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( 12 ) United States Patent 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
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