprotiline, desipromine , nortryptyline , desipramine , dox desired therapeutic effect, ( 3 ) use of a pharmaceutical for - 35 epin , trimipramine , imipramine and protryptyline ; tetracy mulation that delays release of active until gastric transit is clic antidepressants including mianserin , mirtazapine , complete , ( 4 ) use of a pharmaceutical formulation that maprotiline, oxaprotiline , delequamine , levoprotiline , triflu results in lower circulating peak drug levels as compared to carbine , setiptiline , azipramine , aptazapine maleate and an immediate release oral suspension or capsule formulation pirlindole; and major tranquilizers and atypical antipsychot for the same administered dose , and ( 5 ) optimizing the 40 ics including perphenazine, thioridazine , risperidone , clo timing of administration of dose within the day and relative zapine , olanzapine and chlorpromazine. to meals . In one embodiment, a KATP channel opener selected Treatment of patients suffering from Prader Willi Syn from a salt of a compound of Formulae I- VIII is adminis drome, Froelich ' s Syndrome, Cohen Syndrome, Summit tered to an overweight or obese subject as an oral, transder Syndrome, Alstrom Syndrome, Borjesen Syndrome, Bardet - 45 mal or intranasal formulation to reach and maintain the Biedl Syndrome, and hyperlipoproteinemia type I , II , III , threshold concentration required to measurably reduce fast and IV with the current invention using pharmaceutical ing insulin levels for a prolonged period . Preferably the formulations of KATP channel openers selected from salts of KATP channel opener formulation reduces fasting insulin compounds of Formulae I- VIII result in some or all of the levels by at least 20 % , more preferably by at least 30 % , following therapeutic outcomes: ( 1 ) weight loss , ( 2 ) reduced 50 more preferably by at least by 40 % , more preferably by at rates of weight gain , ( 3 ) inhibition of hyperphagia , ( 4 ) least 50 % , more preferably by at least by 60 % , more reduced incidence of impaired glucose tolerance , prediabe - preferably by at least by 70 % , and more preferably by at tes or diabetes, (5 ) reduced incidence of congestive heart least 80 % . Fasting insulin levels are commonly measured failure , (6 ) reduced hypertension , and ( 7 ) reduced rates of all using the glucose tolerance test ( OGTT) . After an overnight cause mortality . 55 fast, a patient ingests a known amount of glucose . Initial Treatment of prediabetic subjects using invention phar - glucose levels are determined by measuring pre -test glucose maceutical formulations of KATP channel openers selected levels in blood and urine . Blood insulin levels are measured from salts of compounds of Formulae I -VIII result in some by a blood is draw every hour after the glucose is consumed or all of the following therapeutic outcomes: ( 1 ) weight loss , for up to three hours. In a fasting glucose assay, subjects ( 2 ) restoration of normal glucose tolerance , ( 3 ) delayed rates 60 with plasma glucose values greater than 200 mg/ dl at 2 hours of progression to diabetes , (4 ) reduced hypertension , and (5 ) post - glucose load indicate an impaired glucose tolerance . reduced rates of all cause mortality . In another embodiment , a KATP channel opener selected Treatment of diabetic subjects using invention pharma- from a salt of a compound of Formulae I - VIII is adminis ceutical formulations of KATP channel openers selected tered to an overweight or obese subject as an oral , transder from salts of compounds of Formulae I - VIII result in some 65 mal or intranasal formulation to reach and maintain the or all of the following therapeutic outcomes: ( 1 ) weight loss, threshold concentration required to induce weight loss for a ( 2 ) restoration of normal glucose tolerance , ( 3 ) delayed rates prolonged period . US 9 , 765 ,043 B2 75 76 In another embodiment, a KATP channel opener selected administered to an subject in need thereof that results in from a salt of a compound of Formulae I -VIII is adminis circulating concentration of active drug sufficient to dimin tered to an overweight or obese subject as an oral, transder - ish the secretion of insulin for 24 or more hours . mal or intranasal formulation to reach and maintain the In another embodiment, a pharmaceutically acceptable threshold concentration required to elevate resting energy 5 formulation of a KATP channel opener selected from a salt expenditure for a prolonged period . In another embodiment, a KATP channel opener selected of a compound of Formulae I -VIII is administered over a from a salt of a compound of Formulae I - VIII is adminis prolonged basis to an subject in need thereof no more than tered to an overweight or obese subject as an oral, transder once per 24 hours that results in circulating concentration of mal or intranasal formulation to reach and maintain the 10 active drug sufficient to diminish the secretion of insulin on threshold concentration required to elevate fat and fatty acid a continuous basis . oxidation for a prolonged period . In another embodiment, a single dose of a pharmaceuti In another embodiment, a KATP channel opener selected cally acceptable formulation of a KATP channel opener from a salt of a compound of Formulae I - VIII is adminis selected from a salt of a compound of Formulae I - VIII is tered to an obesity prone subject as an oral , transdermaltransdermal or 15 administeredaamini to an subject in need thereof that results in intranasal formulation to reach and maintain the threshold circulating concentration of active drug sufficient to elevate concentration required to induce weight loss for a prolonged non - esterified fatty acids in circulation for 24 or more hours . period . In another embodiment, a pharmaceutically acceptable In another embodiment, a KATP channel opener selected formulation of a KATP channel opener selected from a salt from a salt of a compound of Formulae I - VIII is adminis - 20 of a compound of Formulae I - VIII is administered over a tered to an obesity prone subject as an oral, transdermal or prolonged basis to an subject in need thereof no more than intranasal formulation to reach and maintain the threshold once per 24 hours that results in circulating concentration of concentration required to maintain weight for a prolonged active drug sufficient to elevate non - esterified fatty acids in period . circulation on a continuous basis . In another embodiment, a KATP channel opener selected 25 In another embodiment, a single dose of a pharmaceuti from a salt of a compound of Formulae I - VIII is adminis - cally acceptable formulation of a KATP channel opener tered to an overweight or obese subject as an oral, transder selected from a salt of a compound of Formulae I - VIII is mal or intranasal formulation to reach and maintain a drug administered to an subject in need thereof that results in concentration above the threshold concentration required to circulating concentration of active drug sufficient to treat induce weight loss for a prolonged period . 30 hypoglycemia in circulation for 24 or more hours . In another embodiment, a KATP channel opener selected In another embodiment, a pharmaceutically acceptable from a salt of a compound of Formulae I - VIII is adminis - formulation of a KATP channel opener selected from a salt tered to an overweight or obese subject as an oral, transder - of a compound of Formulae I - VIII is administered over a mal or intranasal formulation for a prolonged period of time prolonged basis to an subject in need thereof no more than to reduce body fat by more than 25 % , more preferably by at 35 once per 24 hours that results in circulating concentration of least 50 % , and more preferably by at least 75 % . active drug sufficient to treat hypoglycemia on a continuous In another embodiment, a KATP channel opener selected basis . from a salt of a compound of Formulae I - VIII is adminis - In another embodiment, a pharmaceutically acceptable tered to an overweight or obese subject as an oral, transder- formulation of a KATP channel opener selected from a salt mal or intranasal formulation for a prolonged period of time 40 of a compound of Formulae I - VIII is administered over a to preferentially reduce visceral fat deposits . prolonged basis to an subject in need thereof no more than In another embodiment, a KATP channel opener selected once per 24 hours that results in circulating concentration of from a salt of a compound of Formulae I - VIII is adminis - active drug sufficient to induce weight loss on a continuous tered to an overweight or obese subject as an oral, transder - basis . mal or intranasal formulation for a prolonged period of time 45 In another embodiment, a pharmaceutically acceptable to reduce visceral fat depots and other fat deposits . formulation of a KATP channel opener selected from a salt In another embodiment, a KATP channel opener selected of a compound of Formulae I - VIII is administered over a from a salt of a compound of Formulae I - VIII is adminis - prolonged basis to an subject in need thereof no more than tered to a normoinsulinemic overweight or obese subject as once per 24 hours that results in circulating concentration of an oral, transdermal or intranasal formulation to reach and 50 active drug sufficient to maintain weight on a continuous maintain a drug concentration above the threshold concen - basis , as it is preferable to maintain weight in an obese tration required to induce weight loss for a prolonged period . subject once some weight loss has occurred when the In another embodiment , a KATP channel opener selected alternative is to regain weight. from a salt of a compound of Formulae I - VIII is adminis - In another embodiment, a pharmaceutically acceptable tered to a prediabetic subject as an oral, transdermal or 55 formulation of a KATP channel opener selected from a salt intranasal formulation to reach and maintain a drug concen - of a compound of Formulae I - VIII is administered over a tration above the threshold concentration required to prevent prolonged basis to an subject in need thereof no more than the transition to diabetes for a prolonged period . once per 24 hours that results in circulating concentration of In another embodiment, a KATP channel opener selected active drug sufficient to reduce circulating triglyceride levels from a salt of a compound of Formulae I -VIII is adminis - 60 on a continuous basis . tered to a type 1 diabetic subject as an oral, transdermal or In another embodiment, a single dose of a pharmaceuti intranasal formulation to reach and maintain a drug concen - cally acceptable formulation of a KATP channel opener tration above the threshold concentration required to induce selected from a salt of a compound of Formulae I - VIII is beta cell rest for a prolonged period . administered to an subject in need thereof that results in In another embodiment, a single dose of a pharmaceuti - 65 circulating concentration of active drug sufficient to reduce cally acceptable formulation of a KATP channel opener or prevent ischemic or reperfusion injury in circulation for selected from a salt of a compound of Formulae I - VIII is 24 or more hours . US 9 , 765 ,043 B2 77 78 In another embodiment, a pharmaceutically acceptable transit is complete , in which the maximum circulating formulation of a KATP channel opener selected from a salt concentration of active ingredient is lower than what would of a compound of Formulae I - VIII is administered over a be realized by the administration of the same dose using an prolonged basis to an subject in need thereof no more than oral suspension or capsule formulation , and in which the once per 24 hours that results in circulating concentration of 5 maximum dose is less than 2 . 5 mg/ kg / day . active drug sufficient reduce or prevent ischemic or reper - In another embodiment, the treatment of an overweight or fusion injury on a continuous basis . obese subject is optimized for weight loss by administration In another embodiment, the frequency of adverse effects of a pharmaceutically acceptable formulation of a KATP caused by treatment with a KATP channel opener selected channel opener selected from a salt of a compound of from a salt of a compound of Formulae I - VIII is reduced 10 Formulae I - VIII once per 24 hours in which the release of using a pharmaceutically acceptable formulation of diazox - the active ingredient from the formulation has been modified ide or its derivatives that is administered to an subject in to provide continuous release for at least 6 hours . need thereof on a daily basis in which the first dose is known In another embodiment, the treatment of an overweight or to be subtherapeutic and daily dose is subsequently obese subject is optimized for weight loss by administration increased stepwise until the therapeutic dose is reached . 15 of a pharmaceutically acceptable formulation of a KATP In another embodiment, the frequency of adverse effects channel opener selected from a salt of a compound of caused by treatment with a KATP channel opener selected Formulae I - VIII once per 24 hours in which the release of from a salt of a compound of Formulae I -VIII is reduced the active ingredient from the formulation has been modified using a pharmaceutically acceptable formulation that is to provide continuous release for at least 12 hours . administered to an subject in need thereof on a daily basis in 20 In another embodiment, the treatment of an overweight or which the active ingredient is not released from the formu - obese subject is optimized for weight loss by administration lation until gastric transit is complete . of a pharmaceutically acceptable formulation of a KATP In another embodiment, the frequency of adverse effects channel opener selected from a salt of a compound of caused by treatment with a KATP channel opener selected Formulae I - VIII once per 24 hours in which the release of from a salt of a compound of Formulae I - VIII is reduced 25 the active ingredient from the formulation has been modified using a pharmaceutically acceptable formulation that is to provide a rising drug concentration in circulation for at administered to an subject in need thereof on a daily basis in least 8 hours. which the maximum circulating concentration of active in another embodiment, the treatment of an overweight or ingredient is lower than what would be realized by the obese subject is optimized for weight loss by administration administration of the same dose using an oral suspension or 30 of a pharmaceutically acceptable formulation of a KATP capsule formulation of Proglycem®. channel opener selected from a salt of a compound of In another embodiment, the frequency of adverse effects Formulae I - VIII once per 24 hours in which the release of caused by treatment with a KATP channel opener selected the active ingredient from the formulation has been modified from a salt of a compound of Formulae I - VIII is reduced to provide a rising drug concentration in circulation for at using a pharmaceutically acceptable formulation that is 35 least 12 hours . administered to an subject in need thereof on a daily basis in In another embodiment, the treatment of an overweight or which the first dose is known to be subtherapeutic and daily obese subject is optimized for weight loss by administration dose is subsequently increased stepwise until the therapeutic of a pharmaceutically acceptable formulation of a KATP dose is reached , the active ingredient is not release from the channel opener selected from a salt of a compound of formulation until gastric transit is complete and in which the 40 Formulae I - VIII once per 24 hours in which the release of maximum circulating concentration of active ingredient is the active ingredient from the formulation has been modified lower than what would be realized by the administration of to match the pattern of basal insulin secretion . the same dose using an oral suspension or capsule formu - In another embodiment, the frequency of adverse effects lation of Proglycem® . caused by treatment with a KATP channel opener selected In another embodiment, the frequency of adverse effects 45 from a salt of a compound of Formulae I - VIII is reduced caused by treatment with a KATP channel opener selected using a pharmaceutically acceptable formulation that is from a salt of a compound of Formulae I - VIII is reduced administered to an obesity prone subject in need thereof on using a pharmaceutically acceptable formulation that is a daily basis in which the first dose is known to be sub administered to an overweight or obese subject in need therapeutic and daily dose is subsequently increased step thereof on a daily basis in which the first dose is known to 50 wise until the therapeutic dose is reached , the active ingre be subtherapeutic and daily dose is subsequently increased dient is not release from the formulation until gastric transit stepwise until the therapeutic dose is reached , the active is complete , in which the maximum circulating concentra ingredient is not release from the formulation until gastric t ion of active ingredient is lower than what would be transit is complete, in which the maximum circulating realized by the administration of the same dose using an oral concentration of active ingredient is lower than what would 55 suspension or capsule formulation , and in which the maxi be realized by the administration of the same dose using an mum dose is less than 5 mg/ kg / day . oral suspension or capsule formulation of Proglycem® , and In another embodiment, the frequency of adverse effects in which the maximum dose is less than 5 mg/ kg / day . caused by treatment with a KATP channel opener selected In another embodiment, the frequency of adverse effects from a salt of a compound of Formulae I - VIII is reduced caused by treatment with a KATP channel opener selected 60 using a pharmaceutically acceptable formulation that is from a salt of a compound of Formulae I - VIII is reduced administered to an obesity prone subject in need thereof on using a pharmaceutically acceptable formulation that is a daily basis in which the first dose is known to be sub administered to an overweight or obese subject in need therapeutic and daily dose is subsequently increased step thereof on a daily basis in which the first dose is known to wise until the therapeutic dose is reached , the active ingre be subtherapeutic and daily dose is subsequently increased 65 dient is not release from the formulation until gastric transit stepwise until the therapeutic dose is reached , the active is complete , in which the maximum circulating concentra ingredient is not release from the formulation until gastric t ion of active ingredient is lower than what would be US 9 ,765 , 043 B2 79 80 realized by the administration of the same dose using an oral of a compound of Formulae I- VIII is co -administered with suspension or capsule formulation , and in which the maxi - anti - epileptic to an overweight or obese subject to induce mum dose is less than 2 . 5 mg/ kg / day. weight loss . In another embodiment, the treatment of an obesity prone I n another embodiment, a pharmaceutically acceptable subject is optimized for weight maintenance by administra - 5 formulation of a KATP channel opener is selected from a salt tion of a pharmaceutically acceptable formulation of a of a compound of Formulae I - VIII is co -administered with KATP channel opener selected from a salt of a compound of a non - thiazide diuretic to an overweight or obese subject to Formulae I - VIII once per 24 hours in which the release of induce weight loss. the active ingredient from the formulation has been modified In another embodiment, a pharmaceutically acceptable to provide continuous release for at least 6 hours . 10 formulation of a KATP channel opener selected from a salt In another embodiment, the treatment of an obesity prone of a compound of Formulae I - VIII is co - administered with subject is optimized for weight maintenance by administra - a drug that induces weight loss by a mechanism that is tion of a pharmaceutically acceptable formulation of a distinct from diazoxide to an overweight or obese subject to KATP channel opener selected from a salt of a compound of induce weight loss . Formulae I - VIII once per 24 hours in which the release of 15 In another embodiment, a pharmaceutically acceptable the active ingredient from the formulation has been modified formulation of a KATP channel opener selected from a salt to provide continuous release for at least 12 hours . of a compound of Formulae I - VIII is co -administered with In another embodiment, the treatment of an obesity prone a drug that lowers blood pressure to an overweight, obesity subject is optimized for weight maintenance by administra - prone or obese subject to induce weight loss and treat tion of a pharmaceutically acceptable formulation of a 20 obesity associated co -morbidities . KATP channel opener selected from a salt of a compound of In another embodiment, a pharmaceutically acceptable Formulae I - VIII once per 24 hours in which the release of formulation of a KATP channel opener selected from a salt the active ingredient from the formulation has been modified of a compound of Formulae I - VIII is co - administered with to provide a rising drug concentration in circulation for at a drug that lowers cholesterol to an overweight , obesity least 8 hours . 25 prone or obese subject to induce weight loss and treat In another embodiment , the treatment of an obesity prone obesity associated co -morbidities . subject is optimized for weight maintenance by administra - In another embodiment, a pharmaceutically acceptable tion of a pharmaceutically acceptable formulation of a formulation of a KATP channel opener selected from a salt KATP channel opener selected from a salt of a compound of of a compound of Formulae I - VIII is co - administered with Formulae I -VIII once per 24 hours in which the release of 30 a drug that raises HDL associated cholesterol to an over the active ingredient from the formulation has been modified weight, obesity prone or obese subject to induce weight loss to provide a rising drug concentration in circulation for at and treat obesity associated co -morbidities . least 12 hours . In another embodiment, a pharmaceutically acceptable In another embodiment, the treatment of an obesity prone formulation of a KATP channel opener selected from a salt subject is optimized for weight maintenance by administra - 35 of a compound of Formulae I - VIII is co - administered with tion of a pharmaceutically acceptable formulation of a a drug that improves insulin sensitivity to an overweight, KATP channel opener selected from a salt of a compound of obesity prone or obese subject to induce weight loss and Formulae I -VIII once per 24 hours in which the release of treat obesity associated co -morbidities . the active ingredient from the formulation has been modified In another embodiment, a pharmaceutically acceptable to match the pattern of basal insulin secretion . 40 formulation of a KATP channel opener selected from a salt In another embodiment , a pharmaceutically acceptable of a compound of Formulae I - VIII is co -administered with formulation of a KATP channel opener selected from a salt a an anti- inflammatory to an overweight, obesity prone or of a compound of Formulae I -VIII is co - administered with obese subject to induce weight loss and treat obesity asso sibutramine to an overweight or obese subject to induce ciated co - morbidities . weight loss . 45 In another embodiment, a pharmaceutically acceptable In another embodiment, a pharmaceutically acceptable formulation of a KATP channel opener selected from a salt formulation of a KATP channel opener selected from a salt of a compound of Formulae I - VIII is co -administered with of a compound of Formulae I - VIII is co -administered with a drug that lowers circulating triglycerides to an overweight , orlistat to an overweight or obese subject to induce weight obesity prone or obese subject to induce weight loss and loss . 50 treat obesity associated co -morbidities . In another embodiment , a pharmaceutically acceptable In another embodiment, KATP channel openers selected formulation of a KATP channel opener selected from a salt from salts of compounds of Formulae I - VIII are co -formu of a compound of Formulae I - VIII is co - administered with lated with sibutramine in a pharmaceutically acceptable rimonabant to an overweight or obese subject to induce formulation that is administered to an overweight, obesity weight loss . 55 prone or obese subject to induce weight loss and treat In another embodiment, a pharmaceutically acceptable obesity -associated co -morbidities . formulation of a KATP channel opener selected from a salt In another embodiment, KATP channel openers selected of a compound of Formulae I -VIII is co - administered with from salts of compounds of Formulae I - VIII are co - formu an appetite suppressant to an overweight or obese subject to lated with orlistat or other active that suppresses the action induce weight loss. 60 of gastric lipases in a pharmaceutically acceptable formu In another embodiment, a pharmaceutically acceptable lation that is administered to an overweight, obesity prone or formulation of a KATP channel opener selected from a salt obese subject to induce weight loss and treat obesity of a compound of Formulae I - VIII is co - administered with associated co -morbidities . an anti - depressant to an overweight or obese subject to In another embodiment, KATP channel openers selected induce weight loss . 65 from salts of compounds of Formulae I - VIII are co - formu In another embodiment, a pharmaceutically acceptable lated with a non - thiazide diuretic in a pharmaceutically formulation of a KATP channel opener selected from a salt acceptable formulation that is administered to an over US 9 , 765 ,043 B2 81 82 weight, obesity prone or obese subject to induce weight loss of a KATP channel opener. selected from a salt of a and treat obesity -associated co -morbidities . compound of Formulae I - VIII . In another embodiment, KATP channel openers selected An oral dosage form of KATP channel opener selected from salts of compounds of Formulae I - VIII are co - formu - from a salt of a compound of Formulae I - VIII can be used lated with an appetite suppressant in a pharmaceutically 5 to administer a therapeutically effective dose of KATP acceptable formulation that is administered to an over - channel opener to an overweight or obesity prone subject in weight, obesity prone or obese subject to induce weight loss need thereof to maintain weight, as it is preferable to and treat obesity - associated co -morbidities . maintain weight in an obese subject once some weight loss In another embodiment, KATP channel openers selected has occurred when the alternative is to regain weight. from salts of compounds of Formulae 1 -VIII are co - formu - 10 In another embodiment of the invention , KATP channel lated with a cannabinoid receptor antagonist in a pharma - openers selected from salts of compounds of Formulae ceutically acceptable formulation that is administered to an I - VIII are co - formulated with a drug to treat obesity . Such overweight, obesity prone or obese subject to induce weight co - formulations can be formulated for oral administration loss and treat obesity - associated co -morbidities . once per 24 hours , for delayed release of the active until In another embodiment, KATP channel openers selected 15 gastric transit is complete , and for sustained release of the from salts of compounds of Formulae 1 - VIII are co -formu active over a period of 2 to 24 hours . Such obesity treatment lated with an anti- cholesteremic active in a pharmaceutically drugs include , but are not limited to : sibutramine hydrochlo acceptable formulation that is administered to an over ride ( 5 - 30 mg) , orlistat (50 - 360 mg) , phentermine hydro weight, obesity prone or obese subject to induce weight loss chloride or resin complex ( 15 to 40 mg ) , zonisamide ( 100 to and treat obesity -associated co -morbidities . 20 600 mg ) , topiramate (64 to 400 mg ) , naltrexone hydrochlo In another embodiment, KATP channel openers selected ride (50 to 600 mg ) , or rimonabant (5 to 20 mg) . from salts of compounds of Formulae I- VIII are co - formu- A further embodiment of the co - formulation contains lated with an antihypertensive active in a pharmaceutically KATP channel openers selected from salts of compounds of acceptable formulation that is administered to an over - Formulae I - VIII and a drug to treat obesity . Such co weight, obesity prone or obese subject to induce weight loss 25 formulations can be formulated for oral administration twice and treat obesity -associated co -morbidities . per 24 hours , for delayed release of the active until gastric In another embodiment , KATP channel openers selected transit is complete , and for sustained release of the active from salts of compounds of Formulae I - VIII are co - formu - over a period of 2 to 12 hours . Such obesity treatment drugs lated with an insulin sensitizing active in a pharmaceutically include , but are not limited to : sibutramine hydrochloride acceptable formulation that is administered to an over - 30 ( 2 . 5 to 15 mg) , orlistat (25 to 180 mg) , phentermine hydro weight, obesity prone or obese subject to induce weight loss chloride or resin complex ( 7 . 5 to 20 mg) , zonisamide ( 50 to and treat obesity -associated co -morbidities . 300 mg) , topiramate ( 32 to 200 mg) , naltrexone hydrochlo In another embodiment, KATP channel openers selected ride ( 25 to 300 mg ) , or rimonabant ( 2 .5 to 10 mg) . from salts of compounds of Formulae 1 - VIII are co -formu In another embodiment of the invention KATP channel lated with an anti - inflammatory active in a pharmaceutically 35 openers selected from salts of compounds of Formulas acceptable formulation that is administered to an over - I - VIII are co - formulated with a drug to treat obesity , diabe weight, obesity prone or obese subject to induce weight loss tes, metabolic syndrome or an obesity related comorbidity . and treat obesity - associated co -morbidities . Such drugs to treat these conditions include drugs that: In another embodiment, KATP channel openers selected agonizes the al- noradrenergic receptor ; agonizes the B2 from salts of compounds of Formulae 1 -VIII are co - formu - 40 noradrenergic receptor ; stimulates noradrenalin release ; lated with an anti -depressant active in a pharmaceutically blocks noradrenalin uptake ; stimulates 5 -HT release ; blocks acceptable formulation that is administered to an over - 5 -HT uptake ; is a serotonin ( 5 - hydroxytryptamine ) 2C weight , obesity prone or obese subject to induce weight loss receptor agonist ; antagonizes acetyl- CoA carboxylase 2 , and treat obesity - associated co -morbidities . agonizes the D1- receptor ; antagonizes the H3 - receptor ; is a In another embodiment, KATP channel openers selected 45 leptin analogue ; agonizes the leptin receptor, sensitizes CNS from salts of compounds of Formulae 1 -VIII are co - formu - tissue to the action of leptin ; agonizes the MC4 receptor ; lated with an anti - epileptic active in a pharmaceutically agonizes NPY- Y1 ; agonizes NPY - Y2 ; agonizes NPY - Y4 ; acceptable formulation that is administered to an over- agonizes NPY- Y5 ; antagonizes the MCH receptor; blocks weight, obesity prone or obese subject to induce weight loss CRH - BP ; agonizes the CRH receptor ; agonizes the urocortin and treat obesity -associated co -morbidities . 50 receptor ; antagonizes the galanin receptor ; antagonizes the In another embodiment, KATP channel openers selected orexin receptor; agonizes the CART receptor; agonizes the from salts of compounds of Formulae I -VIII are co - formu Amylin receptor ; agonizes the Apo (AIV receptor ; antago lated with an active that reduces the incidence of athero - nizes the CB - 1 receptor; is an aMSH analogue ; inhibits sclerotic plaque in a pharmaceutically acceptable formula PTP - 1B ; antagonizes PPARy receptor; is a short acting tion that is administered to an overweight, obesity prone or 55 bromocriptine ; agonizes somatostatin ; increases adiponec obese subject to induce weight loss and treat obesity - tin ; increases CCK activity ; increases PYY activity ; associated co -morbidities . increases GLP - 1 activity; decreases ghrelin activity ; is a In another embodiment, KATP channel openers selected selective B3 stimulator or agonist ; agonizes thyroid recep from salts of compounds of Formulae I -VIII are co - formu - tor ; inhibits gastrointestinal lipases or other digestive lated with an active that lowers circulating concentrations of 60 enzymes ; blocks absorption of dietary fat; or block de -novo triglycerides in a pharmaceutically acceptable formulation fatty acid synthesis . Additionally, such drugs to treat obesity that is administered to an overweight, obesity prone or obese may include, but are not limited to those that antagonize or subject to induce weight loss and treat obesity -associated agonize the function or expression of 11B hydroxysteroid co -morbidities . dehydrogenase type 1 ; acetyl- CoA carboxylase 1 ; ADAM The reduction of circulating triglycerides in an over - 65 12 , member 12 of a disintegrin and metalloprotease family weight, obese or obesity prone subject is achieved by the or its shorter secreted form ; agouti related protein ; angio administration of an effective amount of an oral dosage form tensinogen ; adipocyte lipid binding protein ; adipocyte fatty US 9 , 765 ,043 B2 83 84 acid binding protein ; adrenergic receptors ; acylation - stimu In another embodiment of the invention , KATP channel lating protein ; bombesin receptor subtype- 3 ; C /EBP , openers selected from salts of compounds of Formulae CCAAT/ enhancer binding protein ; cocaine - and amphet I- VIII are co - formulated with a drug to treat depression . amine- regulated transcript; cholecystokinin ; cholecystoki Such co - formulations can be formulated for oral adminis nin A receptor; CD36 , fatty acid translocase ; corticotropin - 5 tration once per 24 hours , for delayed release of the active releasing hormone ; diacylglycerol acyltransferases ; E2F until gastric transit is complete , and for sustained release of the active over a period of 2 to 24 hours . Such drugs to treat transcription factor; eukaryotic translation initiation factor depression include , but are not limited to : citalopram hyd 4e binding protein 1 ; estrogen receptor; fatty acid synthase ; robromide ( 10 to 80 mg) , escitalopram hydrobromide (5 to fibroblast growth factor; forkhead box C2 ; glucose- depen 10 40 mg) , fluvoxamine maleate (25 to 300 mg) , paroxetine dent insulinotropic peptide; GIP receptor; inhibitory G pro hydrochloride ( 12 . 5 to 75 mg ) , fluoxetine hydrochloride ( 30 tein alpha - subunit; glucagon - like peptide- 1 ; GLP - 1 recep to 100 mg ) , setraline hydrochloride ( 25 to 200 mg ) , ami tor; glycerol- 3 -phosphate acyltransferase ; glycerol triptyline hydrochloride ( 10 to 200 mg) , desipramine hydro 3 -phosphate dehydrogenase ; stimulatory G protein alpha chloride ( 10 to 300 mg ), nortriptyline hydrochloride ( 10 to subunit ; high -mobility group phosphoprotein isoformsoform I- C ; 15 150 mg) , duloxetine hydrochloride ( 20 to 210 mg) , venla hormone sensitive lipase ; inducible nitric oxide synthase ; faxine hydrochloride (37 . 5 to 150 mg) , phenelzine sulfate Janus kinases ; lipoprotein lipase ; melanocortin - 3 receptor; ( 10 to 30 mg) , bupropion hydrochloride (200 to 400 mg ), or melanocortin - 4 receptor ; mitochondrial GPAT; metallothio mirtazapine ( 7 . 5 to 90 mg ) . nein -I and - II ; nescient helix -loop -helix 2 ; neuropeptide Y ; In a further embodiment, the co - formulation can be for neuropeptide Y - 1 receptor ; neuropeptide Y- 2 receptor; neu - 20 mulated for oral administration twice per 24 hours , for ropeptide Y -4 receptor; neuropeptide Y -5 receptor; plasmi delayed release of the active until gastric transit is complete , nogen activator inhibitor - 1 ; PPARgamma co - activator 1 ; and for sustained release of the active for 2 to 12 hours. Such pro - opiomelanocortin ; peroxisome proliferator -activated drugs to treat depression include, but are not limited to : receptor ; protein tyrosine phosphatase 1B ; regulatory sub - citalopram hydrobromide ( 5 to 40 mg ) , escitalopram hyd unit IIbeta of protein kinase A ; retinoid X receptor ; steroido - 25 robromide ( 2 . 5 to 20 mg) , fluvoxamine maleate ( 12 . 5 to 150 genic factor 1 ; single -minded 1 ; sterol regulatory element mg) , paroxetine hydrochloride (6 .25 to 37 . 5 mg ), fluoxetine binding protein ; tyrosine hydroxylase ; thyroid hormone hydrochloride ( 15 to 50 mg) , setraline hydrochloride ( 12 . 5 receptor a2 ; uncoupling protein ; nerve growth factor to 100 mg ) , amitriptyline hydrochloride ( 5 to 100 mg) , induced protein ; leucine zipper transcription factor ; a- mel desipramine hydrochloride (5 to 150 mg) , nortriptyline anocyte - stimulating hormone . 30 hydrochloride ( 5 to 75 mg) , duloxetine hydrochloride ( 10 to In another embodiment of the invention , KATP channel 100 mg) , venlafaxine hydrochloride ( 18 to 75 mg) , phenel openers selected from salts of compounds of Formulae z ine sulfate (5 to 15 mg ) , bupropion hydrochloride ( 100 to I - VIII are co - formulated with a drug to treat diabetes . Such 200 mg ) , or mirtazapine ( 4 to 45 mg) . co - formulations can be formulated for oral administration In another embodiment of the invention , KATP channel once per 24 hours, for delayed release of the active until 35 openers selected from salts of compounds of Formulae gastric transit is complete , and for sustained release of the I - VIII are co - formulated with a drug to treat hypertension . active over a period of 2 to 24 hours . Such diabetes treatment Such co - formulations can be formulated for oral adminis drugs include , but are not limited to : acarbose (50 to 300 tration once per 24 hours , for delayed release of the active mg) , miglitol ( 25 to 300 mg ) , metformin hydrochloride (300 until gastric transit is complete , and for sustained release of to 2000 mg ), repaglinide ( 1 - 16 mg) , nateglinide (200 to 400 40 the active over a period of 2 to 24 hours. Such drugs to treat mg) , or rosiglitazone ( 5 to 50 mg ) . hypertension include , but are not limited to : enalapril In a further embodiment, the co - formulation can be for- maleate (2 . 5 to 40 mg ), captopril ( 2 .5 to 150 mg) , lisinopril mulated for oral administration twice per 24 hours , for ( 10 to 40 mg) , benzaepril hydrochloride (10 to 80 mg) , delayed release of the active until gastric transit is complete , quinapril hydrochloride (10 to 80 mg) , peridopril erbumine and for sustained release of the active over a period of 2 to 45 ( 4 to 8 mg) , ramipril ( 1 . 25 to 20 mg ), trandolapril ( 1 to 8 12 hours . Such drugs to treat diabetes include , but are not mg) , fosinopril sodium ( 10 to 80 mg) , moexipril hydrochlo limited to : acarbose ( 25 to 150 mg ) , miglitol ( 12 . 5 to 150 ride (5 to 20 mg ) , losartan potassium (25 to 200 mg ) , mg) , metformin hydrochloride ( 150 to 1000 mg) , repaglin - irbesartan (75 to 600 mg) , valsartan (40 to 600 mg ), can ide ( 0 . 5 to 8 mg) , nateglinide (100 to 200 mg) , or rosigli - desartan cilexetil (4 to 64 mg) , olmesartan medoxamil ( 5 to tazone (2 .5 to 25 mg) . 50 80 mg) , telmisartan ( 20 to 160 mg) , eprosartan mesylate ( 75 In another embodiment of the invention , KATP channel to 600 mg ) , atenolol ( 25 to 200 mg ), propranolol hydro openers selected from salts of compounds of Formulae chloride ( 10 to 180 mg) , metoprolol tartrate , succinate or I -VIII are co - formulated with a drug to treat elevated cho - fumarate (25 to 400 mg) , nadolol (20 to 160 mg) , betaxolol lesterol. Such co - formulations can be formulated for oral hydrochloride ( 10 to 40 mg ) , acebutolol hydrochloride ( 200 administration once per 24 hours , for delayed release of the 55 to 800 mg) , pindolol ( 5 to 20 mg) , bisoprolol fumarate ( 5 to active until gastric transit is complete , and for sustained 20 mg) , nifedipine (15 to 100 mg) , felodipine ( 2 . 5 to 20 mg) , release of the active over a period of 2 to 24 hours . Such amlodipine besylate ( 2 . 5 to 20 mg ) , nicardipine ( 10 to 40 drugs to treat elevated cholesterol include , but are not mg) , nisoldipine ( 10 to 80 mg) , terazosin hydrochloride ( 1 to limited to : pravastatin , simvastatin , atorvastatin , fluvastatin , 20 mg ) , doxaxosin mesylate ( 4 to 16 mg) , prazosin hydro rosuvastatin or lovastatin ( 10 to 80 mg) . 60 chloride (2 . 5 to 10 mg) , or alfuzosin hydrochloride (10 to 20 In a further embodiment, the co - formulation can be for - mg) . mulated for oral administration twice per 24 hours , for In a further embodiment, the co - formulation can be for delayed release of the active until gastric transit is complete , mulated for oral administration twice per 24 hours , for and for sustained release of the active over a period of 2 to delayed release of the active until gastric transit is complete , 12 hours . Such drugs to treat elevated cholesterol include , 65 and for sustained release of active over a period of 2 to 12 but are not limited to : pravastatin , simvastatin , atorvastatin , hours . Such drugs to treat hypertension include , but are not fluvastatin , rosuvastatin or lovastatin ( 5 to 40 mg ) . limited to : enalapril maleate ( 1 . 25 to 20 mg) , captopril ( 2 to US 9 , 765 ,043 B2 85 86 75 mg) , lisinopril ( 5 to 20 mg) , benzaepril hydrochloride ( 5 and for sustained release of the active over a period of 2 to to 40 mg) , quinapril hydrochloride (5 to 40 mg) , peridopril 12 hours . Such drugs to treat inflammation or pain include , erbumine ( 2 to 4 mg) , ramipril ( 1 to 10 mg) , trandolapril ( 1 but are not limited to : aspirin ( 100 to 650 mg) , tramadol to 4 mg) , fosinopril sodium ( 5 to 40 mg) , moexipril hydro - hydrochloride (12 to 75 mg) , gabapentin (50 to 400 mg) , chloride ( 2 . 5 to 10 mg) , losartan potassium ( 12 . 5 to 100 mg) , 5 acetaminophen ( 50 to 500 mg ) , carbamazepine ( 50 to 200 irbesartan (37 . 5 to 300 mg) , valsartan ( 20 to 300 mg) , mg) , ibuprofen (50 to 800 mg) , ketoprofen ( 6 to 100 mg) , candesartan cilexetil (2 to 32 mg ) , olmesartan medoxamil fenprofen sodium (50 to 300 mg) , flurbiprofen sodium or ( 2. 5 to 40 mg) , telmisartan ( 10 to 80 mg ), eprosartan flurbiprofen (25 to 100 mg) , or combinations of these with mesylate (37 . 5 to 300 mg) , atenolol ( 12 . 5 to 100 mg) , a steroid or aspirin . propranolol hydrochloride ( 5 to 90 mg) , metoprolol tartrate , 10 A method of inducing loss of greater than 25 % of initial succinate or fumarate ( 12 . 5 to 200 mg) , nadolol ( 10 to 80 body fat in an overweight or obese subject can be achieved mg) , betaxolol hydrochloride (5 to 20 mg) , acebutolol by the prolonged administration of an oral dosage form of a hydrochloride ( 100 to 400 mg) , pindolol ( 2. 5 to 10 mg ), KATP channel opener . selected from a salt of a compound of bisoprolol fumarate ( 2 . 5 to 10 mg) , nifedipine ( 7 . 5 to 50 Formulae I - VIII . mg) , felodipine ( 1 to 10 mg) , amlodipine besylate ( 1 to 10 15 A method of inducing loss of greater than 50 % of initial mg ), nicardipine ( 5 to 20 mg) , nisoldipine ( 5 to 40 mg) , body fat in an overweight or obese subject can be achieved terazosin hydrochloride ( 1 to 10 mg ) , doxaxosin mesylate ( 2 by the prolonged administration of an oral dosage form of a to 8 mg ), prazosin hydrochloride (1 to 5 mg) , or alfuzosin KATP channel opener selected from a salt of a compound of hydrochloride ( 5 to 10 mg) . Formulae I- VIII . In another embodiment of the invention , KATP channel 20 A method of inducing loss of greater than 75 % of initial openers selected from salts of compounds of Formulae body fat in an overweight or obese subject can be achieved I - VIII are co - formulated with a diuretic . Such co - formula - by the prolonged administration of an oral dosage form of a tions can be formulated for oral administration once per 24 KATP channel opener. selected from a salt of a compound of hours , for delayed release of the active until gastric transit is Formulae I - VIII . complete , and for sustained release of the active over a 25 A method of inducing preferential loss of visceral fat in an period of 2 to 24 hours. Such diuretics can include , but are overweight or obese subject can be achieved by the pro not limited to : amiloride hydrochloride ( 1 to 10 mg) , longed administration of an oral dosage form of a KATP spironolactone ( 10 to 100 mg ) , triamterene (25 to 200 mg) , channel opener. selected from a salt of a compound of bumetanide ( 0 . 5 to 4 mg ) , furosemide ( 10 to 160 mg ), Formulae I - VIII . ethacrynic acid or ethacrynate sodium ( 10 to 50 mg) , 30 A method of inducing loss of body fat and reductions in torsemide ( 5 to 100 mg) , chlorthalidone ( 10 to 200 mg ) , circulating triglycerides in an overweight or obese subject indapamide ( 1 to 5 mg ) , hydrochlorothiazide ( 10 to 100 mg) , can be achieved by the prolonged administration of an oral chlorothiazide (50 to 500 mg) , bendroflumethiazide ( 5 to 25 dosage form of a KATP channel opener. selected from a salt mg) , hydroflumethiazide ( 10 to 50 mg) ,mythyclothiazide ( 1 of a compound of Formulae I -VIII . to 5 mg ) , and polythiazide ( 1 to 10 mg ) . 35 In some embodiments , the invention provides a poly In a further embodiment, the co - formulation can be for morph of a salt, which salt includes diazoxide and a cation mulated for oral administration twice per 24 hours, for selected from the group consisting of an alkali metal and a delayed release of the active until gastric transit is complete , compound comprising a tertiary amine or quaternary ammo and for sustained release of the active over a period of 2 to n ium group . In some embodiments , the cation is choline . 12 hours . Such diuretics include , but are not limited to : 40 In some embodiments , the polymorph of diazoxide cho amiloride hydrochloride ( 0 . 5 to 5 mg) , spironolactone ( 5 to line salt is of Form A having characteristic peaks in the 50 mg) , triamterene (12 to 100 mg ) , bumetanide ( 0 . 2 to 2 XRPD pattern at values of two -theta (Cu K , 40 kV, 40 mA ) mg) , furosemide (5 to 80 mg) , ethacrynic acid or ethacrynate at approximately 9 . 8 , 10 .5 , 14 . 9 , 17. 8 , 17. 9 , 18 . 5 , 19. 5 , 22 . 1 , sodium ( 5 to 25 mg ), torsemide ( 2 to 50 mg) , chlorthalidone 22 . 6 , 26 . 2 , 29. 6 , and 31 . 2 degrees . (5 to 100 mg) , indapamide ( 0 . 5 to 2 . 5 mg ), hydrochlorothi - 45 In some embodiments , the polymorph of diazoxide cho azide ( 5 to 50 mg) , chlorothiazide ( 25 to 250 mg) , bendro - line salt is of Form B having characteristic peaks in the flumethiazide ( 2 to 12 . 5 mg ) , hydroflumethiazide ( 5 to 25 XRPD pattern at values of two - theta ( Cu K , 40 kV, 40 mA ) mg) ,mythyclothiazide (0 . 5 to 2 . 5 mg) , and polythiazide ( 0 . 5 at approximately 8 . 9 , 10 . 3 , 12. 0 , 18 . 3 , 20 .6 , 24. 1 , 24 . 5 , 26 . 3 , to 5 mg) . 27 . 1 , and 28 . 9 degrees. In another embodiment of the invention , KATP channel 50 In some embodiments , the polymorph of diazoxide cho openers selected from salts of compounds of Formulae line salt is of Form A having characteristic infrared absor I -VIII are co -formulated with a drug to treat inflammation or bances at 2926 , 2654 , 1592 , 1449 , and 1248 cm - 1 . pain . Such co -formulations can be formulated for oral In some embodiments , the polymorph of diazoxide cho administration once per 24 hours , for delayed release of the line salt is of Form B having characteristic infrared absor active until gastric transit is complete , and for sustained 55 bances at 3256 , 2174 , 2890 , 1605, 1463 , and 1235 cm - 1 . release of the active over a period of 2 to 24 hours . Such In some embodiments , the polymorph of diazoxide drugs to treat inflammation or pain include , but are not includes potassium as the cation . limited to : aspirin ( 100 to 1000 mg ) , tramadol hydrochloride In some embodiments , the polymorph of diazoxide potas ( 25 to 150 mg ) , gabapentin ( 100 to 800 mg ) , acetaminophen sium salt is of Form A having characteristic peaks in the ( 100 to 1000 mg) , carbamazepine ( 100 to 400 mg ), ibupro - 60 XRPD pattern at values of two - theta (Cu K , 40 kV, 40 mA ) fen ( 100 to 1600 mg) , ketoprofen ( 12 to 200 mg) , fenprofen at approximately 6 . 0 , 8 . 1 , 16 . 3 , 17 . 7 , 18 .6 , 19. 1 , 22. 9 , 23 . 3 , sodium ( 100 to 600 mg) , flurbiprofen sodium or flurbiprofen 23 . 7 , 24 . 7 , 25 . 4 , 26 . 1 , 28 . 2 , 29 .6 , and 30 . 2 degrees. (50 to 200 mg) , or combinations of these with a steroid or In some embodiments , the polymorph of diazoxide potas aspirin . sium salt is of Form B having characteristic peaks in the In a further embodiment, the co - formulation can be for - 65 XRPD pattern at values of two - theta ( Cu K , 40 kV, 40 mA ) mulated for oral administration twice per 24 hours , for at approximately 8 . 5 , 10 . 8 , 16 . 9 , 18 . 2 , 21 .6 , 25 . 5 , 26 . 1 , and delayed release of the active until gastric transit is complete , 28 .9 degrees.