Methods for treating a subject with Prader-Willi syndrome or Smith-Magenis syndrome

Abstract

Methods for treating a subject with Prader-Willi syndrome (PWS) or Smith-Magenis syndrome (SMS) are provided. An effective amount of K ATP A method comprising administering to a subject a pharmaceutical formulation comprising a channel opener for at least 10 weeks. ATP The channel opener is diazoxide or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt is diazoxide choline. The diazoxide or a pharmaceutically acceptable salt thereof is orally administered. The pharmaceutical formulation includes at least one excipient that affects the release rate of diazoxide or a pharmaceutically acceptable salt thereof. The pharmaceutical formulation includes at least one excipient that delays the release of diazoxide or a pharmaceutically acceptable salt thereof.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to potassium ATP (K ATP ) pharmaceutical formulations of channel openers and their use for the treatment of various diseases and conditions such as Prader-Willi syndrome (PWS) and Smith-Magenis syndrome (SMS). [Background technology]

[0002] 2. Background of the Invention The following background of the invention is provided merely as an aid in the understanding of the invention and is not admitted to describing or constituting prior art to the invention.

[0003] ATP-sensitive potassium (K ATP ) channels play an important role in various tissues by coupling cellular metabolism to electrical activity. ATP The channel has been identified as an octameric complex of two unrelated proteins that assemble with a 4:4 stoichiometry. The first is the inwardly rectifying K + The first is the pore-forming subunit Kir6.x, which forms a channel, and the second is an ABC (ATP-binding cassette) transporter, also known as the sulfonylurea receptor (SURx) (Babenko, et al., Annu. Rev. Physiol., 60:667-687 (1998)). The Kir6.x pore-forming subunit is involved in the transport of many types of K ATP Common to the channels are two putative transmembrane domains (identified as TM1 and TM2) connected by a pore loop (H5). The subunits that comprise the SUR receptors contain multiple transmembrane domains and two nucleotide-binding folds.

[0004] Due to its tissue localization, K ATPChannels exist in different isoforms or subspecies that result from the assembly of SUR and Kir subunits in multiple combinations. The combination of SUR1 with the Kir6.2 subunit (SUR1 / Kir6.2) typically defines adipocyte and pancreatic B cell type K channels. ATP whereas the combinations of SUR2A / Kir6.2 and SUR2B / Kir6.2 or Kir6.1 typically form cardiac- and smooth muscle-type K channels, respectively. ATP channels (Babenko, et al., Annu. Rev. Physiol., 60:667-687 (1998)). There is also evidence that the channels may contain Kir2.x subunits. This class of potassium channels is inhibited by intracellular ATP and activated by intracellular nucleoside diphosphates. Such K ATP Channels link the metabolic state of the cell to the plasma membrane potential and thus play an important role in regulating cellular activity. In most excitable cells, K ATP The channels are closed under normal physiological conditions and open when tissue metabolism slows down (e.g., when the (ATP:ADP) ratio decreases). This promotes K+ efflux and cell hyperpolarization, thereby preventing the opening of voltage-operated Ca2+ channels (VOCs) (Prog Res Research, (2001) 31:77-80).

[0005] Potassium channel openers (PCOs or KCOs), also called channel activators or channel agonists, block the release of potassium from intracellular nucleotides into the K ATP Diazoxide is a structurally diverse group of compounds with no apparent common pharmacophore that correlates with their ability to antagonize the inhibition of the K channel in pancreatic β cells. ATP(See Trube, et al., Pfluegers Arch kEur J Physiol, 407, 493-99 (1986)). Pinacidil and cromakalim are PCOs that activate sarcolemmal potassium channels (See Escande, et al., Biochem Biophys Res Commun, 154, 620-625 (1988); Babenko, et al., J Biol Chem, 275(2), 717-720 (2000)). Responsiveness to diazoxide has been shown to reside in predicted transmembrane domains 6 to 11 (TMD6-11) and the 11th nucleotide-binding fold of the SUR1 subunit (NBF1).

[0006] Diazoxide, a non-diuretic benzothiadiazine derivative with the formula 7-chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide (empirical formula CHClNOS), is commercially available in three different formulations to treat two different disease indications: (1) hypertensive emergencies and (2) hyperinsulinemic hypoglycemic states. Hypertensive emergencies are treated with Hyperstat IV, an aqueous formulation of diazoxide for intravenous use, adjusted to pH 11.6 with sodium hydroxide. Hyperstat IV is administered into a peripheral vein as a bolus dose to treat malignant hypertension or sulfonylurea overdose. In this use, diazoxide acts to open potassium channels in vascular smooth muscle, stabilizing the membrane potential at resting levels and preventing vascular smooth muscle contraction.

[0007] Hyperinsulinemic hypoglycemic states are treated with Proglycem, an oral pharmaceutical form of diazoxide useful for administration to infants, children, and adults. It is available as a mint chocolate flavored oral suspension containing 7.25% alcohol, sorbitol, chocolate cream flavor, propylene glycol, magnesium aluminum silicate, sodium carboxymethylcellulose, mint flavor, sodium benzoate, methylparaben, hydrochloric acid to adjust pH, poloxamer 188, propylparaben, and water. Diazoxide is also available as capsules containing 50 mg or 100 mg of diazoxide with lactose and magnesium stearate.

[0008] Several experimental formulations of diazoxide have been tested in humans and animals, including an oral solution that has been tested in pharmacodynamic and pharmacokinetic studies, and a tablet formulation that is under development as an antihypertensive drug, but is not commercially available (see Calesnick, et al., J. Pharm. Sci. 54:1277-1280 (1965); Reddy, et al., AAPS Pharm Sci Tech 4(4):1-98,9 (2003); U.S. Patent No. 6,361,795).

[0009] Current oral formulations of diazoxide are labeled for dosing two or three times daily, with eight or twelve hour intervals. Most patients receiving diazoxide receive it three times daily. Commercially available and experimental formulations of diazoxide are characterized by rapid drug release after ingestion, with release complete in approximately two hours.

[0010] Current oral formulations of diazoxide in therapeutic use result in a variety of adverse side effects, including dyspepsia, nausea, diarrhea, fluid retention, edema, decreased excretion rates of sodium, chloride, and uric acid, hyperglycemia, vomiting, abdominal pain, ileus, tachycardia, palpitations, and headache (see current package insert for Proglycem). Oral treatment with diazoxide is used in individuals suffering from severe disease where failure to treat would result in severe morbidity and mortality. The adverse side effects of oral administration are tolerated because of the significant benefits of treatment. The adverse side effect profile of oral diazoxide limits the use of the drug in the treatment of obese patients to doses within the labeled range of 3-8 mg / kg per day.

[0011] The efficacy of diazoxide in animal models of diabetes and obesity (eg, obese and lean Zucker rats) has been reported. See, for example, Alemzadeh et al. (Endocrinology 133:705-712 (1993)), Alemzadeh et al. (Metabolism 45:334-341 (1996)), Alemzadeh et al. (Endocrinology 140:3197-3202 (1999)), Standridge et al. (FASEB J 14:455-460 (2000)), Alemzadeh et al. (Med Sci Monit 10(3):BR53-60 (2004)), Alemzadeh and Tushaus (Endocrinology 145(12):3476-3484 (2004)), Aizawa et al. (J of Pharma Exp Ther 275(1):194-199 (1995)), and Surwit et al. (Endocrinology 141:3630-3637 (2000).

[0012] The effects of diazoxide in obese or diabetic humans have been reported. For example, Wigand and Blackard (Diabetes 28(4):287-291 (1979); Evaluation of diazoxide on the insulin receptor), Ratzmann et al. (Int J Obesity 7(5):453-458 (1983); Glucose tolerance and insulin sensitivity in moderately obese patients), Marugo et al. (Boll Spec It Biol Sper 53:1860-1866 (1977); Moderate-dose diazoxide treatment for weight loss in obese patients), Alemzadeh et al. (J Clin Endocr Metab 83:1911-1915 (1998); Low-dose diazoxide treatment for weight loss in obese hyperinsulinemic patients), Guldstrand et al. (Diabetes and Metabolism 28:448-456 (2002); Diazoxide in obese type II diabetic patients), Ortqvist et al. (Diabetes Care 27(9):2191-2197 (2004); Beta-cell function measured by circulating C-peptide in children at the clinical onset of type 1 diabetes, Bjork et al. (Diabetes Care 21(3):427-430 (1998); Effect of diazoxide on residual insulin secretion in adult type 1 diabetic patients), and Qvigstad et al. (Diabetic Medicine 21:73-76 (2004)).

[0013] No. 5,284,845 describes a method for normalizing blood glucose and insulin levels in an individual who exhibits normal fasting blood glucose and insulin levels and who, in an oral glucose tolerance test, exhibits elevated blood glucose levels and at least one insulin level abnormality selected from the group consisting of a delayed insulin peak, an increased insulin peak, and a secondary elevated insulin peak. According to this reference, the method comprises administering diazoxide in an amount of about 0.4 to about 0.8 mg / kg body weight before each meal in an amount effective to normalize blood glucose and insulin levels.

[0014] U.S. Patent No. 6,197,765 describes the administration of diazoxide as a treatment for Syndrome X and the resulting complications including hyperlipidemia, hypertension, central obesity, hyperinsulinemia, and impaired glucose tolerance. According to this reference, diazoxide interferes with pancreatic islet function by eliminating endogenous insulin secretion, resulting in a state of insulin deficiency and hyperglycemia equivalent to that of diabetic patients who rely on exogenous insulin administration to normalize blood glucose levels.

[0015] US Pat. No. 2,986,573 describes diazoxide and alkali metal salts for the treatment of hypertension.

[0016] US Patent No. 5,629,045 describes diazoxide for local intraocular administration.

[0017] WO98 / 10786 describes the use of diazoxide in the treatment of Syndrome X, including the associated obesity.

[0018] US Patent Application Publication No. 2003 / 0035106 describes diazoxide-containing compounds for reducing consumption of fat-containing foods.

[0019] US Patent Application Publication No. 2004 / 0204472 describes the use of Cox-2 inhibitors and diazoxide in the treatment of obesity.

[0020] US Patent Application Publication No. 2002 / 0035106 discloses a method for reducing the consumption of fat-containing foods, comprising administering diazoxide and a metal salt thereof. ATP The use of channel openers is described. Summary of the Invention

[0021] In this specification, K ATPPharmaceutical formulations of channel openers and their use, optionally in combination with growth hormone, for the treatment of various diseases and conditions, including Prader-Willi syndrome (PWS), Smith-Magenis syndrome (SMS), and the like, are provided. Such formulations are characterized as being bioavailable. K as used herein means ATP A channel opener has any one or more of the following properties: (1) opening the SUR1 / Kir6.2 potassium channel; (2) opening the K ATP (3) inhibiting glucose-induced release of insulin following administration of the compound in vivo. ATP Channel openers have all three properties. ATP Channel openers. K as defined above ATP Channel openers preferably have the structure of the compounds of Formulas I-VII as set forth below.

[0022] According to one aspect of the invention, one or more K (optionally in combination with growth hormone) ATP It has been discovered that channel openers are effective in treating subjects with Prader-Willi syndrome (PWS), Smith-Magenis syndrome (SMS), and the like, and are particularly effective in increasing lean body mass in such subjects. Thus, in one aspect of the invention, there is provided a method of increasing lean body mass in a subject with Prader-Willi syndrome (PWS), Smith-Magenis syndrome (SMS), and the like, comprising administering an effective amount of K (optionally in combination with growth hormone) to said subject. ATP Methods are provided which include administering a channel opener to the subject for at least four weeks.

[0023] In some embodiments, the subject's lean body mass is increased by at least 1%. In some embodiments, the subject's lean body mass is increased by at least 2%. In some embodiments, the subject's lean body mass is increased by at least 3%. In some embodiments, the subject's lean body mass is increased by at least 4%. In some embodiments, the subject's lean body mass is increased by at least 5%.

[0024] In addition to increasing the subject's lean body mass, in some embodiments, the methods of the present invention also reduce overeating in the subject. In some embodiments, the subject's overeating is reduced by at least 10%. In some embodiments, the subject's overeating is reduced by at least 20%. In some embodiments, the subject's overeating is reduced by at least 30%.

[0025] In addition to increasing a subject's lean body mass, in some embodiments, the methods of the present invention also reduce body fat in a subject. In some embodiments, the subject's body fat is reduced by at least 1%. In some embodiments, the subject's body fat is reduced by at least 3%. In some embodiments, the subject's body fat is reduced by at least 5%.

[0026] In another aspect, the present invention provides a method for increasing lean body mass in a subject having Prader-Willi syndrome (PWS), Smith-Magenis syndrome (SMS), or the like, wherein said subject has already been treated by administration of growth hormone to said subject, said method comprising administering, in addition to said growth hormone, an effective amount of K ATP co-administering a channel opener to said subject.

[0027] In yet another aspect, the present invention provides a method for increasing lean body mass in a subject having Prader-Willi syndrome (PWS), Smith-Magenis syndrome (SMS), or the like, comprising administering to the subject an effective amount of K ATP The method further comprises administering a channel opening drug to the subject K ATPMethods are provided which include co-administering to said subject, in addition to the channel opener, an effective amount of growth hormone.

[0028] K defined by formula I ATP Channel openers include: TIFF0007645913000001.tif37128, and all bioequivalents thereof, including salts, prodrugs, and isomers thereof, During the ceremony, R 1a and R 1b is, when present, independently selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, amino, and substituted amino; R 2a and R 2b is, if present, independently selected from the group consisting of hydrogen and lower alkyl; X is a 1, 2, or 3 atom chain, each atom being independently selected from carbon, sulfur, or nitrogen, each atom being optionally substituted with halogen, hydroxyl, lower alkyl, substituted lower alkyl, lower alkoxy, cycloalkyl, substituted cycloalkyl, substituted lower alkoxy, amino, or substituted amino; Rings A and B are each independently saturated, monounsaturated, polyunsaturated, or aromatic.

[0029] In specific embodiments, the compounds of formula I may contain a double bond between positions 1 and 2 or positions 2 and 3 of ring A. When a double bond is present between positions 1 and 2 of ring A, R 2a does not exist, and R 1a and R 1b If a double bond is present between positions 2 and 3 of ring A, then R 2b does not exist, and R 1a and R 1b In a preferred embodiment, one of R 1a and R 1b is not amino. In another preferred embodiment, Ring B does not contain any heteroatoms.

[0030] K defined by formula II, which is a subgenus of formula I ATP Channel openers include: TIFF0007645913000002.tif27128, and all bioequivalents thereof, including salts, prodrugs, and isomers thereof, During the ceremony, R 1 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, amino, and substituted amino; R 2a is selected from the group consisting of hydrogen and lower alkyl; X is a 1, 2, or 3 atom chain, each atom being independently selected from carbon, sulfur, or nitrogen, each atom being optionally substituted with halogen, hydroxyl, lower alkyl, substituted lower alkyl, lower alkoxy, cycloalkyl, substituted cycloalkyl, substituted lower alkoxy, amino, or substituted amino; Ring B is saturated, monounsaturated, polyunsaturated or aromatic.

[0031] In specific embodiments of formula II, X is C(R a )C(R b ) and R a and R b is independently selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkoxy, substituted lower alkoxy, amino, sulfonylamino, aminosulfonyl, sulfonyl, and the like. a and R b is independently selected from the group consisting of hydroxyl, substituted oxy, substituted thiol, alkylthio, substituted alkylthio, sulfinyl, sulfonyl, substituted sulfinyl, substituted sulfonyl, substituted sulfonylamino, substituted amino, substituted amine, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, and the like. 1 is not amino. In another preferred embodiment, Ring B does not contain any heteroatoms.

[0032] K defined by formula III, which is a subgenus of formula I ATP Channel openers include: TIFF0007645913000003.tif31128, and all bioequivalents thereof, including salts, prodrugs, and isomers thereof, During the ceremony, R 1 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, amino, and substituted amino; R 2b is selected from the group consisting of hydrogen and lower alkyl; X is a 1, 2, or 3 atom chain, each atom being independently selected from carbon, sulfur, or nitrogen, each atom being optionally substituted with halogen, hydroxyl, lower alkyl, substituted lower alkyl, lower alkoxy, cycloalkyl, substituted cycloalkyl, substituted lower alkoxy, amino, or substituted amino; Ring B is saturated, monounsaturated, polyunsaturated or aromatic.

[0033] In specific embodiments of formula III, X is C(R a )C(R b ) and R a and R b is independently selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkoxy, substituted lower alkoxy, amino, sulfonylamino, aminosulfonyl, sulfonyl, and the like. a and R b is independently selected from the group consisting of hydroxyl, substituted oxy, substituted thiol, alkylthio, substituted alkylthio, sulfinyl, sulfonyl, substituted sulfinyl, substituted sulfonyl, substituted sulfonylamino, substituted amino, substituted amine, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, and the like. 1 is not amino. In another preferred embodiment, Ring B does not contain any heteroatoms.

[0034] K defined by formula IV, which is a subgenus of formula I ATP Channel openers include: TIFF0007645913000004.tif27128, and all bioequivalents thereof, including salts, prodrugs, and isomers thereof, During the ceremony, R 1 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, amino, and substituted lower amino; R 2a is selected from the group consisting of hydrogen, lower alkyl, and substituted lower alkyl; R 3 is selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, amino, and substituted amino; R 4 is selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, amino, and substituted amino.

[0035] In a specific embodiment of formula IV, R 1 is lower alkyl (preferably ethyl or methyl); R 2a is hydrogen; R 3 and R 4 are each independently a halogen.

[0036] In a preferred embodiment of formula IV, R 1 is not an amino.

[0037] In another embodiment of formula IV, R 1 is methyl; R 2a is hydrogen; R 3 is hydrogen, halogen, lower alkyl, substituted lower alkyl, amino, substituted amino, cycloalkyl, and substituted cycloalkyl; R 4 is chlorine.

[0038] K defined by formula V, which is a subgenus of formula I ATP Channel openers include: TIFF0007645913000005.tif29128, and all bioequivalents thereof, including salts, prodrugs, and isomers thereof, During the ceremony, R 1 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, amino, and substituted lower amino; R 2b is selected from the group consisting of hydrogen, lower alkyl, and substituted lower alkyl; R 3 is selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, amino, and substituted amino; R 4 is selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, amino, and substituted amino.

[0039] In a specific embodiment of formula V, R 1 is lower alkyl (preferably ethyl or methyl); R 2b is hydrogen; R 3 and R 4 are each independently a halogen.

[0040] In a preferred embodiment of formula V, R 1 is not an amino.

[0041] In another embodiment of formula V, R 1 is methyl; R 2b is hydrogen; R 3 is selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, amino, substituted amino, cycloalkyl, and substituted cycloalkyl; R 4 is chlorine.

[0042] K defined by formula VI ATP Channel openers include: TIFF0007645913000006.tif25128, and all bioequivalents thereof, including salts, prodrugs, and isomers thereof, During the ceremony, R 1 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, amino, and substituted lower amino, or R 1 is R 5 Or R 6 may form additional rings in conjunction with R 2a is selected from the group consisting of hydrogen, lower alkyl, and substituted lower alkyl; R 5 is selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, substituted lower alkyl, amino, substituted amino, sulfonyl, aminosulfonyl, and sulfonylamino, or R 5 is R 1 Or R 6 may form additional rings in conjunction with R 6 is selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, amino, substituted amino, sulfonyl, aminosulfonyl, and sulfonylamino, or R 6 is R 1 Or R 5 may form additional rings in conjunction with R 1 and R 5 , or R 1 and R 6 , or R 5 and R 6 the ring formed by the linkage of is saturated, monounsaturated, polyunsaturated or aromatic; R 1 and R 5 , or R 1 and R 6 , or R 5 and R 6 The ring formed by the combination of may be substituted with halogen, hydroxyl, lower alkyl, substituted lower alkyl, amino, substituted amino, sulfonyl, aminosulfonyl, or sulfonylamino.

[0043] In a preferred embodiment, R 1is not an amino substituent.

[0044] In another embodiment of Formula VI, R 5 and R 6 are combined to form a six-membered ring. 5 and R 6 are combined to form a six-membered ring in which at least one nitrogen is present. 5 and R 6 The ring formed by does not contain any heteroatoms.

[0045] K defined by formula VII ATP Channel openers include: TIFF0007645913000007.tif31128, and all bioequivalents thereof, including salts, prodrugs, and isomers thereof, During the ceremony, R 1 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, amino, and substituted lower amino, or R 1 is R 5 Or R 6 may form additional rings in conjunction with R 2b is selected from the group consisting of hydrogen, lower alkyl, and substituted lower alkyl; R 5 is selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, substituted lower alkyl, amino, substituted amino, sulfonyl, aminosulfonyl, and sulfonylamino, or R 5 is R 1 Or R 6 may form additional rings in conjunction with R 6 is selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, amino, substituted amino, sulfonyl, aminosulfonyl, and sulfonylamino, or R 6 is R 1 Or R 5 may form additional rings in conjunction with R 1 and R 5 , or R 1 and R 6 , or R 5 and R 6 the ring formed by the linkage of is saturated, monounsaturated, polyunsaturated or aromatic; R 1 and R 5 , or R 1 and R 6 , or R 5 and R 6 The ring formed by may be substituted with halogen, hydroxyl, lower alkyl, substituted lower alkyl, amino, substituted amino, sulfonyl, aminosulfonyl, or sulfonylamino.

[0046] In a preferred embodiment, R 1 is not an amino substituent.

[0047] In another embodiment of Formula VI, R 5 and R 6 are combined to form a six-membered ring. 5 and R 6 are combined to form a six-membered ring in which at least one nitrogen is present. 5 and R 6 The ring formed by does not contain any heteroatoms.

[0048] Unless otherwise specified, in this application ATP Reference to a channel opener is to a K channel opener having one or more, preferably all three, of the following properties: ATP Channel openers should be understood as referring to: (1) SUR1 / Kir6.2 potassium channel openers; (2) K ATP (3) bind to the SUR1 subunit of the channel; and (4) inhibit glucose-induced release of insulin following administration of the compound in vivo. ATP The channel opener is preferably of formula I-VII, or more preferably, 1is not amino and ring B or its equivalent does not contain any heteroatoms, or more preferably, any of the compounds of formula I-VII, or, more preferably, any of the compounds of formula II or III, or, more preferably, any of the compounds of formula I-VII, 1 The compound has the structure of any of the compounds of formula II or III, where R is not amino and ring B or its equivalent does not contain any heteroatoms, or, more preferably, the structure is diazoxide. Structural variants or biological equivalents of any of the compounds of formula I-VII, such as derivatives, salts, prodrugs, or isomers, are also contemplated. Other Ks contemplated for use herein are ATP Channel openers include BPDZ62, BPDZ73, NN414, BPDZ154.

[0049] K ATP In vitro analysis of glucose-induced release of insulin via channel openers can be determined using rat islets as provided by De Tullio, et al., J. Med. Chem., 46:3342-3353 (2003), or human islets as provided by Bjorklund, et al., Diabetes, 49:1840-1848 (2000).

[0050] In this specification, K ATP Formulations, such as controlled release pharmaceutical formulations, of channel openers, and bioequivalents thereof, are provided. In one embodiment, the controlled release formulations are formulated for oral administration. Such formulations may contain between 10 and 100 mg, between 25 and 100 mg, between 100 and 200 mg, between 200 and 300 mg, between 300 and 500 mg, between 500 and 2000 mg of K in a single dose. ATP In certain embodiments, the formulation contains a channel opener. ATP The dose of the channel opener may be determined based on the weight of the patient to which it is administered, i.e., the formulation may contain between 0.1 and 20 mg K per kg of patient weight in a single administered dose. ATP Channel openers, or between 0.1 and 0.5 mg K per kg of patient body weight ATPchannel opener; or 0.5–1 mg K per kg of patient body weight ATP channel openers; or between 1 and 2 mg K per kg of patient body weight ATP Channel openers, or between 2 and 5 mg of K per kg of patient body weight ATP Channel openers, or between 5 and 10 mg of K per kg of patient body weight ATP Channel openers, or between 10 and 15 mg of K per kg of patient weight ATP Channel openers, or between 15 and 20 mg of K per kg of patient weight ATP It may also contain a channel opener.

[0051] In the present specification, K obtained by at least one of the following: ATP A controlled release pharmaceutical formulation containing a channel opener is provided, which comprises: (a) particle size reduction, including milling, spray drying, or other micronization techniques; (b) K ATP (c) the use of pharmaceutical salts of channel openers; (d) the use of inclusion complexes, such as cyclodextrins; (e) the use of solubilizers, including low viscosity hypromellose, low viscosity methylcellulose or similarly functioning excipients or combinations thereof; ATP (f) Compaction of channel opener, K before formulation ATP Association of channel openers with salts, (g) K ATP (h) the use of solid dispersions of channel openers; (i) the addition of one or more surfactants to the formulation; (j) the use of nanoparticles; or (k) a combination of these approaches.

[0052] Furthermore, as used herein, the K ATP K containing at least one component that substantially inhibits the release of a channel activator. ATPProvided is a controlled release pharmaceutical formulation that contains a channel opener.As used herein, "substantially inhibit" means that the drug from the formulation during gastric passage is released less than 15%, more preferably at least less than 10%, or more preferably at least less than 5%.Release can be measured by standard USP-based in vitro gastric dissolution assay in a calibrated dissolution apparatus (see, for example, United States Pharmacopeia, Chapter 711 (2005)).

[0053] In addition, the K from the formulation was not released until after it had passed through the stomach. ATP K containing at least one component that substantially inhibits the release of a channel opener. ATP Oral pharmaceutical formulations of channel openers are provided, where substantial inhibition of drug release during gastric transit is achieved by inclusion in the formulation of a component selected from the group consisting of: (a) a pH-sensitive polymer or copolymer applied as a compression coating on a tablet, (b) a pH-sensitive polymer or copolymer applied as a thin film on a tablet, (c) a pH-sensitive polymer or copolymer applied as a thin film on an encapsulation system, (d) a pH-sensitive polymer or copolymer applied to an encapsulated microparticle, (e) a water-insoluble polymer or copolymer applied as a compression coating on a tablet, (f) a water-insoluble polymer or copolymer applied as a thin film on a tablet, (g) a water-insoluble polymer applied as a thin film on an encapsulation system, (h) a water-insoluble polymer applied to a microparticle, (i) incorporation of the formulation into an osmotic pump system, (j) use of a system controlled by an ion exchange resin, and (k) a combination of these approaches, where the pH-sensitive polymer or copolymer is resistant to degradation under acidic conditions.

[0054] In addition, in this specification, K ATP A controlled release pharmaceutical formulation of a channel opener is provided, the formulation providing a controlled release of K channel opener over a period of 2 to 4 hours after administration, or over a period of 4 to 8 hours after administration, or over a period of 8 to more than 24 hours after administration. ATPThe formulations contain at least one component that contributes to the sustained release of the channel opener. These formulations are characterized by having one of the following components: (a) a pH-sensitive polymer coating, (b) a hydrogel coating, (c) a membrane coating that controls the rate of diffusion of the drug from the coated matrix, (d) an erodible matrix that controls the rate of drug release, (e) polymer-coated pellets, granules or microparticles of the drug that can be further encapsulated or compressed into a tablet, (f) an osmotic pump system containing the drug, (g) a compression-coated tablet form of the drug, or (h) a combination of these approaches.

[0055] As used herein, an erodible matrix is ​​the core of a tablet formulation that, upon exposure to an aqueous environment, initiates a process of disintegration that facilitates the release of the drug from the matrix. The release rate of the drug from the tablet is controlled by both the solubility of the drug and the disintegration rate of the matrix.

[0056] The above-mentioned formulations may further comprise one or more additional pharmacologic active agents (KA) useful in the treatment of a condition selected from the group consisting of obesity, pre-diabetes, diabetes, hypertension, depression, elevated cholesterol, fluid retention, other obesity-related comorbidities, ischemia and reperfusion injury, epilepsy, schizophrenia, mania, or other psychoses. ATP The therapeutic agent may further comprise a channel opener (other than the channel opener).

[0057] Furthermore, K ATP Controlled release pharmaceutical formulations of channel openers are provided, which upon administration to an obese, overweight, or obesity-prone individual result in at least one of the following: (a) inhibition of fasting insulin secretion, (b) inhibition of stimulated insulin secretion, (c) increased energy expenditure, (d) increased fat beta-oxidation, (e) inhibition of overeating for about 24 hours, or (f) an increase in lean body mass.

[0058] Furthermore, K ATPControlled release pharmaceutical formulations of channel openers are provided which, upon administration to an obese, overweight, or obesity-prone individual, result in at least one of the following: (a) inhibition of fasting insulin secretion, (b) inhibition of glucose-stimulated insulin secretion, (c) increased energy expenditure, (d) increased fat beta-oxidation, (e) inhibition of overeating for approximately 18 hours, or (f) an increase in lean body mass.

[0059] Furthermore, K ATP Controlled release pharmaceutical formulations of channel openers are provided, which upon administration to an obese, overweight, or obesity-prone individual, result in at least one of the following: (a) inhibition of fasting insulin secretion, (b) inhibition of glucose-stimulated insulin secretion, (c) increased energy expenditure, (d) increased fat beta-oxidation, (e) inhibition of overeating for about 24 hours, or (f) an increase in lean body mass.

[0060] Furthermore, K ATP Controlled release pharmaceutical formulations of channel openers are provided, which upon administration to an obese, overweight, or obesity-prone individual, result in at least one of the following: (a) inhibition of fasting insulin secretion, (b) inhibition of glucose-stimulated insulin secretion, (c) increased energy expenditure, (d) increased fat beta-oxidation, (e) inhibition of overeating for about 18 hours, or (f) an increase in lean body mass.

[0061] Provided herein is a method for treating hypoglycemia, comprising administering K ATP Methods are provided that include orally administering a controlled release formulation of a channel opener.

[0062] Further provided herein is a method for treating obesity-related comorbidities in an obese, overweight, or obesity-prone individual, comprising administering a therapeutically effective amount of a solid oral dosage form of K, optionally in combination with growth hormone. ATP Channel openers, or K ATP Methods are provided which include administering a controlled release pharmaceutical formulation of a channel opener. In preferred embodiments, administration is no more than twice per 24 hours, or once per 24 hours.

[0063] Further provided herein is a method for achieving weight loss in an obese, overweight, or obesity-prone individual, comprising administering a therapeutically effective amount of a solid oral dosage form of K, optionally in combination with growth hormone. ATP Channel openers, or K ATP Methods are provided which include administering a controlled release pharmaceutical formulation of a channel opener. In preferred embodiments, administration is no more than twice per 24 hours, or once per 24 hours. The daily dosage is preferably between 50 mg and 180 mg. In certain embodiments, the obese individual is less than 30 kg / m at the start of the method. 2 or 35 kg / m 2 or more than 40 kg / m 2 or more than 50 kg / m 2 or 60 kg / m 2 have a body mass index greater than

[0064] Also provided is a method of maintaining weight loss in an obese, overweight, or obesity-prone individual, comprising administering a therapeutically effective amount of a solid oral dosage form of K, optionally in combination with growth hormone. ATP Channel openers, or K ATP Methods are provided, comprising administering a controlled release pharmaceutical formulation of a channel opener.In obese individuals, once some weight loss occurs, it is preferred to maintain weight, as weight regain is another possibility.In preferred embodiments, administration is no more than twice per 24 hours, or once per 24 hours.

[0065] Further provided is a method of increasing energy expenditure in an overweight, obese, or obesity-prone individual, comprising administering an effective amount of a solid oral dosage form of K ATP Channel openers, or K ATP Methods are provided that include administering a controlled release pharmaceutical formulation of a channel opener. In preferred embodiments, administration is no more than twice per 24 hours, or once per 24 hours. In certain embodiments, the individual is below 20 kg / m at the start of the method. 2or 25 kg / m 2 or 30 kg / m 2 or 35 kg / m 2 or more than 40 kg / m 2 or more than 50 kg / m 2 or 60 kg / m 2 have a body mass index greater than

[0066] Further provided is a method of increasing fat beta-oxidation in an overweight, obese, or obesity-prone individual, comprising administering an effective amount of a solid oral dosage form of K ATP Channel openers, or K ATP Methods are provided that include administering a controlled release pharmaceutical formulation of a channel opener. In preferred embodiments, administration is no more than twice per 24 hours, or once per 24 hours. In certain embodiments, the individual is below 20 kg / m at the start of the method. 2 or 25 kg / m 2 or 30 kg / m 2 or 35 kg / m 2 or more than 40 kg / m 2 or more than 50 kg / m 2 or 60 kg / m 2 have a body mass index greater than

[0067] Further provided is a method for reducing visceral fat in an overweight, obese, or obesity-prone individual, comprising administering to the patient an effective amount of a solid oral dosage form of K, optionally in combination with growth hormone. ATP Channel openers, or K ATP Methods are provided which include administering a controlled release pharmaceutical formulation of a channel opener. In preferred embodiments, administration is no more than twice per 24 hours, or once per 24 hours.

[0068] Further provided is a method for delaying or preventing the transition to diabetes in a prediabetic individual, comprising administering an effective amount of K ATPChannel openers or K ATP Methods are provided which include administering a controlled release pharmaceutical formulation of a channel opener. In preferred embodiments, administration is no more than twice per 24 hours, or once per 24 hours.

[0069] Further provided is a method of restoring normal glucose tolerance in a prediabetic individual, comprising administering an effective amount of K ATP Channel openers or K ATP Methods are provided which include administering a controlled release pharmaceutical formulation of a channel opener. In preferred embodiments, administration is no more than twice per 24 hours, or once per 24 hours.

[0070] Further provided is a method of restoring normal glucose tolerance in a diabetic individual, comprising administering an effective amount of K ATP Channel openers or K ATP Methods are provided which include administering a controlled release pharmaceutical formulation of a channel opener. In preferred embodiments, administration is no more than twice per 24 hours, or once per 24 hours.

[0071] Further provided is a method for delaying or preventing the progression of diabetes in an individual, comprising administering an effective amount of K ATP Channel openers or K ATP Methods are provided which include administering a controlled release pharmaceutical formulation of a channel opener. In preferred embodiments, administration is no more than twice per 24 hours, or once per 24 hours.

[0072] Also provided is a method for preventing or treating weight gain, impaired glucose tolerance, or dyslipidemia associated with the use of antipsychotics to treat a patient, comprising administering to the patient an effective amount of K, optionally in combination with growth hormone. ATP Channel openers or K ATP Methods are provided that include the co-administration of a controlled release pharmaceutical formulation of a channel opener. In preferred embodiments, administration is no more than twice per 24 hours, or once per 24 hours.

[0073] Further provided is a method of increasing lean body mass in a patient with Prader-Willi syndrome, Smith-Magenis syndrome, Frohlich syndrome, Cohen syndrome, Summit syndrome, Alström syndrome, Borjeson syndrome, or Bardet-Biedl syndrome, comprising administering an effective amount of K (optionally in combination with growth hormone) to said patient. ATP Channel openers or K (optionally combined with growth hormone) ATP Methods are provided that include administration of a controlled release pharmaceutical formulation of a channel opener. In preferred embodiments, administration is no more than twice per 24 hours, or once per 24 hours.

[0074] Further provided is a method for treating obesity or elevated triglycerides in a patient suffering from hyperlipoproteinemia Type I, II, III, or IV, comprising administering an effective amount of K ATP Channel openers or K ATP Methods are provided which include administering a controlled release pharmaceutical formulation of a channel opener. In preferred embodiments, administration is no more than twice per 24 hours, or once per 24 hours.

[0075] Also, the effect of K in treating a disease of interest is achieved by any of the following: ATP Methods for reducing the incidence of side effects from administration of a channel opener are provided: (a) reducing the incidence of adverse side effects associated with peak drug levels following administration of C compared to current Proglycem oral suspension or capsule products. max(b) use of a dosage form that delays release until gastric transit is complete to reduce the incidence of adverse side effects associated with drug release in the stomach; (c) initiating dosing at a sub-therapeutic level and increasing the dose daily until a therapeutic dose is reached, with the number of steps being 2 to 10 to reduce the incidence of transient adverse side effects at the start of treatment; (d) use of the lowest dose effective to achieve the desired therapeutic effect to reduce the incidence of adverse side effects that are dose-dependent; or (e) optimizing the timing of administration of the dose within the day and with respect to meals.

[0076] Further provided herein is a method for preventing weight gain, dyslipidemia, or impaired glucose tolerance in a subject being treated with an antipsychotic, comprising administering to a subject, optionally in combination with growth hormone, K ATP Methods are provided that include administering a pharmaceutical formulation of a channel opener.

[0077] Further provided herein is a method of treating weight gain, dyslipidemia, or impaired glucose tolerance in a subject being treated with an antipsychotic, optionally in combination with growth hormone, comprising administering to the subject a dose of K ATP Methods are provided that include administering a pharmaceutical formulation of a channel opener.

[0078] Also disclosed is a method of treating disorders characterized by obesity, hyperphagia, dyslipidemia, or reduced energy expenditure, including (a) Prader-Willi syndrome, (b) Frohlich syndrome, (c) Cohen syndrome, (d) Summit syndrome, (e) Alström syndrome, (f) Borjesen syndrome, (g) Bardet-Biedl syndrome, (h) hyperlipoproteinemia types I, II, III, and IV, or (i) Smith-Magenis syndrome (SMS), comprising administering to the patient a K ATP Methods are provided that include administering a pharmaceutical formulation of a channel opener.

[0079] Furthermore, K ATP K further comprising a pharma- ceutical active agent other than a channel opener. ATPPharmaceutical formulations of channel openers are provided in which the other pharma- ceutical active agent is an agent useful for the treatment of a condition selected from the group consisting of obesity, pre-diabetes, diabetes, hypertension, depression, elevated cholesterol, fluid retention or other obesity-related comorbidities, ischemic and reperfusion injury, epilepsy, schizophrenia, mania, and other psychotic conditions.

[0080] The K described herein ATP Formulations containing channel openers offer improved compliance, efficacy and safety, as well as co-formulation with other drugs. ATP Included are combination formulations of channel openers with one or more additional pharmacoactive agents having complementary or similar activities or targets. ATP Other pharmacoactive agents that can be combined with the channel opener include, but are not limited to, sibutramine, orlistat, phentermine, rimonabant, diuretics, antiepileptics, or other pharmacoactive agents whose therapeutic uses include weight loss. In obese individuals, once some weight loss has occurred, it is preferable to maintain weight, as another possibility is weight regain. K is used to treat type II diabetes or prediabetes. ATP Other pharmacologic active agents that can be combined with the channel opener include acarbose, miglitol, metformin, repaglinide, nateglinide, rosiglitizone, proglitizone, ramipril, metaglidasen, or any other pharmacologic active agent that improves insulin sensitivity or glucose utilization or glycemic control that is not an enhanced insulin secretion mode of action. ATPOther pharma- ceutical active agents that may be combined with the channel openers include drug actives used to lower cholesterol, drug actives used to lower blood pressure, anti-inflammatory drugs that are not cox-2 inhibitors, drugs that are antidepressants, drugs used to treat urinary incontinence, or other drugs that are routinely used to treat disease conditions whose incidence is elevated in overweight or obese patients compared to normal weight individuals, including, but not limited to, drugs to treat atherosclerosis, osteoarthritis, herniated discs, degeneration of the knee and hip, breast cancer, endometrial cancer, cervical cancer, colon cancer, leukemia and prostate cancer, hyperlipidemia, asthma / reactive airway disease, gallstones, GERD, obstructive sleep apnea, obesity hypoventilation syndrome, recurrent abdominal wall hernias, menstrual irregularities, infertility, and the like.

[0081] In the context of this specification, the term "therapeutically effective" or "effective amount" indicates that a material, or amount of a material, is effective to prevent, alleviate or ameliorate one or more symptoms of a disease or medical condition and / or prolong the survival of the subject being treated.

[0082] The term "pharmaceutical acceptable" indicates that the specified material does not possess properties that would prevent a reasonably prudent physician from administering the material to a patient, having regard to the disease or condition being treated and the respective route of administration. For example, such materials are generally required to be essentially sterile, e.g., for injectable formulations.

[0083] As used herein, the term "composition" refers to a formulation suitable for administration to an intended animal subject for therapeutic purposes, with exemplary formulations containing at least one pharma- ceutically active compound and at least one pharma- ceutically acceptable carrier or excipient. Other terms used herein are defined below.

[0084] Adipocyte: Animal connective tissue cell specialized for the synthesis and storage of fat.

[0085] Agonist: A chemical compound that has affinity for and stimulates physiological activity at a cellular receptor that is normally stimulated by a naturally occurring substance that elicits a biochemical response. An agonist of a receptor can also be thought of as an activator of the receptor.

[0086] About: As used herein, the quantitative term means plus or minus 10%.

[0087] Adipose tissue: tissue composed primarily of fat cells.

[0088] Youth: A person between the ages of 10 and 19.

[0089] Adiponectin: A protein hormone produced and secreted exclusively by fat cells that regulates lipid and glucose metabolism. Adiponectin influences the body's response to insulin. Adiponectin also has an anti-inflammatory effect on cells lining the inside walls of blood vessels.

[0090] Amelioration of symptoms of a particular disorder by administration of a particular pharmaceutical composition: refers to any decrease, whether permanent or temporary, lasting or transient, that can result from or be associated with administration of the composition.

[0091] Analog: a compound that is structurally similar to another but differs by at least one atom.

[0092] Antagonist: A substance that tends to neutralize the action of another, as a drug that binds to a cell receptor without eliciting a biological response.

[0093] Atherosclerotic plaque: A buildup of cholesterol and fatty material within blood vessels resulting from the effects of atherosclerosis.

[0094] Bariatric surgery: A range of surgical procedures designed to help manage or treat obesity and related disorders.

[0095] Beta cell rest: temporarily placing beta cells into a state of reduced metabolic stress resulting from inhibited secretion of insulin.

[0096] Double Laminate: A pharmaceutical dosage form component consisting of a lamination of two different materials.

[0097] Bioavailability: refers to the amount or extent to which a therapeutically active substance is released from a drug product and becomes available at the intended site of drug action in the body. The amount or extent of drug released may be established by pharmacokinetic parameters such as the area under the blood or plasma drug concentration-time curve (AUC) and the peak blood or plasma concentration of the drug (Cmax).

[0098] Bioequivalence: Two formulations of the same active agent are bioequivalent if there is no significant difference in the rate and extent to which the active agent becomes available at the site of drug action when administered at the same molar dose under similar conditions. "Formulation" in this definition may include the free base of the active agent, or different salts of the active agent. Bioequivalence may be demonstrated by several in vivo and in vitro methods. These methods include, in descending order of priority, pharmacokinetic, pharmacodynamic, clinical, and in vitro tests. In particular, bioequivalence is demonstrated using statistical criteria, using pharmacokinetic measurements such as the area under the blood or plasma drug concentration-time curve (AUC) and the peak blood or plasma concentration (Cmax) of the drug.

[0099] Cannabinoid receptor: A receptor in the endocannabinoid (EC) system associated with food intake and tobacco dependence. Blockade of cannabinoid receptors can reduce tobacco dependence and food cravings.

[0100] Combination: Refers to any association between two or more items. The combination may be two or more separate items, such as two compositions or two collections. The combination may also be a mixture thereof, such as a single mixture of two or more items, or any variations thereof.

[0101] Composition: refers to any mixture. The composition may be a solution, suspension, liquid, powder, paste, aqueous, non-aqueous or any combination thereof.

[0102] Compressed Tablet: A tablet formed by the application of pressure to a volume of a tablet matrix within a die.

[0103] Compression-coated tablet: A tablet formed by the addition of a coating by compression to a compressed core containing a pharma- ceutical active agent.

[0104] Derivative: A chemical substance derived from another substance by modification or substitution.

[0105] Daily Dosage: The total amount of drug taken in a 24-hour period, whether taken as a single dose or multiple doses.

[0106] Diazoxide: 7-chloro-3-methyl-2-H-1,2,4-benzothiadiazine 1,1 dioxide, having the empirical formula C8H7ClN2O2S and a molecular weight of 230.7.

[0107] Encapsulation system: A structural feature that contains a drug within a pharmaceutical capsule or the like. A gel with a drug incorporated within it is also considered an encapsulation system.

[0108] Equivalent amount: An amount of a derivative of a drug that produces the same effect in an assay or after administration to a subject as a defined amount of the underivatized drug.

[0109] fatty acid synthase central enzyme of a multienzyme complex that catalyzes the formation of palmitate from acetyl-coenzyme A, malonyl-coenzyme A, and NADPH.

[0110] gastric lipase enzyme secreted in the gastrointestinal tract that catalyzes the hydrolysis of dietary triglycerides.

[0111] Glidant: An inactive ingredient in a pharmaceutical formulation that prevents caking of the matrix during processing steps.

[0112] Growth hormone: Also known as somatotropin or somatropin, is a peptide hormone that stimulates growth, cell proliferation and reproduction in humans and other animals. It is a type of mitogen that is specific for only certain types of cells. Growth hormone is a single-chain polypeptide of 191 amino acids that is synthesized, stored and secreted by growth-promoting cells in the lateral wings of the anterior pituitary gland. GH is a stress hormone that increases glucose and free fatty acid concentrations. It also stimulates the production of IGF-1.

[0113] Hyperinsulemia: Excessively high blood insulin levels, as distinguished from hyperinsulinism, which is excessive secretion of insulin by the pancreatic islets. Hyperinsulemia can be the result of a variety of conditions, such as obesity and pregnancy.

[0114] Hyperinsulinism: Excessive secretion of insulin by pancreatic islets.

[0115] Hyperlipidemia: A general term for elevated concentrations of any or all of the lipids in plasma, including cholesterol, triglycerides, and lipoproteins.

[0116] Overeating: Consuming more than optimal amounts of food.

[0117] Components of a pharmaceutical composition: refers to one or more materials used in the manufacture of a pharmaceutical composition. Components may refer to the active ingredient (drug) or other materials in the composition. Components may include water and other solvents, salts, buffers, surfactants, water, non-aqueous solvents, and flavoring agents.

[0118] IGF-1, also called somatomedin C, is a protein that in humans is encoded by the IGF1 gene. IGF-1 is a hormone similar in molecular structure to insulin. It plays an important role in childhood growth and continues to have anabolic effects in adults. IGF-1 consists of 70 amino acids in a single chain with three intramolecular disulfide bridges and has a molecular weight of 7,649 daltons.

[0119] Insulin resistance: A condition in which the body's tissues are reduced in response to insulin.

[0120] Ischemic injury: injury to tissue resulting from hypoxic conditions, usually due to obstruction of the arterial blood supply or inadequate blood flow resulting in hypoxia in the tissue.

[0121] Ketoacidosis: Acidosis accompanied by accumulation of ketone bodies in body tissues and fluids (ketosis), such as in diabetic acidosis.

[0122] Kit: refers to a packaged combination that may optionally include labels, instructions, and / or reagents for use in conjunction with the combination.

[0123] Kir:K ATP The pore-forming subunit of the channel. ATP It is also known as the inward rectifying subunit of the channel, typically existing as Kir6.x and rarely as Kir2.x variants.

[0124] K ATP Channel: An ATP-sensitive potassium ion channel across the cell membrane formed by the association of four copies of the sulfonylurea receptor and four copies of the pore-forming subunit Kir. Stimulation of the channel can result in membrane hyperpolarization.

[0125] Lean body mass: Lean body mass is a component of body composition calculated by subtracting fat mass from total body weight, which is the fat-free plus fat mass. In the formula: Lean body mass is equal to body weight minus body fat (LBM=BW-BF), Lean body mass plus body fat equals body weight (LBM+BF= BW). The percentage of total body mass that is fat-free is not usually quoted, which is typically 60-90%. Instead, the complement, the percentage of body fat, is typically 10-40%. Because body fat is less relevant to metabolism, lean body mass (LBM) has been described as a better index than total body mass for prescribing appropriate levels of medication and for assessing metabolic disorders.

[0126] Leptin: product of the obesity locus (16 kD), which is found in mammalian plasma and exerts hormonal actions that reduce food intake and increase energy expenditure.

[0127] Lipogenesis: The production of new lipids, primarily triacylglycerides. It depends on the action of several different enzymes and transport molecules.

[0128] Lipolysis: The breakdown of fats through the coordinated action of multiple enzymes.

[0129] Lipoprotein lipase: an enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to produce diacylglycerol and fatty acid anions. The enzyme hydrolyzes triacylglycerol, very low density lipoproteins, low density lipoproteins, and diacylglycerol in chylomicrons.

[0130] Lubricant: An inactive ingredient in a pharmaceutical formulation that provides flowability of the material during various processing steps, especially tabletting.

[0131] Microparticles: Particulate material formed in the process of developing a pharmaceutical formulation that can be coated before producing the final dosage form.

[0132] Obesity: An increase in body weight beyond the limits of skeletal and physical requirements as a result of excess accumulation of fat in the body. Officially, it is defined as 30 kg / m 2is defined as having a body mass index greater than

[0133] Obesity-prone: An individual who is at above average risk of becoming obese due to genetic predisposition or a personal history of obesity.

[0134] Obesity-related comorbidity: Any disease or condition in animals or humans that has increased incidence in obese or overweight individuals. Examples of such conditions include hypertension, prediabetes, type 2 diabetes, osteoarthritis, and cardiovascular conditions.

[0135] Osmotically controlled release: A pharmaceutical dosage form in which release of the active drug is achieved primarily by hydration of a swellable component of the formulation.

[0136] Overweight: An individual whose weight exceeds the ideal weight for their height but does not meet the criteria for classification as obese. In humans, the body mass index (kg / m 2 ), an overweight individual has a BMI between 25 and 30.

[0137] Fat oxidation: A series of reactions involving acyl-CoA compounds, which undergo β-oxidation and thiol cleavage to form acetyl-CoA, is the major pathway for fatty acid catabolism in living tissues.

[0138] Pharmaceutical composition: refers to a composition containing a drug and one or more other ingredients, formulated for administration to a subject. Drug refers to the active ingredient of a pharmaceutical composition. Typically, the active ingredient is active in treating a disease or condition. For example, drugs that can be included in a pharmaceutical composition include drugs for treating obesity or diabetes. A pharmacoactive drug can be referred to as a "pharmaceutical active substance."

[0139] Pharmaceutical effect: Refers to the effect observed following administration of a drug intended to treat a disease or disorder, or ameliorate its symptoms.

[0140] Pharmacodynamics: Effects mediated by drug action.

[0141] Pharmacokinetics: Pertaining to the absorption, distribution, metabolism, and elimination of drugs in the body.

[0142] Polymorphs: compounds that share the same chemical properties but have different crystal structures.

[0143] Prader-Willi syndrome (PWS): a complex neurobehavioral / metabolic disorder resulting from the absence of normally active paternally expressed genes from the chromosome 15q11-q13 region. PWS is an imprinted condition, with 70-75% of cases resulting from de novo deletions in the paternally inherited chromosome 15q11-q13 region, 20-30% resulting from maternal uniparental disomy 15 (UPD), and the remaining 2-5% resulting from microdeletions or epimutations in imprinting centers (i.e., imprinting defects) (Bittel and Butler, Expert Rev Mol Med 7(14):1-20 (2005); Cassidy and Driscoll, Eur J Hum Genet 17(1):3-13 (2009)).

[0144] Clinical signs of the condition begin in utero with reduced fetal movement (Miller Am J Med Genet A 155A(5):1-10(2011)). Low lean body mass and hypotension are common in PWS and are present throughout life (Brambilla Am J Clin Nutr 65(5):1369-1374(1997); Lloret-lineras Int J Obes 37:1198-1203(2013)). Mental retardation occurs to varying degrees, with an average IQ of 70 (PWSUSA). PWS patients exhibit a range of behavioral complications, including autism spectrum disorder-like behaviors, obsessive-compulsive behaviors, self-injurious behaviors, and aggressive, threatening, and destructive behaviors. Approximately 80% of PWS patients are growth hormone deficient (Goldstone, Trends Endocrinol Metab 15:12-120 (2004); Davies et al., Front Neuroendocrinol 29:413-427 (2008); Cassidy and Driscoll, 2009, supra). Nearly all PWS patients are hypogonadal and require sex hormone supplementation (Goldstone, 2004, supra; Davies et al., 2008, supra; Cassidy and Driscoll, 2009, supra). These patients have hypothalamic insufficiency / dysfunction (Goldstone Am J Clin Nutr 75(3):468-475 (2002)).

[0145] Excess body fat accumulation can begin at about 2 years of age and continue into adulthood (Miller 2011, supra). The majority of body fat in PWS is subcutaneous (Brambilla 1997, supra; Sode-Carlson, Growth hormone and IGF research 20:179-184 (2010); Bedogni J Endocrinol Invest DOI 10.1007 / s40618-015-0266-y (2015)). Obesity is not common in PWS, unlike the prevalence of low lean body mass and low blood pressure. For example, Sode-Carlson et al. (2010), supra, evaluated 46 adult PWS patients, 25 women and 21 men. The mean BMI in these adult PWS patients was 27.2 kg / m 2 Thus, on average, these patients were overweight rather than obese, but in fact, by best metrics, more than half of the patients were not obese. Similarly, Brambilla et al. Nutr Metab Cardiovasc Dis 21(4):269-276 (2011) conducted a study on a population of 109 children with PWS. They found that by best metrics, 54% would not be classified as obese. Thus, in both adults and children with PWS, obesity is not only uncommon, but may actually occur in less than half of the population. At all ages, subcutaneous fat accounts for a higher percentage of total fat in PWS than in obese controls (Sode-Carlson 2010, supra).

[0146] Binge eating with associated problematic food-related behaviors begins on average at about age 8 (Miller 2011, supra). These patients feel hungry when they are not. After the onset of binge eating, individuals with PWS may eat any food in sight, wake up in the middle of the night to eat, rummage through garbage for food, steal food, eat frozen foods, pet food, spoiled food, and even eat non-food items (Miller 2011, supra). They may become angry or throw tantrums if food is denied. Access to food is severely restricted and shelves and refrigerators are locked for the rest of their lives after this stage. Meal times and structure are tightly controlled to limit food-related anxiety.

[0147] Mortality in PWS patients is three times higher than in the general population at all ages (Cassidy Genet Med 14(1):10-26(2012)), with the average age at death being approximately 29 years (PWSUSA Mortality Database, n=488). On the other hand, being obese but not morbidly obese has little effect on life expectancy (Anon(2011) National Research Council Panel on Understanding Divergent Trends in Longevity in High-Income Countries; Crimmons, EM, Preston, SH, Cohen, B, editors. National Academies Press).

[0148] Prader-Willi patients consume less energy and are more sedentary than the general population, obese controls, or patients with similar intellectual disabilities. Butler et al. Am J Med Gent A 143A(5):449-459(2007)) compared the energy expenditure and total work of a group of 48 PWS patients with a group of 24 obese controls. Compared to controls, PWS patients had significantly reduced total energy expenditure (-20%), resting energy expenditure (-16%), and mechanical work (-35%). After adjusting for between-group differences in lean body mass, the differences remained significant for mechanical work.

[0149] In a study by van Mil et al., Int J Obes Relat Metab Disord 24(4):429-434 (2000), the authors measured basal metabolic rate (BMR), average daily metabolic rate (ADMR), activity-induced energy expenditure (AEE), and ADMR / BMR (PAL) in a group of PWS patients and matched controls. ADMR, AEE, and PAL were significantly lower (P<0.01) in the PWS group compared with the controls (-28.2%, -58.2%, and -14.2%, respectively).

[0150] De Lind van Wijngaarden et al., J Clin Endocrinol Metab 95(4):1758-1766 (2010) evaluated cardiovascular and metabolic risk factors in children with PWS. They showed that 63% of infants and 73% of prepubertal children with PWS had at least one cardiovascular risk factor defined as dyslipidemia or hypertension. Thus, cardiometabolic risk in PWS is elevated even in younger children.

[0151] Preadipocyte: A precursor cell to fat cells.

[0152] Prediabetes: The state before type II diabetes is diagnosed. Type II diabetes is a form of diabetes characterized by insulin insensitivity or resistance.

[0153] Prodrug: refers to a compound that produces the desired active compound when metabolized. Typically, prodrugs are inactive or less active than the active compound, but may provide advantageous handling, administration, or metabolic properties. For example, some prodrugs are esters of the active compound, and during metabolism, the ester group is cleaved to produce the active drug. Also, some prodrugs are enzymatically activated to produce the active compound, or the active compound after further chemical reaction.

[0154] Chronic administration (chronic basis): Administration of a pharma- ceutically acceptable formulation of a drug for 7 days or more. Typically, chronic administration is for at least 2 weeks, preferably at least 1 month, and even more preferably at least 2 months (i.e., at least 18 weeks).

[0155] Rapidly Dissolving Dosage Formulation: A pharmaceutical formulation capable of releasing substantially all of the drug active from the formulation within 10 minutes after oral administration.

[0156] Extended release formulation (or "sustained release formulation"): A formulation of a pharmaceutical product that provides release of an active agent over a period of time that is extended after administration to an animal than that provided by a formulation of the same pharma- ceutical active agent that results in rapid uptake. Similar terms are extended release, prolonged release, and sustained release. In all cases, by definition, the preparation has a reduced release rate of the active agent.

[0157] Delayed release formulations (or "delayed release formulations"): Delayed release products are modified release, but not extended release. They involve the release of different amounts of drug after some time from drug administration, such as enteric coated products, and exhibit a lag time during which little or no absorption occurs.

[0158] Controlled release formulation (or "controlled release formulation"): A formulation of a pharmaceutical product that can include both delayed release of a pharma- ceutical active substance after administration, and controlled release in the manner described for sustained release.

[0159] Salt: A neutral, basic, or acidic compound formed by the union of an acid radical or an acid radical with a base radical or a base radical.

[0160] Smith-Magenis syndrome (SMS; OMIM #182290, *607642): A complex, generally sporadic genetic disorder caused by haploinsufficiency of the retinoic acid-induced 1 (RAI1) gene. Caused by a 17p11.2 deletion that includes a mutation in the retinoic acid-induced 1 (RAI1) gene or RAI1 (see, for example, Burns et al., in Human Molecular Genetics, 2010, Vol. 19, No. 20, pp. 4026-4042).

[0161] Smith-Magenis syndrome is characterized by a clinically recognizable phenotype that includes physical, developmental, neurological, and behavioral features. Short stature (<5th percentile) was observed in approximately 67% of juvenile patients. Short stature resolves over time, with most individuals reaching the 10th-25th percentile by adulthood (see, e.g., Burns et al., supra). Also, the majority of children with SMS have significant early-onset obesity (see, e.g., European Journal of Human Genetics (2008) 16,412-421). Obesity in teens and adults is common, typically with broad-chested and truncal obesity. RAI1 haploinsufficiency represents a monogenic model of hyperphagia, abnormal fat distribution, and altered hypothalamic gene expression associated with satiety, food intake, behavior, and obesity.

[0162] Hearing loss is fluctuating and often associated with chronic ear infections. Ophthalmologic features are present in over 60% of SMS patients and include myopia, iris abnormalities, strabismus, microcornea, and rarely retinal detachment (often resulting from violent behavior).

[0163] Prenatal history of SMS is notable for significantly reduced fetal movement in 50% of pregnancies. Early infancy is complicated by feeding difficulties resulting in failure to thrive, marked oral sensorimotor dysfunction with poor sucking reflex, gastroesophageal reflux, and hypotension.

[0164] Most SMS individuals have mild to moderate mental retardation. IQ declines with childhood age, eventually resulting in individuals falling into the mild mental retardation range by adulthood. Speech impairment, with or without hearing loss, occurs in 96% of SMS patients. In addition, impaired fine and gross motor skills, problems with intersensory integration, and poor adaptive functioning are seen. Other neurological features include pes cavus or pes planus, an abnormal "accelerated" gait, balance problems, and decreased sensation to pain observed in association with self-injury in this disorder.

[0165] Sleep disturbances are reported in 75-100% of SMS cases. Infants typically experience hypersomnia during the first year of life. Sleep disturbances in older children include difficulty falling asleep, reduced REM sleep, reduced 24-hour and nocturnal sleep, fragmented and shortened sleep cycles with frequent nighttime and early morning awakenings, and excessive daytime sleepiness.

[0166] Behavioral problems are one of the unique defining characteristics of SMS. Maladaptive behaviors are a major source of concern and include frequent emotional outbursts / tantrums, attention-seeking behaviors, aggression, defiance, distractibility, and self-injurious behaviors. Self-injurious behaviors include head banging, skin pinching, wrist biting, nail plucking, and foreign object insertion. The behavioral phenotype of SMS escalates with age, typically the onset of puberty. Age, degree of developmental delay, severity of any associated systemic disorders, and degree of sleep disturbance have a large impact on maladaptive behaviors. Individuals also lack respect for personal space during conversations and are emotionally excitable.

[0167] Individuals with SMS share many characteristics in common with those with PWS, including: (1) reduced fetal movement; (2) low blood pressure; (3) feeding difficulties in early infancy; (4) short stature; (5) early-onset obesity that may include overeating; (6) growth retardation; (7) mental retardation; (8) emotional outbursts; (9) aggressive behavior; (10) self-injurious behavior; (11) excessive sleepiness in infancy with similar sleep difficulties in older children and adults; (12) frequent ear infections; (13) scoliosis; and (14) strabismus. Although the underlying genetic basis of these disorders is quite different, the symptoms and natural history of the disease are very similar.

[0168] Solid oral dosage form: Pharmaceutical preparations designed for oral administration, including capsules and tablets.

[0169] Subject: refers to animals, including mammals, such as humans.

[0170] Sulfonylurea receptor: sulfonylureas, other K ATP Channel antagonists, diazoxide and other K ATP K interacts with channel agonists ATP The channel component.

[0171] Tablet: A pharmaceutical dosage form produced by molding a volume of a matrix containing a pharma- ceutical active substance and excipients into a size and shape suitable for oral administration.

[0172] Thermogenesis: the physiological process of heat production in the body.

[0173] Threshold Concentration: The minimum circulating concentration of a drug required to produce a specific metabolic, physiological, or compositional change in the body of the human or animal being treated.

[0174] Treatment: means any manner in which the symptoms of a condition, disorder or disease or other indication are ameliorated or otherwise beneficially altered.

[0175] Triglyceride: Depot fat in animal and human adipose tissue consisting primarily of glycerol esters of saturated fatty acids.

[0176] Type I diabetes: A chronic condition in which the pancreas produces little or no insulin because beta cells are destroyed.

[0177] uncoupling proteins family of proteins that allow oxidation in mitochondria to proceed without the usual concomitant phosphorylation that produces ATP.

[0178] Visceral fat: human adipose tissue found primarily under the subcutaneous and muscle layers of the body. [The present invention 1001] A method of treating a subject having Prader-Willi syndrome (PWS) or Smith-Magenis syndrome (SMS), comprising administering to a subject an effective amount of K ATP A method comprising administering to the subject a pharmaceutical formulation comprising a channel opener for at least 10 weeks. [The present invention 1002] The above K ATP The method of claim 10, wherein the channel opener is diazoxide or a pharma- ceutically acceptable salt thereof. [The present invention 1003] The method of claim 1002, wherein said pharma- ceutically acceptable salt is diazoxide choline. [The present invention 1004] The method of claim 1002, wherein said diazoxide or a pharma- ceutically acceptable salt thereof is administered orally. [The present invention 1005] The method of claim 1002, wherein said pharmaceutical formulation comprises at least one excipient that affects the release rate of diazoxide or a pharma- ceutically acceptable salt thereof. [The present invention 1006] The method of claim 10, wherein said pharmaceutical formulation comprises at least one excipient that delays the release of diazoxide or a pharma- ceutically acceptable salt thereof. [The present invention 1007] The method of claim 10, wherein said formulation further comprises at least one other active ingredient. [The present invention 1008] The method of claim 1001, further comprising administering to said subject human growth hormone. [The present invention 1009] The method of claim 1008, wherein said human growth hormone is administered by injection. [The present invention 1010] The method of claim 1001, wherein said subject's lean body mass or lean body mass / fat mass ratio is increased by at least 1%. [The present invention 1011] The method of claim 1001, wherein said subject's lean body mass or lean body mass / fat mass ratio is increased by at least 2%. [The present invention 1012] The method of claim 1001, wherein said subject's lean body mass or lean body mass / fat mass ratio is increased by at least 3%. [The present invention 1013] The method of claim 1001, wherein said subject's lean body mass or lean body mass / fat mass ratio is increased by at least 4%. [The present invention 1014] The method of claim 1001, wherein said subject's lean body mass or lean body mass / fat mass ratio is increased by at least 5%. [The present invention 1015] The method of claim 1001, wherein said administering is effected for one year or more. [The present invention 1016] The method of claim 1001, wherein said subject's overeating is reduced by at least 10%. [The present invention 1017] The method of claim 1001, wherein said subject's overeating is reduced by at least 20%. [The present invention 1018] The method of claim 1001, wherein said subject's overeating is reduced by at least 30%. [The present invention 1019] The method of the present invention 1001, wherein the circulating concentration of IGF-1 is not increased. [The present invention 1020] 1. A method of increasing lean body mass in a subject with Prader-Willi syndrome, said subject having been previously treated with administration of growth hormone to said subject, said method comprising administering to said subject, in addition to said growth hormone, an effective amount of K ATP co-administering a channel opener to said subject. [The present invention 1021] 1. A method for increasing lean body mass in a subject with Prader-Willi syndrome, comprising administering to the subject an effective amount of K ATP The method further comprises administering a channel opening drug to the subject K ATP The method comprising co-administering to said subject, in addition to the channel opener, an effective amount of growth hormone. [The present invention 1022] A method for increasing lower limb muscle mass in a subject with Smith-Magenis syndrome (SMS), comprising administering to said subject an effective amount of K ATP administering a channel opener to said subject. [The present invention 1023] Unit dose of K ATP A channel opener; A unit dose of growth hormone and Kit including: [The present invention 1024] 1. A method for reducing one or more aggressive behaviors in a subject with Prader-Willi syndrome (PWS) or Smith-Magenis syndrome (SMS), the method comprising administering an effective amount of K ATP A method comprising administering a channel opener to said subject for at least 10 weeks, wherein administration reduces one or more aggressive behaviors in said subject. [The present invention 1025] The method of claim 1024, wherein a second therapeutic product is administered, said second product intended to further reduce said one or more aggressive behaviors. [The present invention 1026] 1. A method of reducing hyperghrelinemia in a subject with Prader-Willi syndrome (PWS) or Smith-Magenis syndrome (SMS), comprising administering an effective amount of K ATPA method comprising administering a channel opener to said subject for at least 10 weeks, wherein administration reduces one or more aggressive behaviors in said subject. [The present invention 1027] The method of claim 10, wherein said pharmaceutical formulation is administered twice daily. [The present invention 1028] The method of claim 10, wherein said pharmaceutical formulation is administered once daily. [Brief description of the drawings]

[0179] [Figure 1] FIG. 1 summarizes the change in binge eating scores in all subjects who participated in clinical trial PC025. [Diagram 2] FIG. 1 summarizes the percent change in lean body mass in all subjects participating in clinical trial PC025. [Diagram 3] FIG. 1 summarizes the percent change in body fat mass in all subjects who participated in clinical trial PC025. [Figure 4] FIG. 1 summarizes the percentage change in lean body mass / fat mass ratio in all subjects participating in clinical trial PC025. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0180] Detailed Description of the Invention As used herein, specific K-binding proteins are provided that, when administered to a subject, achieve novel pharmacodynamic, pharmacokinetic, therapeutic, physiological, and metabolic outcomes. ATP Pharmaceutical formulations of channel openers are provided. Also provided are specific K channel openers, optionally in combination with growth hormone, that achieve therapeutic outcomes while reducing the incidence of side effects. ATP Pharmaceutical formulations of channel openers, methods of administration and dosing thereof are provided.

[0181] In particular, pharmaceutical formulations formulated for oral administration exhibit advantageous properties including facilitating absorption across treated patients, consistency of pharmacokinetic and pharmacodynamic responses, contributing to patient compliance, and improving the safety profile of the product by, for example, reducing the frequency of serious side effects. Methods of treating metabolic and other diseases in humans and animals by administering the formulations are also provided.

[0182] Compounds of formulas II and III, IV and V, and VI and VII, such as diazoxide (shown below), may be proton tautomers. Proton tautomers are isomers that differ from each other only in the location of the hydrogen atom and the double bond. The hydrogen atom and the double bond exchange locations between the carbon atom and the heteroatom, such as N. Thus, when the nitrogen substituent is hydrogen, the two isomeric chemical structures may be used interchangeably. TIFF0007645913000008.tif20128

[0183] Specific K that may be used in the formulations of the present invention ATP Channel openers include any of those within formulas I to VII. Exemplary such compounds include diazoxide, BPDZ62, BPDZ73, NN414, and BPDZ154 (see, e.g., Schou, et al., Bioorg. Med. Chem., 13, 141-155 (2005)). The compound BPDZ154 has also been shown to be an effective K channel opener in patients with hyperinsulinism and in patients with pancreatic insulinomas. ATP The synthesis of BPDZ compounds is described in Cosgrove, et al., J. Clin. Endocrinol. Metab., 87, 4860-4868 (2002).

[0184] Analogs of diazoxide include 3-isopropylamino-7-methoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide, a selective Kir6.2 / SUR1 channel opener (see Dabrowski, et al., Diabetes, 51, 1896-1906 (2002)). Included are 2-alkyl-substituted diazoxides (see, e.g., Ouedraogo, et al., Biol. Chem., 383, 1759-1768 (2002)); these channel openers show reduced activity in inhibiting insulin release and increased activity in vascular smooth muscle tissue. Additionally, 2-alkyl-substituted diazoxides generally do not function as conventional potassium channel activators, but instead act as Ca channel activators. 2+ Shows potential as a blocker.

[0185] Other diazoxide analogs are described in Schou, et al., Bioorg. Med. Chem., 13, 141-155 (2005) and are shown below. TIFF0007645913000009.tif44128

[0186] Diazoxide analogs with different alkyl substituents at the 3-position of the molecule (R 3 (identified as ) are described in Bertolino, et al., Receptors and Channels, 1, 267-278 (1993). TIFF0007645913000010.tif59128

[0187] K of Formulas I-VII and related compounds ATP Channel activity can be measured by membrane potential assays as described in Schou, et al., Bioorg. Med. Chem., 13, 141-155 (2005) and Dabrowski, et al., Diabetes, 51, 1896-1906 (2002).

[0188] Measurement of inhibition of glucose-stimulated insulin release from βTC6 cells is described in Schou, et al., Bioorg. Med. Chem., 13, 141-155 (2005). ATP The potency of channel openers can be demonstrated as described by Ouedraogo, et al., Biol. Chem., 383, 1759-1768 (2002).

[0189] K ATP Recombinant K channel opener ATP Channel activation can be examined by monitoring macroscopic currents in inside-out membrane patches of Xenopus oocytes co-expressing Kir6.2 and either SUR1, SUR2A or SUR2B. SUR-expressing membranes can be prepared by known methods. See, e.g., Dabrowski, et al., Diabetes, 51, 1896-1906 (2002).

[0190] Using binding experiments, K binding to SUR1, SUR2A and SUR2B was ATP The potency of channel openers can be determined. See, e.g., Schwanstecher, et al., EMBO J., 17, 5529-5535 (1998).

[0191] Preparation of SUR1 and SUR2A chimeras allows for comparison of the pharmacological profiles (i.e., sulfonyl sensitivity and responsiveness to diazoxide or other potassium channel openers) of SUR1 / Kir6.2 and SUR2A / Kir6.2 potassium channels as described by Babenko et al. See Babenko, et al., J. Biol. Chem., 275(2), 717-720 (2000). Sulfonylurea receptors and inwardly rectifying K +Cloning of the channels is described by Isomoto, et al., J. Biol. Chem., 271(40), 24321-24324 (1996); D'hahan, et al., PNAS, 96(21), 12162-12167 (1999).

[0192] The differences between the human SUR1 and SUR2 genes are described and illustrated in Aguilar-Bryan, et al., Physiological Review, 78(1), 227-245 (1998).

[0193] "Halo" and "halogen" refer to all halogens, that is, chloro (Cl), fluoro (F), bromo (Br), or iodo (I).

[0194] "Hydroxyl" and "hydroxy" refer to the --OH group.

[0195] "Substituted oxy" is -OR f R f is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl.

[0196] "Substituted thiol" refers to the group -SR, where R is alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl.

[0197] "Alkyl" refers to an alkane-derived radical containing from 1 to 10, preferably 1 to 6, carbon atoms. Alkyl includes straight chain alkyl, branched alkyl and cycloalkyl, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and the like. Straight chain or branched alkyl groups contain 1 to 10, preferably 1 to 6, more preferably 1 to 4, and even more preferably 1 to 2 carbon atoms. The alkyl group may be attached at any available point to produce a stable compound.

[0198] "Substituted alkyl" refers to an alkyl group independently substituted with one or more, e.g., one, two or three, groups or substituents, such as halo, hydroxy, optionally substituted alkoxy, optionally substituted alkylthio, alkylsulfinyl, alkylsulfonyl, optionally substituted amino, substituted amido, amidino, optionally alkyl-substituted urea, optionally N-monosubstituted or N,N-disubstituted aminosulfonyl with alkyl, alkylsulfonylamino, carboxyl, heterocycle, substituted heterocycle, nitro, cyano, thiol, sulfonylamino, etc., attached at any available point to produce a stable compound. In particular, "fluoro-substituted" refers to substitution with one or more, e.g., one, two or three, fluorine atoms. "Optionally fluoro-substituted" means that the substitution, if present, is fluoro.

[0199] "Lower alkyl" refers to an alkyl group having 1 to 6 carbon atoms.

[0200] A "substituted lower alkyl" is a lower alkyl substituted with one or more, for example, one, two, or three, groups or substituents as defined above that are attached at any available point to produce a stable compound.

[0201] "Cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic, bicyclic or tricyclic carbocyclic ring system of three to eight, more preferably three to six, ring members per ring, e.g., cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, etc. "Cycloalkylene" is a divalent cycloalkyl.

[0202] "Alkoxy" is -OR f represents a group, f is lower alkyl.

[0203] "Substituted alkoxy" refers to -OR f’ represents a group, f’ is a substituted lower alkyl.

[0204] "Alkylthio" or "thioalkoxy" refers to the group --SR where R is lower alkyl.

[0205] "Substituted alkylthio" or "substituted thioalkoxy" refers to the group --SR where R is a substituted lower alkyl.

[0206] "Sulfinyl" refers to the group -S(O)-.

[0207] "Sulfonyl" refers to the group -S(O)2-.

[0208] "Substituted sulfinyl" refers to the group -S(O)-R, where R is lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, aralkyl, or substituted aralkyl.

[0209] "Substituted sulfonyl" refers to the group -S(O)2-R, where R is lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, aralkyl, or substituted aralkyl.

[0210] "Sulfonylamino" refers to the group -NRS(O)2- where R is hydrogen or lower alkyl.

[0211] "Substituted sulfonylamino" is -NR a S(O)2-R b represents a group, a is hydrogen or lower alkyl, R b is lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, aralkyl or substituted aralkyl.

[0212] "Amino" or "amine" refers to the -NH group. "Divalent amine" refers to the -NH- group. "Substituted divalent amine" refers to the -NR- group, where R is lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl, substituted acyl, sulfonyl, or substituted sulfonyl.

[0213] A "substituted amino" or "substituted amine" is -NR i R j represents a group, i and R j is independently hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl, substituted acyl, sulfonyl, substituted sulfonyl, or cycloalkyl, with the proviso that R i and R jAt least one of R is not hydrogen. i R j may combine with the nitrogen to form an optionally substituted heterocyclic or heteroaryl ring.

[0214] "Alkylsulfinyl" is -S(O)R p represents a group, p is optionally substituted alkyl.

[0215] "Alkylsulfonyl" is -S(O)R p represents a group, p is optionally substituted alkyl.

[0216] "Alkylsulfonylamino" is -NR q S(O)2R p represents a group, p is optionally substituted alkyl, R q is hydrogen or lower alkyl.

[0217] K ATP Pharmaceutical formulations containing channel openers include the free base of the drug or a salt of the drug. Such salts can have one or more of the following characteristics: (1) stability in solution during synthesis and formulation, (2) stability in the solid state, (3) compatibility with excipients used in the manufacture of tablet formulations, (4) K after exposure to simulated or real gastric and duodenal conditions. ATP (5) Quantitative production of channel openers from particles small enough to be easily dissolved and absorbed. ATP (6) when incorporated into a pharmaceutical formulation, provides absorption of greater than 80% of the administered dose; (7) ATP (8) exhibit no increased risk of toxicity compared to the free base of the channel opener; (9) be capable of being formulated into acceptable pharmaceutical preparations for treating obesity and other diseases in humans; (10) be capable of being FDA-accepted as a base for drug products; (11) be capable of being recrystallized to improve purity; ATP(11) can be used to form co-crystals of two or more salts of a channel opener; (12) have limited hygroscopicity to improve stability; or (13) the synthesis and crystallization conditions under which the salt is formed can be modified so that different crystal structures (polymorphs) can be controlled in the synthesis of the salt.

[0218] K ATP The channel opener can be formulated as a pharmaceutically acceptable salt. A pharmaceutically acceptable salt is a non-toxic salt in the amount and concentration at which it is administered. The preparation of such salts can facilitate pharmacological use by modifying the physical characteristics of the compound without preventing it from exerting its physiological effect. Useful modifications of physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering a lower effective dose of the drug.

[0219] Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be derived from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid and quinic acid.

[0220] Pharmaceutically acceptable salts also include base addition salts when an acidic functional group is present, such as a carboxylic acid or a phenol, such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamines, zinc, and the like. See, e.g., Remington's Pharmaceutical Sciences, 1999. thed., Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995. Such salts can be prepared using the appropriate corresponding base.

[0221] Pharmaceutically acceptable salts can be prepared, for example, by dissolving the free base form of the compound in a suitable solvent, such as water or water-alcohol in a solution containing the appropriate acid, and then isolating by evaporating the solution. In another example, salts are prepared by reacting the free base and an acid in an organic solvent.

[0222] Pharmaceutically acceptable salts of different compounds may exist as complexes. Examples of complexes include 8-chlorotheophylline complexes (e.g., dimenhydrinate:diphenhydramine 8-chlorotheophylline (1:1) complex; similar to Dramamine) and various cyclodextrin inclusion complexes.

[0223] K ATPSalts of channel openers, and specific salts of diazoxide, include acetate, acetonide, acetyl, adipate, aspartate, besylate, biacetate, bitartrate, bromide, butoxide, butyrate, calcium, camsylate, caproate, carbonate, citrate, cyprionate, decaroate, diacetate, dimeglumine, dinitrate, dipotassium, dipropionate, disodium, disulfide, edisylate, enanthate, estolate, etabonate, ethylsuccinate, fumarate, furoate, gluceptate, glucoside, and the like. phosphate, hexacetonide, hippurate, hyclate, hydrobromide, hydrochloride, isethionate, lactobionate, malate, maleate, meglumine, methyl bromide, methyl sulfate, metrizoate, nafate, napsylate, nitrate, oleate, palmitate, pamoate, phenpropionate, phosphate, pivalate, polistirex, polygalacturonate, probutate, propionate, saccharate, sodium glycinate, sodium phosphate, podium succinate In some embodiments, the salts may include, but are not limited to, succinate, state, succinate, sulfate, sulfonate, sulfosalicylate, tartrate, tebutate, terephalate, terephthalate, tosylate, triflate, trihydrate, trisilicate, tromethamine, valerate, xinafolate, and the like.

[0224] The formulations described herein exhibit some or all of the following characteristics: (1) are stable at ambient temperatures for at least one year; (2) provide ease of oral administration; (3) facilitate patient compliance with dosing; (4) consistently promote high levels of absorption of the pharmacologic active agent following administration; and (5) provide no significant improvement in K after once or twice daily oral administration. ATP The K ATP(6) achieve these results independent of the pH of the gastrointestinal tract of the individual being treated; and (7) delay release until gastric transit is complete or nearly complete.

[0225] Formulations designed for oral administration may be provided, for example, as capsules or tablets. Capsule or tablet formulations contain several characteristic components. ATP One component is to improve absorption of the channel opener. Another sustains the release of the drug for more than two hours. The third delays substantial release of the drug until gastric transit is complete.

[0226] The formulations disclosed herein have improved K ATP These advantageous properties are achieved by any one or more of the following techniques: (1) reducing the particle size of the formulation by milling, spray drying, or other micronization techniques; (2) reducing the particle size of the formulation by K ATP (3) using ion exchange resins in the formulation; (4) using inclusion complexes, e.g., using cyclodextrins; (5) using K+ with solubilizing agents, including low viscosity hypromellose, low viscosity methylcellulose, or similarly functional excipients and combinations thereof. ATP (6) Compaction of channel openers, K ATP Associating a channel opener with a salt; (7) K ATP (8) using a solid dispersion of the channel opener, (9) using a self-emulsifying system, (10) adding one or more surfactants to the formulation, (11) using nanoparticles in the formulation, or (12) a combination of these approaches. ATP When the channel opener is a salt of diazoxide, the salt is not the sodium salt.

[0227] K over a sustained period (2-24 hours) ATPRelease of the channel opener is achieved by the use of one or more techniques, including, but not limited to, (1) the use of a pH-sensitive polymer coating, (2) the use of a hydrogel, (3) the use of a membrane coating to control the rate of diffusion of the drug from the coated matrix, (4) the use of an erodible matrix to control the rate of drug release, (5) the use of polymer-coated pellets, granules or microparticles that may be further encapsulated or compressed into a tablet, (6) the use of an osmotic pump system, or (7) the use of a compression-coated tablet, or (8) a combination of these techniques.

[0228] K from preparations until gastric passage ATP The delayed release of the channel opener is achieved in the formulations described herein by any of several mechanisms. A pH-sensitive polymer or copolymer is used that, when applied around the drug matrix, acts as an effective barrier to the release of the active agent at pH 3.0 or below, but is unstable at pH 5.5 or above. This provides control of the release of the active compound in the stomach, but allows for rapid release once the dosage form has passed into the small intestine. An alternative to a pH-sensitive polymer or copolymer is a water-insoluble polymer or copolymer. The degree of resistance to release in the gastric environment can be controlled by coating with a blend of water-insoluble and water-soluble polymers. In this approach, none of the blended polymers or copolymers are pH-sensitive. One example of a pH-sensitive copolymer is Eudragit methacrylic acid copolymer, including Eudragit L100, S100 or L100-55 solids, L30 D-55 or FS 30D dispersions, or L12,5 or S12,5 organic solutions.

[0229] The release-retarding polymer can be applied to the tablet by spray coating (as a thin film) or by compression coating. If a capsule is used, the polymer can be applied on the surface of the capsule or to the drug microparticles, which can be encapsulated, such as in a capsule or gel. If the capsule is coated, it resists disintegration until after stomach passage. If the microparticles are coated, the capsule may disintegrate in the stomach, but little or no drug is released until after the free microparticles have completed stomach passage. Finally, osmotic pump systems, for example using swellable hydrogels, may be used to delay drug release in the stomach. The swellable hydrogel absorbs water after administration. The swelling of the gel pushes the drug out of the system and is absorbed. The timing and rate of drug release depends on the gel used and the rate at which water reaches the gel, which can be controlled by the size of the opening in the system through which the fluid enters. See Drug Delivery Technologies online article Dong et al. "L-OROS® SOFTCAP™ for Controlled Release of Non-Aqueous Liquid Formulations".

[0230] Therefore, the K from the formulation of the present invention until after gastric transit is complete. ATPThe delayed release of the channel opener is achieved in the formulations described herein by any of several mechanisms, including, but not limited to, (a) a pH-sensitive polymer or copolymer applied as a compression coating on a tablet; (b) a pH-sensitive polymer or copolymer applied as a thin film on a tablet; (c) a pH-sensitive polymer or copolymer applied as a thin film on an encapsulation system; (d) a pH-sensitive polymer or copolymer applied to an encapsulated microparticle, (e) a water-insoluble polymer or copolymer applied as a compression coating on a tablet; (f) a water-insoluble polymer or copolymer applied as a thin film on a tablet; (g) a water-insoluble polymer applied as a thin film on an encapsulation system; (h) a water-insoluble polymer applied to a microparticle; (i) incorporation of the formulation into an osmotic pump system, or (j) use of an ion exchange resin controlled system, or (k) a combination of these approaches, where the pH-sensitive polymer or copolymer is resistant to degradation under acidic conditions.

[0231] Formulations designed for administration once a day (per 24 hours) are provided. These contain between 25 mg and 500 mg of K ATP Formulations are also provided that are for administration twice daily (per 24 hours). These may contain between 25 mg and 250 mg of K ATP It may contain a channel opener.

[0232] The formulations provided herein show improved safety of the administered drug product. This improvement in safety occurs through at least two mechanisms. First, delaying the release of active drug until gastric transit is complete can reduce the incidence of a series of adverse gastrointestinal side effects, including nausea, vomiting, dyspepsia, abdominal pain, diarrhea and ileus. Second, sustaining the release of active drug over 2 hours to as long as 24 hours reduces peak drug levels compared to the peak drug levels observed for the same administered dose using any oral formulation that does not have sustained or controlled release. This reduction in peak drug levels can contribute to reducing side effects that are determined in part or entirely by peak drug levels. These side effects include fluid retention, edema, hyperglycemia with associated reduced excretion rates of sodium, chloride and uric acid, and associated ketoacidosis, cataracts, and possible progression to non-ketotic hyperosmolar coma, headache, tachycardia, and palpitations.

[0233] Also, in the present specification, there is provided a method for producing a compound having one feature from each of A to D as shown in Table 1. ATP Controlled release formulations of the channel openers are provided.

[0234] (Table 1) Characteristics and properties of controlled release formulations TIFF0007645913000011.tif76128

[0235] For example, the controlled release composition may contain 25 to 100 mg of K ATP It may also be a tablet containing a channel opener, and such a tablet is administered once daily to achieve a controlled release time of 2 to 4 hours. All of these formulations may further include a feature that substantially delays release of the pharmacologic active until after gastric transit is complete.

[0236] Additionally, any of the above formulations from Table 1 may be used with ATP It may include at least one feature that improves the dissolution or absorption of the channel opener.

[0237] The controlled release formulations provided herein contain an active compound (e.g., K, optionally in combination with growth hormone). ATP The active compound entrapped within the gel is gradually released into the body after dissolution of the gel. The active compound may be uniformly dispersed within the matrix or may be present as pockets of drug within the matrix. For example, the drug may be formulated as microgranules dispersed within the matrix. Additionally, the drug granules may also comprise the matrix, thus providing a primary and secondary matrix, as described in U.S. Patent No. 4,880,830 to Rhodes.

[0238] The gelling agent is preferably a polymeric material, which may include, for example, any pharma- ceutically acceptable water-soluble or water-insoluble sustained-release polymer, such as xanthan gum, gelatin, cellulose ethers, gum arabic, locust bean gum, guar gum, carboxyvinyl polymers, agar, acacia gum, tragacanth, veegum, sodium alginate or alginic acid, polyvinylpyrrolidone, polyvinyl alcohol, or film-forming polymers, such as methylcellulose (MC), carboxymethylcellulose (CMC), hydroxypropylmethylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), ethylcellulose (EC), acrylic resins, or mixtures of the above (see U.S. Pat. No. 5,415,871).

[0239] The gelling agent of the matrix may also be a heterodisperse gum containing heteropolysaccharide and homopolysaccharide components that produce a fast-forming and firm gel, as described in U.S. Patent No. 5,399,359. The matrix may also contain a crosslinking agent, such as a monovalent or polyvalent metal cation, to provide additional rigidity and reduce dissolution of the matrix, thus further slowing drug release. The amount of crosslinking agent to add may be determined using methods routine to those skilled in the art.

[0240] The matrix of the controlled release composition may also include one or more pharma- ceutically acceptable excipients, i.e., formulation excipients, as recognized by those skilled in the art. Such excipients include, for example, binders: polyvinylpyrrolidone, gelatin, starch paste, microcrystalline cellulose; diluents (or fillers): starch, sucrose, dextrose, lactose, fructose, xylitol, sorbitol, sodium chloride, dextrin, calcium phosphate, calcium sulfate; and lubricants: stearic acid, magnesium stearate, calcium stearate, Precirol™, and flow aids, such as talc or colloidal silicon dioxide.

[0241] The matrix of the controlled release composition may further comprise a hydrophobic material that retards hydration of the gelling agent without interfering with the hydrophilicity of the matrix, as described in U.S. Patent No. 5,399,359.Hydrophobic polymers may include, for example, alkylcelluloses such as ethylcellulose, other hydrophobic cellulosic materials, polymers or copolymers derived from acrylic or methacrylic acid esters, copolymers of acrylic and methacrylic acid esters, zein, wax, shellac, hydrogenated vegetable oils, waxes and waxy substances such as carnauba wax, spermaceti, candelilla wax, cocoa butter, cetosteryl alcohol, beeswax, ceresin, paraffin, myristyl alcohol, stearyl alcohol, cetyl alcohol and stearic acid, and any other pharma- ceutically acceptable hydrophobic material known to those skilled in the art.

[0242] The amount of hydrophobic material incorporated into the controlled release composition is an amount effective to retard hydration of the gelling agent without interfering with the hydrophilic matrix formed after exposure to environmental fluid. In certain preferred embodiments, the hydrophobic material is included in the matrix in an amount of about 1 to about 20 weight percent, replacing a corresponding amount of formulation excipients. The solvent for the hydrophobic material may be aqueous or organic, or a mixture thereof.

[0243] Examples of commercially available acrylic celluloses are Aquacoat® (an aqueous dispersion of ethylcellulose available from FMC) and Surelease® (an aqueous dispersion of ethylcellulose available from Colorcon). Examples of commercially available acrylic acid polymers suitable for use as the hydrophobic material include Eudragit® RS and RL (copolymers of acrylic and methacrylic acid esters with low contents (e.g. 1:20 or 1:40) of quaternary ammonium compounds).

[0244] The controlled release composition may also be coated to inhibit access of liquids to the active compound and / or inhibit release of the active compound through the membrane coating. The membrane coating may provide gastro-resistant and enteric characteristics by resisting rapid dissolution of the composition in the digestive tract. The membrane coating generally comprises about 5-15% by weight of the controlled release composition. Preferably, the core comprises about 90% of the composition by weight, with the remaining 10% provided by the coating. Such coatings may be membrane coatings as are well known in the art and may include gels, waxes, fats, emulsifiers, combinations of fats and emulsifiers, polymers, starches, and the like.

[0245] Polymers and copolymers are useful as thin film coatings. Solution coatings and dispersion coatings can be used to coat the active compound alone or in combination with a matrix. The coating is preferably applied to the drug as a solid core of material or a combination of drug and matrix, as is well known in the art.

[0246] Coating solutions can include the polymer in both organic solvent and aqueous solvent systems, and typically further include one or more compounds that function as plasticizers. Polymers useful for coating the composition include, for example, methylcellulose (Methocel® A; Dow Chemical Co.), hydroxypropyl methylcellulose having a molecular weight between 1,000 and 4,000,000 (Methocel® E; Dow Chemical Co. or Pharmacoat®; Shin Etsu), hydroxypropyl cellulose having a molecular weight between 2,000 and 2,000,000, ethyl cellulose, cellulose acetate, cellulose triacetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate (Eastman Kodak), carboxymethylcellulose (Duodcel®), hydroxypropyl methylcellulose phthalate, ethyl cellulose, methyl cellulose, and, in general, cellulose derivatives, oligomethacrylic acid-methacrylic acid copolymers (Type A 1:1 Eudragit L100; Type B 1:2 Eudragit S100; and Type C 1:1 Eudragit S100). L100-55, aqueous dispersion 30% solids, Eudragit L30D), poly(meth)acrylic ester: poly(ethyl acrylate, methyl methacrylate 2:1), Eudragit NE30D aqueous dispersion 30% solids, polyamino methacrylate Eudragit E100, poly(trimethylammonioethyl methacrylate chloride) ammonio methacrylate copolymer, Eudragit RL30D and Eudragit RS30D, carboxyvinyl polymers, polyvinyl alcohol, glucan scleroglucan, mannan, and xanthan.

[0247] Aqueous polymer dispersions include Eudragit L30D and RS / RL30D and NE30D, Aquacoat brand ethylcellulose, Surelease brand ethylcellulose, EC brand N-10F ethylcellulose, Aquateric brand cellulose acetate phthalate, Coateric brand poly(vinyl acetate phthalate), and Aqacoat brand hydroxypropyl methylcellulose acetate succinate. Most of these dispersions are latex, pseudolatex powders or micronized powder media.

[0248] Plasticizers may be included in the coating to improve the elasticity and stability of the polymer film and to prevent changes in polymer permeability over long-term storage. Such changes may affect the drug release rate. Suitable conventional plasticizers include, for example, diethyl phthalate, glycerol triacetate, acetylated monoglyceride, acetyl tributyl citrate, acetyl triethyl citrate, castor oil, citrate esters, dibutyl phthalate, dibutyl sebacate, diethyl oxalate, diethyl malate, diethyl fumarate, diethyl phthalate, diethyl succinate, diethyl malonate, diethyl tartrate, dimethyl phthalate, glycerin, glycerol, glyceryl triacetate, glyceryl tributyrate, mineral oil and lanolin alcohol, petrolatum and lanolin alcohol, phthalate esters, polyethylene glycol, propylene glycol, rapeseed oil, sesame oil, triacetin, tributyl citrate, triethyl citrate, and acetyl triethyl citrate, or a mixture of any two or more of the above. Plasticizers that can be used in aqueous coatings include, for example, propylene glycol, polyethylene glycol (PEG 400), triacetin, polysorbate 80, triethyl citrate, and diethyl d-tartrate.

[0249] A coating solution containing a mixture of hydroxypropyl methylcellulose and aqueous ethylcellulose (e.g. Aquacoat brand) as polymers and dibutyl sebacate as plasticizer can be used to coat the microparticles (Aquacoat is an aqueous polymer dispersion of ethylcellulose, containing sodium lauryl sulfate and cetyl alcohol). Preferably, the plasticizer comprises about 1-2% of the composition.

[0250] In addition to the polymer, the coating layer may contain excipients to assist in the formulation of coating solution.Such excipients may include lubricants or wetting agents.Suitable lubricants as excipients for film coating include, for example, talc, calcium stearate, colloidal silicon dioxide, glycerin, magnesium stearate, mineral oil, polyethylene glycol, and zinc stearate, aluminum stearate, or any mixture of two or more of the above. Suitable wetting agents include, for example, sodium lauryl sulfate, acacia, benzalkonium chloride, cetomacrogol emulsifying wax, cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolamine, docusate sodium, sodium stearate, emulsifying wax, glyceryl monostearate, hydroxypropyl cellulose, lanolin alcohol, lecithin, mineral oil, onoethanolamine, poloxamer, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, propylene glycol alginate, sorbitan esters, stearyl alcohol and triethanolamine, or a mixture of any two or more of the above.

[0251] The tablet or capsule formulations specified in Table 1 are (K ATPIn addition to the channel opener, the drug may include a combination formulation with an obesity treatment drug. Obesity treatment drugs that may be used include, but are not limited to, sibutramine hydrochloride (5-30 mg / unit), orlistat, (50-360 mg / unit), phentermine hydrochloride or resin complex (15-40 mg / unit), zonisamide (100-600 mg / unit), topiramate (64-400 mg / unit), naltrexone hydrochloride (50-600 mg / unit), rimonabant (5-20 mg / unit), ADP356 (5-25 mg / unit), ATL962 (20-400 mg / unit), or AOD9604 (1-10 mg / unit). These formulations are preferably used once a day. In the case of twice a day dosing, K ATPThe amount of channel opener is one-half of that contained in the once-daily formulation, and the co-formulated obesity treatment is one-half the amount specified. Alternative obesity treatments include selective serotonin 2c receptor agonists, dopamine antagonists, cannabinoid-1 receptor antagonists, leptin analogs, leptin transporter and / or leptin receptor promoters, neuropeptide Y and agouti-related peptide antagonists, proopiomelanocortin and cocaine- and amphetamine-regulated transcription promoters, melanocyte-stimulating hormone analogs, melanocortin-4 receptor agonists, and agents that affect insulin metabolism / activity and include protein-tyrosine phosphatase-1B inhibitors, peroxisome proliferator-activated receptor-receptor antagonists, short-acting bromocriptine (ergoset), somatostatin agonists (octreotide), adiponectin, those that increase cholecystokinin activity, those that increase glucagon-like peptide 1 activity (exocretin). These may include gastrointestinal-neural pathway agents including those that increase protein YY3-36 activity and those that decrease ghrelin activity, as well as amylin analogues, agents that may increase resting metabolic rate ("selective" beta-3 stimulators / agonists, uncoupling protein homologues, and thyroid receptor agonists), melanin-concentrating hormone antagonists, phytostanol analogues, amylase inhibitors, growth hormone fragments, synthetic analogues of dehydroepiandrosterone sulfate, antagonists of adipocyte 11B hydroxysteroid dehydrogenase type 1 activity, corticotropin releasing hormone agonists, inhibitors of fatty acid synthesis, carboxypeptidase inhibitors, indanones / indanols, aminosterols, and other gastrointestinal lipase inhibitors.

[0252] The tablet or capsule formulations specified in Table 1 are (K ATPIn addition to the channel opener, the drug may also include a combination formulation with a diabetes treatment drug. Diabetes treatment drugs that may be used include, but are not limited to, acarbose (50 to 300 mg / unit), miglitol (25 to 300 mg / unit), metformin hydrochloride (300 to 2000 mg / unit), repaglinide (1 to 16 mg / unit), nateglinide (200 to 400 mg / unit), rosiglitizone (5 to 50 mg / unit), metaglidasen (100 to 400 mg / unit), or any drug that improves insulin sensitivity or improves glucose utilization and uptake. These formulations are preferably used once a day. For twice a day dosing, K ATP The amount of channel opener is half that contained in the once-daily formulation and the co-formulated diabetes treatment is at half the amount specified.

[0253] The specified tablet or capsule formulations in Table 1 may also include combination formulations with cholesterol-lowering drugs. Cholesterol-lowering drugs that may be used include, but are not limited to, pravastatin or simvastatin or atorvastatin or fluvastatin or rosuvastatin or lovastatin (all at 10 to 80 mg / unit). These formulations are preferably used once daily. For twice daily dosing, K ATP The amount of channel opener is preferably 25 to 200 mg / unit and the cholesterol lowering drug is co-formulated at half the specified amount.

[0254] The tablet or capsule formulations specified in Table 1 may also include combination formulations with depression treatments. Depression treatments that may be used include citalopram hydrobromide (10 to 80 mg / unit), escitalopram hydrobromide (5 to 40 mg / unit), fluvoxamine maleate (25 to 300 mg / unit), paroxetine hydrochloride (12.5 to 75 mg / unit), fluoxetine hydrochloride (30 to 100 mg / unit), cetraline hydrochloride (25 to 200 mg / unit), amitriptyline hydrochloride (10 to 200 mg / unit). , desipramine hydrochloride (10 to 300 mg / unit), nortriptyline hydrochloride (10 to 150 mg / unit), duloxetine hydrochloride (20 to 210 mg / unit), venlafaxine hydrochloride (37.5 to 150 mg / unit), phenelzine sulfate (10 to 30 mg / unit), bupropion hydrochloride (200 to 400 mg / unit), or mirtazapine (7.5 to 90 mg / unit). These formulations are preferably used once daily. For twice daily dosing, K ATP The amount of channel opener is preferably half the amount contained in a once daily formulation and the co-formulated depression treatment is at half the amount specified.

[0255] The tablet or capsule formulations specified in Table 1 may also include combination formulations with hypertension treatment drugs. Hypertension treatment drugs that may be used include enalapril maleate (2.5 to 40 mg / unit), captopril (2.5 to 150 mg / unit), lisinopril (10 to 40 mg / unit), benzaepril hydrochloride (10 to 80 mg / unit), quinapril hydrochloride (10 to 80 mg / unit), peridopril erbumine (4 to 8 mg / unit), ramipril (1.25 to 20 mg / unit), trandolapril (1 to 8 mg / unit), fos ... Nopril sodium (10 to 80 mg / unit), moexipril hydrochloride (5 to 20 mg / unit), losartan potassium (25 to 200 mg / unit), irbesartan (75 to 600 mg / unit), valsartan (40 to 600 mg / unit), candesartan cilexetil (4 to 64 mg / unit), olmesartan medoxamil (5 to 80 mg / unit), telmisartan (20 to 160 mg / unit), eprosartan mesylate (75 to 600 mg / unit), g / unit), atenolol (25 to 200 mg / unit), propranolol hydrochloride (10 to 180 mg / unit), metoprolol tartrate, succinate or fumarate (all 25 to 400 mg / unit), nadolol (20 to 160 mg / unit), betaxolol hydrochloride (10 to 40 mg / unit), acebutolol hydrochloride (200 to 800 mg / unit), pindolol (5 to 20 mg / unit), bisoprolol fumarate (5 to 20 mg / unit), nifedipine (15 These formulations include, but are not limited to, terazosin hydrochloride (1 to 20 mg / unit), amlodipine besylate (2.5 to 20 mg / unit), nicardipine (10 to 40 mg / unit), nisoldipine (10 to 80 mg / unit), terazosin hydrochloride (1 to 20 mg / unit), doxasoxin mesylate (4 to 16 mg / unit), prazosin hydrochloride (2.5 to 10 mg / unit), or alfuzosin hydrochloride (10 to 20 mg / unit). These formulations are preferably used once daily. For twice daily dosing, K ATPThe amount of channel opener is preferably half the amount contained in a once daily formulation and the co-formulated hypertension treatment is at half the specified amount.

[0256] The specified tablet or capsule formulations in Table 1 may also include combination formulations with diuretics to treat edema. Diuretics that may be used include amiloride hydrochloride (1 to 10 mg / unit), spironolactone (10 to 100 mg / unit), triamterene (25 to 200 mg / unit), bumetanide (0.5 to 4 mg / unit), furosemide (10 to 160 mg / unit), ethacrynic acid or sodium ethacrynate (all 10 to 50 mg / unit), tosemide (5 to 100 mg / unit), chlorthalide (10 to 150 mg / unit), chloramphenicol ... Suitable formulations include, but are not limited to, thiazide (10 to 200 mg / unit), indapamide (1 to 5 mg / unit), hydrochlorothiazide (10 to 100 mg / unit), chlorothiazide (50 to 500 mg / unit), bendroflumethiazide (5 to 25 mg / unit), hydroflumethiazide (10 to 50 mg / unit), methylclothiazide (1 to 5 mg / unit), or polythiazide (1 to 10 mg / unit). These formulations are preferably used once daily. For twice daily dosing, K ATP The amount of channel opener is preferably half the amount contained in a once daily formulation and the co-formulated diuretic is at half the specified amount.

[0257] The specified tablet or capsule formulations in Table 1 may also include combination formulations with drugs for treating inflammation or pain. Drugs for treating inflammation or pain that may be used include, but are not limited to, aspirin (100 to 1000 mg / unit), tramadol hydrochloride (25 to 150 mg / unit), gabapentin (100 to 800 mg / unit), acetominophen (100 to 1000 mg / unit), carbamazepine (100 to 400 mg / unit), ibuprofen (100 to 1600 mg / unit), ketoprofen (12 to 200 mg / unit), fenprofen sodium (100 to 600 mg / unit), flurbiprofen sodium or flurbiprofen (both 50 to 200 mg / unit), or any of these in combination with a steroid or aspirin. These formulations are preferably used once a day. For twice a day dosing, K ATP The amount of channel opener is preferably half the amount contained in a once daily formulation and the co-formulated diuretic is at half the specified amount.

[0258] The specified tablet or capsule formulations of Table 1 may include combination formulations with drugs for treating obesity-related comorbidities, including those specified above for treating diabetes, cholesterol, depression, hypertension and edema, or drugs for treating atherosclerosis, osteoarthritis, herniated discs, degeneration of the knee and hip, breast cancer, endometrial cancer, cervical cancer, colon cancer, leukemia and prostate cancer, hyperlipidemia, asthma / reactive airway disease, gallstones, GERD, obstructive sleep apnea, obesity hypoventilation syndrome, recurrent abdominal wall hernia, menstrual irregularities, and infertility.

[0259] The specified tablet or capsule formulations in Table 1 may include combination formulations with antipsychotic combinations used to treat psychotic conditions and to treat or prevent weight gain, dyslipidemia, or glucose intolerance in the individual being treated. Drugs for treating various psychotic conditions that may be used include, but are not limited to, lithium or its salts (250 to 2500 mg / unit), carbamazepine or its salts (50 to 1200 mg / unit), valproate, valproic acid, or divalproex (125 to 2500 mg / unit), lamotrigine (12.5 to 200 mg / unit), olanzapine (5 to 20 mg / unit), clozapine (12.5 to 450 mg / unit), or risperidone (0.25 to 4 mg / unit). These combination formulations are preferably for once-daily administration. For twice-daily dosing, K ATP The amount of channel opener is preferably half the amount contained in a once-daily formulation and the co-formulated antipsychotic is at half the specified amount.

[0260] The specified tablet or capsule formulations in Table 1 may include combination formulations with drugs for treating or preventing ischemic or reperfusion injury. Drugs for treating or preventing ischemic or reperfusion injury that may be used include low molecular weight heparins (dalteparin, enoxaparin, nadroparin, tinzaparin, or danaparoid), ancrd, pentoxifylline, nimodipine, flunarizine, ebselen, tirilazad, clomethiazole, AMPA agonists (GYKI 52466, NBQX, YM90K, zonampanel, or MPQX), SYM 2081, celhotel, Cerestat, CP-101,606, dextrophan, dextromethorphan, MK-801, NPS 1502, remacemide, ACEA 1021, GV150526, eliprodil, ifenprodil, lubelozole, naloxone, nalfemene citicoline, acetyl-l-carnitine, nifedipine, resveratrol, nitrone derivatives, clopidogrel, dabigatram, prasugrel, troxoprodil, AGY-94806, or KAI-9803.

[0261] Sufficient K to induce weight loss ATP The formulation is provided to be administered once or twice daily to obese or overweight subjects on an ongoing basis to produce blood levels of the channel opener. Weight loss occurs through selective reduction of body fat. When the formulation is administered in combination with a reduced calorie diet, further weight loss can occur.

[0262] A method for treating obesity, overweight, or obesity-prone subjects, comprising administering to said obese, overweight, or obesity-prone subjects a single dose of K that results in inhibition of fasting or glucose-stimulated insulin secretion for about 24 hours or about 18 hours. ATP Formulations of channel openers are provided.

[0263] A method for administering K to an obese, overweight, or obesity-prone subject as a single dose, which method results in an increase in energy expenditure for about 24 hours or about 18 hours.ATP Formulations of channel openers are provided.

[0264] A method for treating obesity, comprising administering to an obese, overweight, or obesity-prone subject a single dose of K that results in increased beta-oxidation of fat for about 24 hours or about 18 hours. ATP Formulations of channel openers are provided.

[0265] K administered as a single dose to an obese, overweight, or obesity-prone overeating subject, which results in inhibition of overeating for about 24 hours or about 18 hours. ATP Formulations of channel openers are provided.

[0266] Sufficient K to induce β-cell rest or improved insulin sensitivity, or both ATP Formulations are provided that are administered once or twice daily (per 24 hours) to subjects, which provide continuous blood levels of channel openers. Such improved beta cell rest and insulin sensitivity can contribute to the effective treatment of type I diabetes, type II diabetes and pre-diabetes. Such improved beta cell rest and insulin sensitivity can contribute to the effective restoration of normal glucose tolerance in type II diabetes and pre-diabetes subjects.

[0267] Various pharmaceutical K ATPChannel opener formulations are useful in the treatment of: (1) obesity; (2) prevention of weight gain in individuals prone to obesity; (3) treatment of hyperinsulinemia or hyperinsulinemia; (4) treatment of hypoglycemia; (5) treatment of hyperlipidemia; (6) treatment of type II diabetes; (7) preservation of pancreatic function in type I diabetes; (8) treatment of metabolic syndrome (or syndrome X); (9) prevention of the transition from prediabetes to diabetes; (10) correction of defects in insulin secretion and insulin sensitivity that contribute to prediabetes and type II diabetes; (11) treatment of polycystic ovary syndrome; (12) prevention of ischemic or reperfusion injury; (13) weight gain, dyslipidemia, or glucose tolerance in subjects being treated with antipsychotics. (14) prevention of weight gain, dyslipidemia, or glucose tolerance disorders in subjects being treated with antipsychotics, and (15) treatment of any disease in which hyperlipidemia, hyperinsulinemia, hyperinsulinism, hyperlipidemia, overeating, or obesity is a contributing factor to the severity or progression of the disease, including, but not limited to, Prader-Willi syndrome, Smith-Magenis syndrome, Frohlich syndrome, Cohen syndrome, Summit syndrome, Alstrom syndrome, Borjesen syndrome, Bardet-Biedl syndrome, hyperlipoproteinemia types I, II, III, and IV.

[0268] In one embodiment, K ATP The channel opener is administered to an overweight or obese individual as a solid oral dose once per 24 hours, optionally in combination with growth hormone, to induce weight loss.In a further embodiment, the individual (a) is not type I diabetes, (b) is not type II diabetes, (c) does not experience chronic, recurrent or drug-induced hypoglycemia, (d) does not have metabolic syndrome, or (e) does not experience malignant hypertension.

[0269] In one embodiment, K ATPThe channel opener is administered to overweight or obese individuals as a solid oral dose twice per 24 hours, optionally in combination with growth hormone, to induce weight loss.This treatment may be the only treatment to induce weight loss.In a further embodiment, the overweight or obese individual (a) does not have insulin secreting tumors, (b) does not suffer from polycystic ovarian syndrome, (c) does not have type I diabetes, (d) does not have type II diabetes, (e) does not have metabolic syndrome, (f) does not experience chronic, recurrent or drug-induced hypoglycemia, (g) does not receive treatment for schizophrenia with haloperidol, or (h) does not experience malignant hypertension.In a further embodiment, the overweight or obese youth (a) has not been diagnosed with type I or type II diabetes, (b) does not experience chronic, recurrent or drug-induced hypoglycemia, or (c) has not been diagnosed with metabolic syndrome.

[0270] In another embodiment, K ATP The channel opener is administered to overweight or obese individuals in solid oral dosage form three times per 24 hours, optionally in combination with growth hormone, to induce weight loss.This treatment may be the only treatment to induce weight loss.In a further embodiment, the overweight or obese individual (a) does not have insulin-secreting tumors, (b) does not suffer from polycystic ovarian syndrome, (c) does not have type I diabetes, (d) does not have type II diabetes, (e) does not have metabolic syndrome, or (f) does not experience chronic, recurrent or drug-induced hypoglycemia.

[0271] In another embodiment, K ATP The channel opener is administered to overweight or obese adolescents three times per 24 hours as a solid oral dosage form, optionally in combination with growth hormone, to induce weight loss.This treatment may be the only treatment to induce weight loss.In a further embodiment, the overweight or obese adolescents (a) do not have type I or type II diabetes, (b) do not experience chronic, recurrent or drug-induced hypoglycemia, or (c) do not have metabolic syndrome.

[0272] In another embodiment, K ATP The channel opener is administered in a solid oral dosage form three times per 24 hours, optionally in combination with growth hormone, to induce weight loss to overweight or obese adults who are (a) not receiving concomitant glucagon injections, triiodothyroxine or furosemide, (b) not being treated for schizophrenia with haloperidol, or (c) not experiencing malignant hypertension.

[0273] In another embodiment, K ATP The channel openers are administered as solid oral dosage forms four times per 24 hours to overweight or obese individuals, optionally in combination with growth hormone, to induce weight loss.

[0274] In another embodiment, K ATP The channel opener is administered as a solid oral dosage form at a daily dose of 50 to 275 mg, optionally in combination with growth hormone, to an overweight or obese individual, dosed 1, 2, 3, or 4 times per 24 hours, to induce weight loss. In a further embodiment, the overweight or obese individual (a) does not have type I diabetes, (b) does not have type II diabetes, (c) does not suffer from chronic, recurrent or drug-induced hypoglycemia, or (d) does not have metabolic syndrome.

[0275] In another embodiment, K ATP The channel opener is administered as a solid oral dosage form at a daily dose of 130 to 275 mg, optionally in combination with growth hormone, to an overweight or obese individual, dosed 1, 2, 3, or 4 times per 24 hours, in order to induce weight loss. In a further embodiment, the overweight or obese individual (a) is not type I diabetes, (b) is not type II diabetes, (c) does not suffer from chronic, recurrent or drug-induced hypoglycemia, or (d) does not have metabolic syndrome.

[0276] In another embodiment, K ATPThe channel opener is administered as a solid oral dosage form to an overweight or obese individual once, twice, three times, or four times per 24 hours, optionally in combination with growth hormone, to maintain weight loss, since once some weight loss has occurred in an obese individual, it is preferable to maintain weight if weight regain is another possibility. ATP The administered daily dose of the channel opener is between 50 and 275 mg.

[0277] In another embodiment, K ATP The channel openers are administered as solid oral dosage forms to overweight, obese, or obesity-prone individuals, optionally in combination with growth hormone, to (a) increase energy expenditure, (b) increase fat beta-oxidation, or (c) reduce blood triglyceride concentrations.

[0278] In another embodiment, K ATP A solid oral dosage of the channel opener is administered on a chronic basis to an individual in need thereof to induce a reduction of 25%, 50%, or 75% of initial body fat.

[0279] In another embodiment, K ATP A solid oral dosage of a channel opener is administered on a chronic basis to an individual in need thereof, optionally in combination with growth hormone, to induce (a) a selective reduction in body fat, or (b) a selective reduction in visceral body fat.

[0280] In a further embodiment, K ATP A solid oral dosage of a channel opener is administered to an individual on a chronic basis at a daily dose of 50 to 275 mg once, twice, or three times per 24 hours, optionally in combination with growth hormone, to (a) induce a 25%, 50%, or 75% reduction in initial body fat, (b) induce a selective reduction in body fat, or (c) induce a selective reduction in visceral fat.

[0281] In another embodiment, K ATPA solid oral dosage of the channel opener is administered to an individual, optionally in combination with growth hormone, to induce selective loss of body fat and to induce a reduction in blood triglycerides.

[0282] In another embodiment, K ATP A solid oral dosage of the channel opener is co-administered with the growth hormone.

[0283] In yet another embodiment, K ATP Solid oral dosages of channel openers may be administered in conjunction with growth hormone, and optionally with sibutramine, orlistat, rimonabant, appetite suppressants, antidepressants, antiepileptics, non-furosemide diuretics, K-stimulants, or combination therapies to induce weight loss in overweight, obese, or obesity-prone individuals and / or to treat obesity-related comorbidities. ATP Drugs that induce weight loss through a mechanism different from that of channel openers, K ATP It is co-administered with one or more drugs that induce weight loss by a mechanism different from the channel opener, but are not metformin, furosemide or triiodothyroxine, or drugs that lower blood pressure. In a further embodiment, the overweight, obese, or obesity-prone individual (a) has type I diabetes, (b) is not type II diabetes, (c) does not suffer from chronic, recurrent or drug-induced hypoglycemia, or (d) does not have metabolic syndrome.

[0284] In another embodiment, K ATP A solid oral dosage of a channel opener is co-administered with growth hormone to an overweight, obese, or obesity-prone individual, and optionally with one or more of an antidepressant, a blood pressure lowering drug, a cholesterol lowering drug, a HDL raising drug, an anti-inflammatory drug that is not a Cox-2 inhibitor, a blood triglyceride lowering drug, to induce weight loss and / or treat obesity-related comorbidities. In a further embodiment, the overweight, obese, or obesity-prone individual (a) is not type I diabetes, (b) is not type II diabetes, (c) does not suffer from chronic, recurrent or drug-induced hypoglycemia, or (d) does not have metabolic syndrome.

[0285] In another embodiment, K ATP A solid oral dosage of a channel opener is co-administered with growth hormone, and optionally with one or more of blood pressure lowering drugs, cholesterol lowering drugs, HDL raising drugs, anti-inflammatory drugs that are not Cox-2 inhibitors, blood triglyceride lowering drugs, to maintain weight and / or treat obesity-related comorbidities in overweight, obese, or obesity-prone individuals, since once some weight loss has occurred in an obese individual, it is preferable to maintain weight if weight regain is another possibility. In a further embodiment, the overweight, obese, or obesity-prone individual (a) is not type I diabetes, (b) is not type II diabetes, (c) does not suffer from chronic, recurrent or drug-induced hypoglycemia, or (d) does not have metabolic syndrome.

[0286] In a further embodiment, K ATP Tablet formulations of channel openers are administered at therapeutically effective doses of K to (a) provide beta cell rest, (b) treat type I or type II diabetes, or (c) prevent the onset of diabetes. ATP The channel opener is used to be administered to an obese, overweight, or obesity-prone individual in need thereof.

[0287] In a further embodiment, K ATP A solid oral dosage form or tablet formulation of the channel opener is co-administered with growth hormone, and optionally with phentermine or one or more of its derivatives, to obese adults or adolescents to induce weight loss and / or treat obesity and obesity-related comorbidities. ATP A solid oral dosage form or tablet formulation of the channel opener is co-administered with phentermine or a derivative thereof, optionally in combination with growth hormone, to obese adults or adolescents to treat metabolic syndrome in patients in need thereof.

[0288] In a further embodiment, K at a dose of 50 to 275 mg / dayATP A pharma- ceutically acceptable formulation of a channel opener is co-administered with a daily dose of 15 to 37.5 mg of growth hormone, and optionally one or more of phentermine or its derivatives, to an overweight or obese individual to induce weight loss, treat metabolic syndrome, or induce weight loss and treat obesity-related comorbidities. In another embodiment, a tablet formulation is co-administered with growth hormone, and optionally one or more of phentermine or its derivatives, to treat metabolic syndrome in a patient.

[0289] In another embodiment, K, optionally in combination with growth hormone, ATP A rapidly dissolving formulation of a channel opener is used to provide a therapeutically effective dose to a patient in need thereof.

[0290] In a further embodiment, K ATP Channel openers are administered at doses of 125 mg to 275 mg once per 24 hours, optionally in combination with growth hormone, to overweight or obese individuals who do not have type II diabetes and are not receiving treatment for nocturnal hypoglycemia.

[0291] In a further embodiment, K ATP The channel opener is formulated as a tablet or capsule for oral administration. The tablet or capsule may be co-formulated with metformin. In another embodiment, K ATP The channel openers are formulated as oral suspensions, which in another embodiment may be further encapsulated.

[0292] In another embodiment, K ATP The pharmaceutical salt of the channel opener is formulated as a tablet or capsule for oral administration, or as an oral suspension or solution, or as an encapsulated oral solution. When the channel opener is diazoxide, the salt is preferably not a sodium salt.

[0293] In another embodiment, K ATPThe channel opener is co-formulated with hydrochlorothiazide, chlorothiazide, cyclothiazide, benzthiazide, methyclothiazide, bendroflumethiazide, hydroflumethiazide, trichlormethiazide, or polythiazide in a pharmaceutical formulation suitable for oral administration.

[0294] Following administration of the formulations described herein to humans or animals, some or all of the following effects are observed: (1) reduced production of lipoprotein lipase by adipocytes; (2) increased lipolysis by adipocytes; (3) reduced expression of fatty acid synthase by adipocytes; (4) reduced glyceraldehyde phosphate dehydrogenase activity in adipocytes; (5) little or no new triglyceride synthesis and storage by adipocytes; (6) increased expression of β3 adrenergic receptors (β3AR), improving adrenergic function in adipocytes; (7) reduced glucose-stimulated secretion of insulin by pancreatic B cells; (8) reduced insulinemia; (9) improved blood glucose levels; (10) increased secretion of insulin by adipocytes. (11) increased expression of uncoupling protein 1 in white and brown adipose tissue; (12) reduced plasma triglyceride concentrations; (13) reduced circulating leptin concentrations; (14) upregulation of insulin receptors; (15) improved glucose uptake; (16) reduced adipocyte hyperplasia; (17) reduced adipocyte hypertrophy; (18) reduced rate of preadipocyte to adipocyte conversion; (19) reduced rate of hyperphagia, (20) increased protection of the CNS, heart and other tissues from ischemic or reperfusion injury, (21) improved insulin sensitivity, (22) increased CSF insulin concentrations, (23) increased circulating adiponectin concentrations, (25) reduced circulating triglyceride concentrations, (26) improved beta cell rest, and / or (27) increased lean body mass.

[0295] The threshold concentration of the present invention is (1) a measurable suppression of fasting insulin levels; (2) a K ATP (3) suppression of fasting insulin levels by at least 20% from baseline measurements in the same individual prior to treatment with a channel opener; ATP(4) suppression of fasting insulin levels by at least 30% from baseline measurements in the same individual prior to treatment with a channel opener; ATP Suppression of fasting insulin levels by at least 40% from baseline measurements in the same individual prior to treatment with a channel opener; (5)K ATP Suppression of fasting insulin levels by at least 50% from baseline measurements in the same individual prior to treatment with a channel opener; (6)K ATP Suppression of fasting insulin levels by at least 60% from baseline measurements in the same individual prior to treatment with a channel opener. (7)K ATP Suppression of fasting insulin levels by at least 70% from baseline measurements in the same individual prior to treatment with a channel opener; (8)K ATP (9) suppression of fasting insulin levels by at least 80% from a baseline measurement in the same individual prior to treatment with a channel opener; (10) a reduction in body weight; (11) an increase in resting energy expenditure; or (12) an increase in fat or fatty acid oxidation, resulting from administration of the drug as an iv formulation, immediate release oral formulation, controlled release formulation, transdermal formulation, or intranasal formulation to an overweight or obese individual, optionally in combination with growth hormone. ATP Including those blood concentrations of channel openers.

[0296] The threshold effect of the present invention results from administration of an iv formulation of a drug, or an immediate release oral formulation of a drug, or a controlled release formulation of a drug, or an extended release or transdermal or intranasal formulation of a drug to an obesity-prone individual, resulting in (1) weight loss, and (2) weight maintenance. ATP Including those blood concentrations of channel openers.

[0297] The threshold effect of the present invention results from administration of an iv formulation of a drug, or an immediate release oral formulation of a drug, or a controlled release formulation of a drug, or an extended release or transdermal or intranasal formulation of a drug to a prediabetic individual, resulting in prevention of the transition to diabetes. ATP Including those blood concentrations of channel openers.

[0298] The threshold effect of the present invention results from administration of an iv formulation of a drug, or an immediate release oral formulation of a drug, or a controlled release formulation of a drug, or an extended release or transdermal or intranasal formulation of a drug to an individual with type 1 diabetes that results in beta cell rest. ATP Including those blood concentrations of channel openers.

[0299] The administration of K to an overweight, obese, or obesity-prone individual as provided herein ATP The modes of action resulting from chronic administration of channel openers to maintain or lose body weight include, but are not limited to, one or more of: (1) increased energy expenditure, (2) increased fat and fatty acid oxidation, (3) increased lipolysis in adipose tissue, (4) increased glucose uptake by tissues, increased insulin sensitivity, (5) improved beta adrenergic response, and (6) increased lean body mass. ATP The mode of action resulting in weight maintenance or loss resulting from chronic administration of channel openers may also include appetite suppression.

[0300] Administration of K, optionally in combination with growth hormone, to overweight or obese humans or animals ATPLong-term administration of pharmaceutical formulations of channel openers results in substantial and sustained weight loss including some or all of the following effects: (1) selective reduction in body fat; (2) greater than 25% reduction in initial body fat mass; (3) greater than 50% reduction in initial body fat mass; (4) greater than 75% reduction in initial body fat mass; (5) significant increase in resting energy expenditure; (6) increased fat and fatty acid oxidation; (7) reduced blood pressure; (8) reduced production of lipoprotein lipase by adipocytes; (9) increased lipolysis by adipocytes; (10) reduced expression of fatty acid synthase enzymes by adipocytes; (11) reduced glyceraldehyde phosphate dehydrogenase activity in adipocytes; (12) little or no new triglycerides synthesized and stored by adipocytes; (13) increased expression of β3 adrenergic receptors (β3AR) and improved adrenergic function in adipocytes; (14) increased pancreatic (15) reduced glucose-stimulated secretion of insulin by B cells; (16) increased blood glucose levels; (17) increased expression of uncoupling protein 1 in adipocytes; (18) increased thermogenesis in white and brown adipose tissue; (19) reduced plasma triglyceride concentrations; (20) reduced blood leptin concentrations; (21) upregulation of insulin receptors; (22) increased glucose uptake; (23) reduced adipocyte hyperplasia; (24) reduced adipocyte hypertrophy; (25) reduced rate of preadipocyte to adipocyte conversion; (26) reduced rate of hyperphagia; (27) sequential reduction of the most metabolically active adipose tissue (visceral) first, followed by less metabolically active adipose tissue; (28) increased blood adiponectin concentrations; (29) increased cerebrospinal fluid insulin levels; (30) increased pancreatic islet insulin mRNA and insulin content; (31) increased efficiency of insulin metabolism; or (32) increased lean body mass.

[0301] Administration of K, optionally in combination with growth hormone, to obese humans or animals, including individuals who have undergone various types of bariatric surgery. ATPLong-term administration of channel opener formulations results in sustained maintenance of body weight, including some or all of the following effects: (1) increased resting energy expenditure; (2) increased fat and fatty acid oxidation; (3) reduced blood pressure; (4) reduced production of lipoprotein lipase by adipocytes; (5) increased lipolysis by adipocytes; (6) reduced expression of fatty acid synthase by adipocytes; (7) reduced glyceraldehyde phosphate dehydrogenase activity in adipocytes; (8) little or no new triglyceride synthesis and storage by adipocytes; (9) increased expression of β3 adrenergic receptors (β3AR) and improved adrenergic function in adipocytes; (10) increased uptake of insulin by pancreatic B cells. (11) reduced glucose stimulated secretion; (12) improved blood glucose levels; (13) increased expression of uncoupling protein 1 in adipocytes; (14) improved thermogenesis in white and brown adipose tissue; (15) reduced plasma triglyceride concentrations; (16) reduced blood leptin concentrations; (17) upregulation of insulin receptors; (18) improved glucose uptake; (19) reduced adipocyte hyperplasia; (20) reduced adipocyte hypertrophy; (21) reduced rate of preadipocyte to adipocyte conversion; and (22) reduced rate of hyperphagia; (23) increased blood adiponectin concentrations; (24) increased cerebrospinal fluid insulin levels; (25) improved pancreatic islet insulin mRNA and insulin content; or (26) improved efficiency of insulin metabolism.

[0302] Administration of K, optionally in combination with growth hormone, to humans or animals with prediabetes or type I diabetes ATPAcute or chronic administration of channel opener formulations results in prevention of beta cell failure, improved glycemic control, and prevention of the transition from prediabetes to diabetes, including some or all of the following effects: (1) increased resting energy expenditure; (2) increased fat and fatty acid oxidation; (3) reduced blood pressure; (4) reduced production of lipoprotein lipase by adipocytes; (5) increased lipolysis by adipocytes; (6) reduced expression of fatty acid synthase by adipocytes; (7) reduced glyceraldehyde phosphate dehydrogenase activity in adipocytes; (8) little or no new triglyceride synthesis and storage by adipocytes; (9) increased expression of beta3 adrenergic receptors (beta3AR) and adrenergic function in adipocytes. improvement; (10) reduction in glucose-stimulated secretion of insulin by pancreatic B cells; (11) reduction in insulinemia; (12) improvement in blood glucose levels; (13) increase in expression of uncoupling protein 1 in adipocytes; (14) improvement in thermogenesis in white and brown adipose tissue; (15) reduction in plasma triglyceride concentrations; (16) reduction in blood leptin concentrations; (17) upregulation of insulin receptors; (18) improvement in glucose uptake; (19) reduction in adipocyte hyperplasia; (20) reduction in adipocyte hypertrophy; (21) reduction in the rate of preadipocyte conversion to adipocytes; (22) reduction in the rate of hyperphagia; (23) increase in blood adiponectin concentrations; (24) increase in cerebrospinal fluid insulin levels; (25) improvement in pancreatic islet insulin mRNA and insulin content; or (26) improvement in the metabolic efficiency of insulin.

[0303] Administration of K, optionally in combination with growth hormone, to humans or animals at risk of myocardial infarction or stroke, or undergoing surgical procedures to restore blood flow to the heart or brain. ATP Acute or chronic administration of channel opener formulations results in improved therapeutic outcomes following surgery or the occurrence of myocardial infarction or stroke by improving tissue survival after blood flow is restored, reducing tissue stunning, and modifying the nature of the inflammatory response.

[0304] The pharmaceutical formulations described herein are designed for use in the treatment of obesity, hyperlipidemia, hypertension, weight maintenance, type I diabetes, pre-diabetes, type II diabetes, or any condition in which weight loss, reduction of blood triglycerides, or beta cell rest contributes to a therapeutic outcome, and are intended to provide a therapeutically effective dose of K, optionally in combination with growth hormone. ATP Provide a series of significant changes in pharmacodynamic and pharmacokinetic responses to channel openers, including one or more of the following: (1) extending the pharmacodynamic effect of an administered dose for greater than 24 hours, as measured by inhibition of insulin secretion; (2) providing substantial uptake of the active pharmaceutical component in the small intestine; (3) providing substantial uptake of the active pharmaceutical component in the large intestine; (4) resulting in a reduced Cmax relative to current oral suspension or capsule products of the active pharmaceutical component at the same administered dose; (5) providing blood concentrations of the unbound active pharmaceutical component that exceed a threshold concentration for greater than 24 hours from a single administered dose; and (6) providing more consistent drug absorption by treated individuals compared to existing capsule formulations.

[0305] The pharmaceutical combination formulations of the present invention, which are designed to treat a range of conditions in humans and animals, ATP Combinations of a channel opener with a growth hormone, and optionally one or more of: (1) a diuretic, (2) a drug that reduces blood pressure, (3) a drug that suppresses appetite, (4) a cannabinoid receptor antagonist, (5) a drug that inhibits the action of gastric lipase, (6) a drug used to induce weight loss, (7) a drug that reduces cholesterol, (8) a drug that reduces LDL-bound cholesterol, (9) a drug that improves insulin sensitivity, (10) a drug that improves glucose utilization or uptake, (11) a drug that reduces the incidence of atherosclerotic plaque, (12) a drug that reduces inflammation, (13) a drug that is an antidepressant, (14) a drug that is an antiepileptic, or (15) a drug that is an antipsychotic.

[0306] K, optionally combined with growth hormone ATPTreatment of humans or animals with pharmaceutical formulations of channel openers according to the invention results in a reduced incidence of adverse side effects including, but not limited to, edema, fluid retention, reduced excretion rates of sodium, chloride and uric acid, hyperglycemia, ketoacidosis, nausea, vomiting, dyspepsia, ileus and headache. These reductions in frequency of adverse side effects are achieved by (1) starting the individual on a sub-therapeutic dose and escalating the dose daily until a therapeutic dose is reached, with the number of days on which dose escalations are performed being 2 to 10, (2) using the lowest effective dose to achieve the desired therapeutic outcome, (3) using pharmaceutical formulations that delay release of the active agent until gastric transit is complete, (4) using pharmaceutical formulations that delay release of the active agent until gastric transit is complete, (5) using pharmaceutical formulations that result in lower peak drug levels in the blood compared to immediate release oral suspension or capsule formulations of the same administered dose, and (6) optimizing the timing of administration of the dose within the day and relative to meals.

[0307] K, optionally in combination with growth hormone, in patients with Prader-Willi syndrome, Smith-Magenis syndrome, Frohlich syndrome, Cohen syndrome, Summit syndrome, Alström syndrome, Borjesen syndrome, Bardet-Biedl syndrome, and hyperlipoproteinemia types I, II, III, and IV. ATP Treatment according to the present invention with a pharmaceutical formulation of a channel opener results in some or all of the following therapeutic outcomes: (1) weight loss, (2) reduced rate of weight gain, (3) inhibition of overeating, (4) reduced incidence of glucose intolerance, pre-diabetes, or diabetes, (5) reduced incidence of congestive heart failure, (6) reduced hypertension, and (7) reduced all-cause mortality.

[0308] Optionally in combination with growth hormone ATP Treatment of pre-diabetic subjects according to the present invention with a pharmaceutical formulation of a channel opener results in some or all of the following therapeutic outcomes: (1) weight loss, (2) restoration of normal glucose tolerance, (3) slowing of the rate of progression to diabetes, (4) reduction in hypertension, and (5) reduction in all-cause mortality.

[0309] Optionally in combination with growth hormone ATP Treatment of diabetic subjects according to the present invention with a pharmaceutical formulation of a channel opener results in some or all of the following therapeutic outcomes: (1) weight loss, (2) restoration of normal glucose tolerance, (3) slowing of the rate of progression of diabetes, (4) improved glucose tolerance, (5) reduction in hypertension, and (6) reduction in all-cause mortality.

[0310] The use of drugs and K in the treatment of diseases in overweight, obese, or obesity-prone human and animal subjects ATP Coadministration of channel opener formulations reduces K ATP The co-administration of a pharma- ceutically acceptable formulation of a channel opener with growth hormone, and optionally one or more of (1) sibutramine, (2) orlistat, (3) rimonabant, (4) a drug that is an appetite suppressant, (5) any drug used to induce weight loss in obese or overweight individuals, (6) a non-thiazide diuretic, (7) a drug that lowers cholesterol, (8) a drug that raises HDL cholesterol, (9) a drug that lowers LDL cholesterol, (10) a drug that lowers blood pressure, (11) a drug that is an antidepressant, (12) a drug that improves insulin sensitivity, (13) a drug that improves glucose utilization and uptake, (14) a drug that is an antiepileptic drug, (15) a drug that is an anti-inflammatory drug, or (16) a drug that lowers blood triglycerides.

[0311] Drug and K in the treatment or prevention of weight gain, dyslipidemia, or impaired glucose tolerance in subjects treated with antipsychotics ATP Coadministration of channel opener formulations reduces K ATPA pharma- ceutically acceptable formulation of a channel opener and growth hormone, and optionally, lithium, carbamazepine, valproic acid, and divalproex, as well as antidepressants generally classified as monoamine oxidase inhibitors, including lamotrigine, isocarboxazid, phenelzine sulfate, and tranylcypromine sulfate, tricyclic antidepressants, including doxepin, clomipramine, amitriptyline, maproiline, desipromine, nortriptyline, desipramine, doxepin, trimipramine, imipramine, and protriptyline, mianserin, mirtazapine, maprotiline, orthopedic acid, steroids ... Co-administration with one or more of the accepted formulations of the major sedatives and atypical antipsychotics including tetracyclic antidepressants, including oxaprotline, delequamine, levoprotline, triflucarbine, setiptiline, lortalaline, azipramine, aptazapine, maleates, and pirlindole, as well as paloproxidol, perphenazine, thioridazine, risperidone, clozapine, olanzapine, and chlorpromazine.

[0312] In one embodiment, K, optionally in combination with growth hormone, ATP The channel openers are administered to overweight or obese individuals as oral suspensions, or immediate release capsules or tablets, or controlled release formulations, or transdermal formulations, or intranasal formulations to achieve and maintain the threshold concentration required to measurably reduce fasting insulin levels over an extended period of time. ATPThe channel opener formulation reduces fasting insulin levels by at least 20%, more preferably at least 30%, more preferably at least 40%, more preferably at least 50%, more preferably at least 60%, more preferably at least 70%, more preferably at least 80%. Fasting insulin levels are generally measured using an OGTT. After an overnight fast, the patient ingests a known amount of glucose. Initial glucose levels are determined by measuring pre-test glucose levels in blood and urine. Blood insulin levels are measured with blood drawn hourly after glucose consumption for up to three hours. In a fasting glucose assay, individuals with plasma glucose values ​​above 200 mg / dl two hours after a glucose load are indicative of impaired glucose tolerance.

[0313] In another embodiment, K, optionally in combination with growth hormone, ATP Channel openers are administered to overweight or obese individuals as oral suspensions, or immediate release capsules or tablets, or controlled release formulations, or transdermal or intranasal formulations to achieve and maintain the threshold concentrations necessary to induce weight loss over the long term.

[0314] In another embodiment, K, optionally in combination with growth hormone, ATP Channel openers are administered as oral suspensions, or immediate release capsules or tablets, or controlled release formulations, or transdermal or intranasal formulations to overweight or obese individuals to achieve and maintain the threshold concentrations necessary to increase resting energy expenditure for extended periods of time.

[0315] In another embodiment, K, optionally in combination with growth hormone, ATP Channel openers are administered to overweight or obese individuals as oral suspensions, or immediate release capsules or tablets, or controlled release formulations, or transdermal or intranasal formulations to achieve and maintain the threshold concentrations necessary to increase fat and fatty acid oxidation for extended periods of time.

[0316] In another embodiment, K, optionally in combination with growth hormone, ATP Channel openers are administered to obesity-prone individuals as oral suspensions, or immediate release capsules or tablets, or controlled release formulations, or transdermal or intranasal formulations to achieve and maintain the threshold concentrations necessary to induce weight loss over the long term.

[0317] In another embodiment, K, optionally in combination with growth hormone, ATP Channel openers are administered to obesity-prone individuals as oral suspensions, or immediate release capsules or tablets, or controlled release formulations, or transdermal or intranasal formulations to achieve and maintain the threshold concentrations necessary to maintain body weight over the long term.

[0318] In another embodiment, K, optionally in combination with growth hormone, ATP Channel openers are administered to overweight or obese individuals as oral suspensions, or immediate release capsules or tablets, or controlled release formulations, or transdermal or intranasal formulations to achieve and maintain drug concentrations above the threshold concentration required to induce weight loss over an extended period of time.

[0319] In another embodiment, K, optionally in combination with growth hormone, ATP The channel openers are administered chronically as oral suspensions, or immediate release capsules or tablets, or controlled release formulations, or transdermal formulations, or intranasal formulations to overweight or obese individuals to reduce body fat by more than 25%, more preferably at least 50%, more preferably at least 75%.

[0320] In another embodiment, K, optionally in combination with growth hormone, ATP The channel openers are administered chronically as oral suspensions, or immediate release capsules or tablets, or controlled release formulations, or transdermal or intranasal formulations to overweight or obese individuals to selectively reduce visceral fat deposits.

[0321] In another embodiment, K, optionally in combination with growth hormone, ATP Channel openers are administered chronically as oral suspensions, or immediate release capsules or tablets, or controlled release formulations, or transdermal or intranasal formulations to overweight or obese individuals to reduce visceral and other fat deposits.

[0322] In another embodiment, K, optionally in combination with growth hormone, ATP Channel openers are administered as oral suspensions, or immediate release capsules or tablets, or controlled release formulations, or transdermal or intranasal formulations to insulin-normal overweight or obese individuals to achieve and maintain drug concentrations above the threshold concentration required to induce weight loss over an extended period of time.

[0323] In another embodiment, K, optionally in combination with growth hormone, ATP Channel openers are administered to pre-diabetic individuals as oral suspensions, or immediate release capsules or tablets, or controlled release formulations, or transdermal or intranasal formulations to achieve and maintain drug concentrations above the threshold concentration required to prevent progression to diabetes long term.

[0324] In another embodiment, K, optionally in combination with growth hormone, ATP Channel openers are administered to individuals with type 1 diabetes as oral suspensions, or immediate release capsules or tablets, or controlled release formulations, or transdermal or intranasal formulations to achieve and maintain drug concentrations above the threshold concentration required to induce beta cell rest for extended periods of time.

[0325] In another embodiment, a K1000 inhibitor, optionally in combination with growth hormone, is used to provide a blood concentration of active drug sufficient to reduce insulin secretion for 24 hours or more. ATP A single dose of a pharma- ceutically acceptable formulation of a channel opener is administered to an individual in need thereof.

[0326] In another embodiment, a K1000 inhibitor, optionally in combination with growth hormone, is used to provide a blood concentration of the active drug sufficient to continuously reduce insulin secretion. ATP A pharma- ceutically acceptable formulation of a channel opener is administered to an individual in need thereof no more than once per 24 hours for an extended period of time.

[0327] In another embodiment, a K1000 inhibitor, optionally in combination with growth hormone, is used to provide a blood concentration of the active drug sufficient to elevate circulating non-esterified fatty acids for 24 hours or more. ATP A single dose of a pharma- ceutically acceptable formulation of a channel opener is administered to an individual in need thereof.

[0328] In another embodiment, a K, optionally in combination with growth hormone, is used to provide a blood concentration of the active drug sufficient to continuously elevate circulating non-esterified fatty acids. ATP A pharma- ceutically acceptable formulation of a channel opener is administered to an individual in need thereof no more than once per 24 hours for an extended period of time.

[0329] In another embodiment, a K, optionally in combination with growth hormone, that provides a blood concentration of active drug sufficient to treat hypoglycemia in the circulation for 24 hours or more. ATP A single dose of a pharma- ceutically acceptable formulation of a channel opener is administered to an individual in need thereof.

[0330] In another embodiment, a K, optionally in combination with growth hormone, is used to provide a blood concentration of active drug sufficient to treat hypoglycemia on an ongoing basis. ATP A pharma- ceutically acceptable formulation of a channel opener is administered to an individual in need thereof no more than once per 24 hours for an extended period of time.

[0331] In another embodiment, a K1000 inhibitor, optionally in combination with growth hormone, is used to provide a blood concentration of active drug sufficient to induce sustained weight loss. ATPA pharma- ceutically acceptable formulation of a channel opener is administered to an individual in need thereof no more than once per 24 hours for an extended period of time.

[0332] In another embodiment, a K, optionally in combination with growth hormone, is used to provide a blood concentration of active drug sufficient to sustain weight maintenance. ATP A pharma- ceutically acceptable formulation of a channel opener is administered to an individual in need thereof not more than once per 24 hours for an extended period of time, since in an obese individual, once any weight loss has occurred, it is preferable to maintain weight if weight regain is an alternative possibility.

[0333] In another embodiment, a K1000 inhibitor, optionally in combination with growth hormone, is used to provide a blood concentration of the active drug sufficient to continuously reduce blood triglyceride levels. ATP A pharma- ceutically acceptable formulation of a channel opener is administered to an individual in need thereof no more than once per 24 hours for an extended period of time.

[0334] In another embodiment, a K, optionally in combination with growth hormone, that provides a blood concentration of the active drug sufficient to reduce or prevent ischemic or reperfusion injury in the circulation for 24 hours or more. ATP A single dose of a pharma- ceutically acceptable formulation of a channel opener is administered to an individual in need thereof.

[0335] In another embodiment, a K, optionally in combination with growth hormone, is administered to provide a blood concentration of the active drug sufficient to reduce or prevent ischemic or reperfusion injury on a sustained basis. ATP A pharma- ceutically acceptable formulation of a channel opener is administered to an individual in need thereof no more than once per 24 hours for an extended period of time.

[0336] In another embodiment, K, optionally in combination with growth hormone, ATPThe side effects of frequent treatment with channel openers are reduced using a pharma- ceutically acceptable formulation of diazoxide or a derivative thereof administered daily to an individual in need thereof, with the first dose being found to be sub-therapeutic, followed by incremental increases in the daily dose until a therapeutic dose is reached.

[0337] In another embodiment, K, optionally in combination with growth hormone, ATP The side effects of frequent treatment with channel openers are due to the fact that K is administered daily to individuals in need thereof, where the active component is not released from the formulation until gastric transit is complete. ATP This is reduced using a pharma- ceutically acceptable formulation of a channel opener.

[0338] In another embodiment, K, optionally in combination with growth hormone, ATP The side effects of frequent treatment with channel openers are due to the fact that K is administered daily to individuals in need thereof, where the active component is not released from the formulation until gastric transit is complete. ATP This is reduced using a pharma- ceutically acceptable formulation of a channel opener.

[0339] In another embodiment, K, optionally in combination with growth hormone, ATP The side effects of frequent treatment with channel openers are associated with the development of K12, optionally combined with growth hormone, administered daily to individuals in need thereof, where the maximum blood concentration of the active component is lower than that achieved by administration of the same dose using an oral suspension or capsule formulation. ATP This is reduced using a pharma- ceutically acceptable formulation of a channel opener.

[0340] In another embodiment, K, optionally in combination with growth hormone, ATPThe side effects of frequent treatment with channel openers are known to be subtherapeutic at first doses, followed by incremental increases in daily doses until a therapeutic dose is reached, the active ingredient is not released from the formulation until gastric transit is complete, and the maximum blood concentration of the active ingredient is lower than that achieved by administration of the same dose using an oral suspension or capsule formulation, and K, optionally combined with growth hormone, is administered daily to individuals in need thereof. ATP This is reduced using a pharma- ceutically acceptable formulation of a channel opener.

[0341] In another embodiment, K, optionally in combination with growth hormone, ATP The side effects of frequent treatment with channel openers are known to be subtherapeutic at first doses, followed by incremental increases in daily doses until a therapeutic dose is reached, the active ingredient is not released from the formulation until gastric transit is complete, and the maximum blood concentration of the active ingredient is lower than that achieved by administration of the same dose using an oral suspension or capsule formulation, with a maximum dose of less than 2.5 mg / kg / day, and optionally combined with growth hormone, administered daily to overweight or obese individuals in need thereof. ATP This is reduced using a pharma- ceutically acceptable formulation of a channel opener.

[0342] In another embodiment, K, optionally in combination with growth hormone, ATP The side effects of frequent treatment with channel openers are known to be subtherapeutic at first doses, followed by incremental increases in daily doses until a therapeutic dose is reached, the active ingredient is not released from the formulation until gastric transit is complete, and the maximum blood concentration of the active ingredient is lower than that achieved by administration of the same dose using an oral suspension or capsule formulation, with a maximum dose of less than 1.75 mg / kg / day, and optionally combined with growth hormone, administered daily to overweight or obese individuals in need thereof. ATP This is reduced using a pharma- ceutically acceptable formulation of a channel opener.

[0343] In another embodiment, treatment of an overweight or obese individual is achieved with K1000, optionally in combination with growth hormone, where the release of the active component from the formulation is modified to provide a near-zero order release for at least 12 hours. ATP Administration of a pharma- ceutically acceptable formulation of a channel opener once per 24 hours is optimized for weight loss.

[0344] In another embodiment, treatment of an overweight or obese individual is achieved with K1000, optionally in combination with growth hormone, where the release of the active component from the formulation is modified to provide a near-zero order release for at least 18 hours. ATP Administration of a pharma- ceutically acceptable formulation of a channel opener once per 24 hours is optimized for weight loss.

[0345] In another embodiment, treatment of an overweight or obese individual is achieved with K1000, optionally in combination with growth hormone, where the release of the active component from the formulation is modified to provide elevated drug concentrations in the circulation for at least 12 hours. ATP Administration of a pharma- ceutically acceptable formulation of a channel opener once per 24 hours is optimized for weight loss.

[0346] In another embodiment, treatment of an overweight or obese individual is achieved with K1000, optionally in combination with growth hormone, where the release of the active component from the formulation is modified to provide elevated drug concentrations in the circulation for at least 18 hours. ATP Administration of a pharma- ceutically acceptable formulation of a channel opener once per 24 hours is optimized for weight loss.

[0347] In another embodiment, treatment of overweight or obese individuals is achieved with K2+, optionally in combination with growth hormone, where the release of the active component from the formulation is modified to match the pattern of basal insulin secretion. ATP Administration of a pharma- ceutically acceptable formulation of a channel opener once per 24 hours is optimized for weight loss.

[0348] In another embodiment, K ATP The frequency of side effects following treatment with a channel opener has been found to be subtherapeutic at the first dose, followed by incremental increases in daily dose until a therapeutic dose is reached, the active ingredient is not released from the formulation until gastric transit is complete, and the maximum blood concentration of the active ingredient is lower than that achieved by administration of the same dose using an oral suspension or capsule formulation, with a maximum dose of less than 2.5 mg / kg / day, when administered daily to an obese individual in need thereof, optionally in combination with growth hormone. ATP This is reduced using a pharma- ceutically acceptable formulation of a channel opener.

[0349] In another embodiment, K, optionally in combination with growth hormone, ATP The frequency of side effects following treatment with a channel opener is known to be subtherapeutic at the first dose, followed by incremental increases in daily dose until a therapeutic dose is reached, the active ingredient is not released from the formulation until gastric transit is complete, and the maximum blood concentration of the active ingredient is lower than that achieved by administration of the same dose using an oral suspension or capsule formulation, with a maximum dose of less than 1.75 mg / kg / day, when administered daily to an obese individual in need thereof, optionally in combination with growth hormone. ATP This is reduced using a pharma- ceutically acceptable formulation of a channel opener.

[0350] In another embodiment, the treatment of obesity-prone individuals is achieved by administering to the patient a K1000 formulation, optionally in combination with growth hormone, where the release of the active component from the formulation is modified to provide a near-zero order release for at least 12 hours. ATP Administration of a pharma- ceutically acceptable formulation of a channel opener once per 24 hours is optimized for weight maintenance.

[0351] In another embodiment, the treatment of obesity-prone individuals is achieved by administering to the patient a K1000 or K2000 supplement, optionally in combination with growth hormone, where the release of the active component from the formulation is modified to provide a near-zero order release for at least 18 hours. ATPAdministration of a pharma- ceutically acceptable formulation of a channel opener once per 24 hours is optimized for weight maintenance.

[0352] In another embodiment, the treatment of obesity-prone individuals is with K1000, optionally in combination with growth hormone, where the release of the active component from the formulation is modified to provide elevated drug concentrations in the circulation for at least 12 hours. ATP Administration of a pharma- ceutically acceptable formulation of a channel opener once per 24 hours is optimized for weight maintenance.

[0353] In another embodiment, the treatment of obesity-prone individuals is with K1000, optionally in combination with growth hormone, where the release of the active component from the formulation is modified to provide elevated drug concentrations in the circulation for at least 18 hours. ATP Administration of a pharma- ceutically acceptable formulation of a channel opener once per 24 hours is optimized for weight maintenance.

[0354] In another embodiment, the treatment of obesity-prone individuals is by administration of K2+, optionally in combination with growth hormone, where the release of the active component from the formulation is modified to match the pattern of basal insulin secretion. ATP Administration of a pharma- ceutically acceptable formulation of a channel opener once per 24 hours is optimized for weight maintenance.

[0355] In another embodiment, K, optionally in combination with growth hormone, ATP A pharma- ceutically acceptable formulation of a channel opener is co-administered with sibutramine to an overweight or obese individual to induce weight loss.

[0356] In another embodiment, K, optionally in combination with growth hormone, ATP A pharma- ceutically acceptable formulation of a channel opener is co-administered with orlistat to an overweight or obese individual to induce weight loss.

[0357] In another embodiment, K, optionally in combination with growth hormone,ATP A pharma- ceutically acceptable formulation of a channel opener is co-administered with rimonabant to overweight or obese individuals to induce weight loss.

[0358] In another embodiment, K, optionally in combination with growth hormone, ATP Pharmaceutically acceptable formulations of channel openers are co-administered with appetite suppressants to overweight or obese individuals to induce weight loss.

[0359] In another embodiment, K, optionally in combination with growth hormone, ATP Pharmaceutically acceptable formulations of channel openers are co-administered with antidepressants to overweight or obese individuals to induce weight loss.

[0360] In another embodiment, K, optionally in combination with growth hormone, ATP Pharmaceutically acceptable formulations of channel openers are co-administered with anti-epileptic drugs to overweight or obese individuals to induce weight loss.

[0361] In another embodiment, K, optionally in combination with growth hormone, ATP Pharmaceutically acceptable formulations of channel openers are co-administered with non-thiazide diuretics to overweight or obese individuals to induce weight loss.

[0362] In another embodiment, K, optionally in combination with growth hormone, ATP Pharmaceutically acceptable formulations of channel openers are co-administered to overweight or obese individuals to induce weight loss, along with drugs that induce weight loss by a mechanism different from diazoxide.

[0363] In another embodiment, K, optionally in combination with growth hormone, ATP Pharmaceutically acceptable formulations of channel openers are co-administered with blood pressure lowering drugs to overweight, obesity-prone, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0364] In another embodiment, K, optionally in combination with growth hormone, ATP Pharmaceutically acceptable formulations of channel openers are co-administered with cholesterol-lowering drugs to overweight, obesity-prone, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0365] In another embodiment, K, optionally in combination with growth hormone, ATP Pharmaceutically acceptable formulations of channel openers are co-administered with drugs that raise HDL-associated cholesterol to overweight, obesity-prone, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0366] In another embodiment, K, optionally in combination with growth hormone, ATP Pharmaceutically acceptable formulations of channel openers are co-administered with drugs that improve insulin sensitivity to overweight, obesity-prone, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0367] In another embodiment, K, optionally in combination with growth hormone, ATP Pharmaceutically acceptable formulations of channel openers are co-administered with anti-inflammatory drugs to overweight, obesity-prone, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0368] In another embodiment, K, optionally in combination with growth hormone, ATP Pharmaceutically acceptable formulations of channel openers are co-administered with blood triglyceride lowering drugs to overweight, obesity-prone, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0369] In another embodiment, K, optionally in combination with growth hormone, ATPThe channel openers are co-formulated with sibutramine in a pharma- ceutically acceptable formulation administered to overweight, obesity-prone, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0370] In another embodiment, K, optionally in combination with growth hormone, ATP The channel openers are co-formulated with orlistat or other active agents that inhibit the action of gastric lipase in pharma- ceutically acceptable formulations administered to overweight, obesity-prone, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0371] In another embodiment, K, optionally in combination with growth hormone, ATP The channel openers are co-formulated with non-thiazide diuretics in pharma- ceutically acceptable formulations administered to overweight, obesity-prone, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0372] In another embodiment, K, optionally in combination with growth hormone, ATP The channel openers are co-formulated with appetite suppressants in pharma- ceutically acceptable formulations administered to overweight, obesity-prone, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0373] In another embodiment, K, optionally in combination with growth hormone, ATP The channel opener is co-formulated with a cannabinoid receptor antagonist in a pharma- ceutically acceptable formulation administered to overweight, obesity-prone, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0374] In another embodiment, K, optionally in combination with growth hormone, ATPThe channel openers are co-formulated with anticholesterol active agents in pharma- ceutically acceptable formulations administered to overweight, obesity-prone, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0375] In another embodiment, K, optionally in combination with growth hormone, ATP The channel openers are co-formulated with antihypertensive actives in pharma- ceutically acceptable formulations administered to overweight, obesity-prone, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0376] In another embodiment, K, optionally in combination with growth hormone, ATP The channel openers are co-formulated with insulin sensitizing active agents in pharma- ceutically acceptable formulations administered to overweight, obesity-prone, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0377] In another embodiment, K, optionally in combination with growth hormone, ATP The channel openers are co-formulated with anti-inflammatory actives in pharma- ceutically acceptable formulations administered to overweight, obesity-prone, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0378] In another embodiment, K, optionally in combination with growth hormone, ATP The channel openers are co-formulated with antidepressants in pharma- ceutically acceptable formulations administered to overweight, obesity-prone, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0379] In another embodiment, K, optionally in combination with growth hormone, ATP The channel openers are co-formulated with anti-epileptic drugs in pharma- ceutically acceptable formulations administered to overweight, obesity-prone, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0380] In another embodiment, K, optionally in combination with growth hormone, ATP The channel openers are co-formulated with active agents that reduce the incidence of atherosclerotic plaques in pharma- ceutically acceptable formulations that are administered to overweight, obesity-prone, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0381] In another embodiment, K, optionally in combination with growth hormone, ATP The channel opener is co-formulated with an active agent that reduces blood levels of triglycerides in a pharma- ceutically acceptable formulation that is administered to overweight, obesity-prone, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0382] Reduction of blood triglycerides in overweight, obese, or obesity-prone individuals may be achieved by administering K, optionally in combination with growth hormone. ATP This is achieved by administration of a solid oral dosage form of an effective amount of a channel opener.

[0383] K ATP A solid oral dosage form of the channel opener can be administered to an overweight or obese individual in need thereof in order to maintain body weight in a therapeutically effective amount of K ATP It may be used to administer a channel opener since, once some weight loss has occurred in an obese individual, it is preferable to maintain weight if another possibility is that weight will be regained.

[0384] The method of inducing a greater than 25% reduction in initial body fat in an overweight or obese individual comprises administering K, optionally in combination with growth hormone. ATP This may be achieved by chronic administration of a solid oral dosage form of the channel opener.

[0385] The method for inducing a greater than 50% reduction in initial body fat in an overweight or obese individual comprises administering K, optionally in combination with growth hormone. ATPThis may be achieved by chronic administration of a solid oral dosage form of the channel opener.

[0386] The method of inducing a greater than 75% reduction in initial body fat in overweight or obese individuals comprises administering K, optionally in combination with growth hormone. ATP This may be achieved by chronic administration of a solid oral dosage form of the channel opener.

[0387] A method for inducing selective reduction of visceral fat in overweight or obese individuals comprises administering K, optionally in combination with growth hormone. ATP This may be achieved by chronic administration of a solid oral dosage form of the channel opener.

[0388] A method for inducing a loss of body fat and a reduction in blood triglycerides in an overweight or obese individual comprises administering K, optionally in combination with growth hormone. ATP This may be achieved by chronic administration of a solid oral dosage form of the channel opener.

[0389] The invention will now be described with reference to the following non-limiting examples. EXAMPLES

[0390] Example 1: Potassium ATP channel activator containing formulation 1. Compressed Tablet Formulation About 15-30% by weight of diazoxide or a derivative thereof is mixed with about 55-80% by weight of hydroxypropylmethylcellulose, about 3-10% by weight of ethylcellulose, and less than 3% by weight each of magnesium stearate (as a lubricant) and talc (as a glidant). The mixture is used to produce compressed tablets as described in Reddy et al., AAPS Pharm Sci Tech 4(4):1-9 (2003). The tablets may be coated with a thin film as described below for particulates.

[0391] A tablet containing 100 mg of diazoxide or a derivative thereof also contains about 400 mg of hydroxypropylcellulose and 10 mg of ethylcellulose. A tablet containing 50 mg of diazoxide or a derivative thereof also contains about 200 mg of hydroxypropylcellulose and 5 mg of ethylcellulose. A tablet containing 25 mg of diazoxide or a derivative thereof also contains about 100 mg of hydroxypropylcellulose and 2.5 mg of ethylcellulose.

[0392] 2. Encapsulated Coated Microparticle Formulations of Diazoxide Diazoxide or a derivative thereof is encapsulated in the microparticles according to well-known methods (see, for example, U.S. Patent No. 6,022,562). Microparticles between 100 and 500 micrometers in diameter containing diazoxide or a derivative, alone or in combination with one or more suitable excipients, are formed using a granulator and then sieved to separate microparticles having the appropriate size. The microparticles are coated with a thin film by spray drying using commercial equipment (e.g., Uniglatt Spray Coating Machine). The thin film includes ethyl cellulose, cellulose acetate, polyvinylpyrrolidone, and / or polyacrylamide. The coating solution for the thin film may include a plasticizer, which may be castor oil, diethyl phthalate, triethyl citrate, and salicylic acid. The coating solution may also include a lubricant, which may be magnesium stearate, sodium oleate, or polyoxyethylated sorbitan laurate. The coating solution may further contain excipients such as talc, colloidal silica, or a mixture of the two at 1.5 to 3% by weight to prevent caking of the membrane coated particles.

[0393] 3. Formulation of Diazoxide or Derivatives in Tablet Form for Controlled Release Prior to blending, both the active ingredient and hydroxypropyl methylcellulose (Dow Methocel K4M P) are passed through an ASTM 80 mesh sieve. A blend is formed of 1 part diazoxide or derivative to 4 parts hydroxypropyl methylcellulose. After thorough blending, a sufficient volume of ethanolic solution of ethylcellulose as a granulating agent is slowly added. The amount of ethylcellulose per tablet in the final formulation is about 1 / 10 parts. The mass obtained from blending the granulating agent is sieved through a 22 / 44 mesh. The resulting granules are dried at 40°C for 12 hours and then kept at room temperature in a desiccator for 12 hours. Once dried, the granules remaining on the 44 mesh are blended with 15% fines (granules that passed through the 44 mesh). Talc and magnesium stearate are added at 2% by weight each as glidants and lubricants. Coloring agents are also added. Tablets are compressed using a simplex tablet press.

[0394] 4. Formulation of compressed tablet form of diazoxide or its derivatives providing controlled release 20-40% by weight of diazoxide or a derivative thereof is mixed with 30% by weight of hydroxypropyl methylcellulose (Dow Methocel K100LV P) and 20-40% by weight of fine lactose. The mixture is granulated with the addition of water. The granulated mixture is wet milled and then dried at 110°C for 12 hours. The dry mixture is dry milled. After milling, 25% by weight of ethylcellulose resin is added (Dow Ethocel 10FP or Ethocel 100FP), followed by 0.5% by weight of magnesium stearate. Coloring agents are also added. Tablets are compressed using a simplex tablet press (Dasbach, et al, Poster at AAPS Annual Meeting Nov 10-14(2002)).

[0395] 5. Compression-coated tableted formulations of diazoxide or its derivatives that provide controlled release Core tablets are formulated by mixing 100 mg of diazoxide or its derivatives with 10 mg of ethylcellulose (Dow Ethocel 10FP), or by mixing 75 mg of diazoxide or its derivatives with 25 mg of lactose and 10 mg of ethylcellulose (Dow Ethocel 10FP), or by mixing 50 mg of diazoxide or its derivatives with 50 mg of lactose and 10 mg of ethylcellulose (Dow Ethocel 10FP). Core tablets are formed on an automated press with a concave tool. A compression coating consisting of 400 mg of ethylene oxide (Union Carbide POLYOX WSR Coagulant) is applied and compressed to 3000 psi (Dasbach, et al., Poster at AAPS Annual Meeting Oct 26-30 (2003)).

[0396] 6. Controlled release dosage forms of diazoxide or its derivatives using an osmotic controlled release system Diazoxide or a derivative thereof is formulated as an osmotically controlled release system. In general, the two components, and the expandable hydrogel that drives the release of the active drug, are assembled into a semipermeable double laminate shell with diazoxide or a derivative thereof. After assembly, the shell is perforated to facilitate the release of the active agent after hydration of the hydrogel.

[0397] The dosage form adapted, designed and molded as an osmotic delivery system is prepared as follows: First, a composition of diazoxide or a derivative thereof is provided by blending polyethylene oxide, diazoxide or a derivative thereof and hydroxypropyl methylcellulose together until a homogenous blend is obtained. Then, a volume of denatured anhydrous ethanol, weighing 70% of the dry mass, is gradually added with continuous mixing for 5 minutes. The freshly prepared wet granulation is sieved through a 20 mesh screen, dried at room temperature for 16 hours, and sieved again through a 20 mesh screen. Finally, the sieved granulation is mixed with 0.5% by weight magnesium stearate for 5 minutes.

[0398] The hydrogel composition is prepared as follows: First, 69% by weight of polyethylene oxide, 25% by weight of sodium chloride, and 1% by weight of iron oxide are separately sieved through a 40 mesh screen. Then, all the sieved components are mixed with 5% by weight of hydroxypropylmethylcellulose to produce a homogenous blend. Next, a volume of denatured anhydrous alcohol equal to 50% of the dry mass is gradually added to the blend with continuous mixing for 5 minutes. The freshly prepared wet granulation is passed through a 20 mesh screen, dried at room temperature for 16 hours, and passed through a 20 mesh screen again. The sieved granulation is mixed with 0.5% by weight of magnesium stearate for 5 minutes (see U.S. Patent No. 6,361,795 to Kuczynski et al.).

[0399] The diazoxide or a derivative thereof composition and the hydrogel composition are compressed into a double laminate tablet, the diazoxide or a derivative thereof composition being packed first, followed by the hydrogel composition, and the laminates are pressed into a contact laminate configuration under a pressure head of 2 tons.

[0400] The bilaminate construction is coated with a semi-permeable wall (i.e., a thin film). The wall-forming composition comprises 93% cellulose acetate with an acetyl content of 39.8%, and 7% polyethylene glycol. The wall-forming composition is sprayed onto and around the bilaminate.

[0401] Finally, the semipermeable wall is perforated with an exit passageway connecting the diazoxide or derivative drug layer with the outside of the delivery system. Residual solvent is removed by drying at 50° C. and 50% humidity. The osmotic system is then dried at 50° C. to remove excess water (see U.S. Patent No. 6,361,795 to Kuczynski et al.).

[0402] 7. Preparation of Diazoxide Salts The hydrochloride salt of diazoxide is prepared by dissolving 1 mole of diazoxide (230.7 g) in 500 ml of Et2O. Dry HCl is passed through the solution until the weight of the vessel increases by 36 g. During the addition of HCl, the HCl salt of diazoxide precipitates as a powder. The salt is filtered and washed with Et2O.

[0403] Example 2: In vivo obesity study 1. Obesity Animal Models Formulations of diazoxide or derivatives prepared as described herein can be tested for efficacy in animal models of obesity as described by Surwit et al. (Endocrinology 141:3630-3637 (2000)). Briefly, 4-week-old B6 male mice are housed 5 / cage in a temperature-controlled (22°C) room with a 12-hour light, 12-hour dark cycle. High-fat (HF) and low-fat (LF) experimental diets contain 58% and 11% calories from fat, respectively. Groups of mice are fed the HF diet for the first 4 weeks of the study, while the remaining 15 mice are fed the LF diet. Mice assigned to the LF diet are maintained on this diet throughout the study as a reference group of lean control mice. At week 4, all HF-fed mice are reassigned to two groups of mice. The first group is maintained on the HF diet throughout the study as an obese control group. The remaining three groups of mice are fed a HF diet and receive a controlled release formulation of diazoxide or a derivative at approximately 150 mg / kg of active substance per day as a single dose administered by oral gavage. The animals are weighed weekly and food consumption is measured per cage twice a week until the diet is changed in week 4, after which weight and food intake are determined daily. Feed efficiency (grams of body weight gained per calorie intake) is calculated per cage. Samples for insulin, glucose, and leptin analysis are taken on day 24 (4 days before the diet is changed), day 32 (4 days after the change), and every two weeks thereafter. In all cases, food is removed 8 hours before samples are taken. Glucose is analyzed by the glucose oxidase method. Insulin and leptin concentrations are determined by double antibody RIA. The insulin assay is based on a rat standard and the leptin assay uses a mouse standard. At the end of the study, postprandial plasma samples are collected and analyzed for triglyceride and nonesterified fatty acid concentrations. Four weeks after drug treatment, a subgroup of 10 animals from each group is sacrificed. Epididymal white adipose tissue (EWAT), retroperitoneal (RP) fat, interscapular brown adipose tissue (IBAT) fat pads, and gastrocnemius muscle are removed, dissected, and weighed. Percent body fat is estimated from the weight of the epididymal fat pad. A subgroup of 5 animals from each group is injected ip with 0.5 g / kg glucose.Thirty minutes after injection, plasma samples are taken and analyzed for glucose content by the glucose oxidase method.

[0404] 2. Treatment of Obesity in Humans Formulations of diazoxide or derivatives prepared as described herein can be tested for efficacy in obese humans. Studies are performed as described by Alemzadeh (Alemzadeh, et al., J Clin Endocr Metab 83:1911-1915 (1998)). Subjects are aged 30 kg / m 2 The study consisted of moderately to morbidly obese adults with a body mass index (BMI) of 10 or greater. Each subject underwent a complete physical examination at the initial evaluation, had their weight measured on a standard electronic scale, and had their body composition measured by DEXA.

[0405] Prior to the start of the study, all subjects will be placed on a low calorie diet for a one week run-in period, designed to weed out poorly adapted individuals and to ensure stable body weight prior to treatment. Up to 50 patients will be tested with each dosage of drug. Daily dosages will be set at 100, 200, and 300 mg / day. The daily dose will be split into two doses for administration. Doses will be administered as one, two, or three 50 mg capsules or tablets at each administration time. Individual patients will be dosed daily for up to 12 months. Patients will be seen weekly, weighed, and questioned regarding any side effects or complications.

[0406] Each patient is administered a 24-hour dietary recall. Recalled meals are analyzed using a standard computer software program. All patients are placed on a reduced calorie diet and participate in regular exercise.

[0407] Before the start of the study and after completion, the following laboratory test results are obtained: blood pressure, fasting plasma glucose, insulin, cholesterol, triglycerides, free fatty acids (FFA), and glycated hemoglobin, as well as measurements of the rates of appearance and oxidation of plasma derived fatty acids. In addition, routine chemistry profiles and fasting plasma glucose are obtained weekly to identify subjects with evidence of impaired glucose tolerance and / or electrolyte abnormalities. Glucose is analyzed in plasma by the glucose oxidase method.

[0408] Insulin concentrations are determined by RIA using a double antibody kit. Cholesterol and triglyceride concentrations are measured by enzymatic methods. Plama FFA are determined by enzymatic colorimetry. SI was assessed by iv glucose tolerance test (IVGTT) using a modified minimal model. After an overnight fast, a bolus of glucose (300 mg / kg) was administered iv, followed (20 min later) by a bolus of insulin. Blood for glucose and insulin determination is obtained from the contralateral vein at -30, -15, 0, 2, 3, 4, 5, 6, 8, 10, 19, 22, 25, 30, 40, 50, 70, 100, 140, and 180 min. SI and glucose availability (SG) are calculated before and after the test is completed using Bergman's modified minimal model computer program. Acute insulin response to glucose is determined over the first 19 minutes of the IVGTT, and glucose disappearance rate (Kg) is determined from minutes 8-19 of the IVGTT. Body composition is measured by bioelectrical impedance before and after completion of the test. Resting energy expenditure (REE) is measured by indirect calorimetry after subjects are placed in a supine position for a 30 minute period and fasted overnight for 12 hours. Urine is collected over a corresponding 24 hour period before and after the test for measurement of total nitrogen and determination of substrate utilization.

[0409] 3. Treatment of obesity in humans by co-administration of diazoxide and phentermine 30kg / m 2To evaluate the chronic co-administration of solid oral dosage forms of diazoxide or a derivative thereof and phentermine in moderately to morbidly obese humans with a body mass index (BMI) of 100 or greater. Each subject will undergo a complete physical examination at the initial evaluation, have their weight measured on a standard electronic scale, and have their body composition measured by DEXA.

[0410] Prior to the start of the study, all subjects will be placed on a low calorie diet for a one week run-in period. This is designed to exclude poorly adapted individuals and ensure stable body weight prior to treatment. Up to 100 subjects will be studied. The daily dosage of diazoxide will be set at 200 mg. The daily dose will be divided into two doses for administration. The dose will be administered as a 100 mg capsule or 100 mg tablet at each administration time. Individual patients will be medicated daily for up to 12 months. Phentermine will be administered as a single daily dose of 15 mg. Patients will be seen every two weeks, weighed, and questioned regarding any side effects or complications.

[0411] All patients will be maintained on a reduced calorie diet and will participate in regular exercise. Prior to the start and completion of the study, laboratory test results will be obtained as described in the Examples above.

[0412] 4. Preventing diabetes in prediabetic people This example describes the use of diazoxide to prevent the development of diabetes in prediabetic individuals. All individuals included in the study have a high risk of developing diabetes, as measured by one of two methods. In a fasting glucose assay, the individual has a plasma glucose value between 100 and 125 mg / dl, indicating impaired fasting glucose, or in an oral glucose tolerance test, the individual has a plasma glucose value between 140 and 199 mg / dl two hours after a glucose load, indicating impaired glucose tolerance. Treatment is initiated in any individual who meets either criterion. Treated individuals are given 200 mg of diazoxide per day, either as a 100 mg capsule or tablet twice daily, or as two 100 mg capsules or tablets once daily. Placebo-treated individuals are given one placebo capsule or tablet twice daily, or two placebo capsules or tablets once daily.

[0413] Treatment will continue for one year with monthly OGTT or fasting glucose measurements.

[0414] 5. A sustained release combination formulation of diazoxide HCl and metformin HCl used to treat diabetic patients. A sustained release combination formulation of diazoxide HCl and metformin HCl is produced by forming a compressed tablet matrix containing 750 mg metformin HCl and 100 mg diazoxide HCl. These active components are blended with sodium carboxymethylcellulose (about 5% (w / w)), hypromellose (about 25% (w / w)), and magnesium stearate (<2% (w / w)). To control the rate of hydration and drug release, the compressed tablets are further coated as a thin film with a combination of ethylcellulose (80% (w / w)) and methylcellulose (20% (w / w)).

[0415] Patients with type II diabetes are treated with the oral dosage form by administration of two tablets once a day or one tablet every 12 hours. Patients are continued to be treated with the drug until one of two treatment end points is achieved or as long as the patient derives therapeutic benefit from the administration. The two treatment end points that serve as the basis for the decision to discontinue treatment are a body mass index (BMI (kg / m)) between 18 and 25. 2 )) or re-establishment of normal glucose tolerance in the absence of treatment. Patients are regularly monitored for (a) glucose tolerance using an oral glucose tolerance test, (b) glycemic control using standard blood glucose assays, (c) weight gain or loss, (d) progression of diabetic complications, and (e) side effects associated with the use of these active components.

[0416] 6. Prevention or treatment of weight gain in patients treated with olanzapine Pharmacotherapy for schizophrenia is initiated in patients who meet DSM III-R criteria for schizophrenia. The patient is administered 10 mg olanzapine (Zyprexa, Lilly) once daily. Adjunctive therapy for patients with schizophrenia includes valproic acid equivalent to 250 mg as divalproex sodium (Depakote, Abbott Labs). Weight gain, dyslipidemia and glucose intolerance, as well as metabolic syndrome, are frequent adverse events in patients treated with this antipsychotic combination. Weight gain, dyslipidemia, glucose intolerance, or metabolic syndrome are common adverse events in patients treated with this antipsychotic combination. ATPThe patient is treated with the concomitant administration of a therapeutically effective dose of a channel opener. The patient is treated with 200 mg / day of diazoxide in a once-daily tablet formulation. Diazoxide administration is continued until weight gain, dyslipidemia, glucose intolerance, or metabolic syndrome is corrected or the patient is discontinued from treatment with olanzapine. Dyslipidemia is detected by measuring blood levels of total, HDL, and LDL cholesterol, triglycerides, and nonesterified fatty acids. Glucose intolerance is detected by the use of oral or IV glucose tolerance tests. Metabolic syndrome is detected by measuring major risk factors, including central obesity, dyslipidemia, glucose intolerance, and blood levels of key inflammatory cytokines.

[0417] Example 3: Clinical Trials in Obese Pediatric and Adult PWS Patients A double-blind, placebo-controlled, single-center, open-label, single-arm clinical trial (PC025) with randomized extended withdrawal was conducted. Patients were initiated on a DCCR dose of approximately 1.5 mg / kg (maximum starting dose 145 mg) and titrated every 14 days to approximately 2.4 mg / kg, 3.3 mg / kg, and 4.2 mg / kg (maximum dose 507.5 mg). These DCCR doses are equivalent to diazoxide doses of 1.03, 1.66, 2.28, and 2.9 mg / kg, respectively. Patients were titrated at each visit at the discretion of the investigator. Any patient who demonstrated an increase in resting energy expenditure and / or a decrease in binge eating from baseline to Day 27 or Day 55 was designated a responder and was eligible for randomization in the double-blind phase. All who completed the open-label phase were responders, were randomized in the double-blind phase, and completed this phase. During the double-blind, placebo-controlled, randomized withdrawal phase, responders were randomized in a 1:1 ratio to continue active treatment at the dose administered on day 55 or a placebo equivalent of that dose for an additional 4 weeks (29 days). Non-responders continued open-label treatment with DCCR at the dose administered on day 55 for an additional 29 days. A total of 12 patients were enrolled in the study. TIFF0007645913000012.tif55149 * All screening procedures must be completed by day -14.

[0418] Inclusion criteria: Basic requirements ·Ability to follow verbal or written instructions with or without the assistance of a caregiver · Informed consent form signed by the subject or their legal guardian The screening process must be completed 2 to 4 weeks prior to the baseline visit. General demographic characteristics Male and female patients aged between 10 and 22 years at the time of administration Genetically confirmed Prader-Willi syndrome BMI > 95th percentile for age-specific BMI on the CDC BMI chart or body fat ≥ 35% (body fat criteria are used only if the measurement was taken within 12 months of the screening visit and if the patient has not shown weight loss since the measurement. In all other situations, BMI criteria apply.) Be in general good health as reported by medical history, physical examination, assessment of vital signs, 12-lead electrocardiogram (ECG), and clinical laboratory evaluation Specific Laboratory Test Results Fasting glucose ≦126mg / dL HbA1c≦6.5%

[0419] Endpoints and statistical analysis All endpoints are measured in two time frames: (1) during the open-label treatment phase as change (or percent change) from baseline to day 69, and (2) during the double-blind, placebo-controlled, randomized withdrawal phase as change (or percent change) from day 69 to day 97.

[0420] Endpoints measured during the open-label treatment phase were analyzed by paired t-tests, whereas endpoints measured during the double-blind, placebo-controlled treatment phase were subjected to ANOVA and paired t-tests.

[0421] Efficacy endpoints included binge eating (measured using parent / caregiver responses to a modified Dykens binge eating question, converted to a numeric score between 0 and 34); body weight; body fat (measured by DEXA); lean body mass (measured by DEXA); resting energy expenditure (measured by indirect calorimetry); respiratory quotient (measured by indirect calorimetry); waist circumference; BMI; ghrelin; leptin; triglycerides; total cholesterol; HDL cholesterol; non-HDL cholesterol and LDL cholesterol. Additional information was collected in behavioral questions. Tables 2 and 3 summarize the visits at which each efficacy parameter was measured.

[0422] Table 2. Time points for evaluation of efficacy parameters during the open-label phase TIFF0007645913000013.tif78132

[0423] Table 3. Time points for evaluation of efficacy parameters during double-blind treatment TIFF0007645913000014.tif62157

[0424] Patients in the study Demographic information and relevant medical history for each patient are shown in Table 4. Eleven of the thirteen subjects who participated in clinical trial PC025 completed the open-label phase. All were identified as responders and therefore randomized in the double-blind phase of the study. All subjects randomized in the double-blind phase of the study completed this phase.

[0425] The baseline characteristics of the patients enrolled in the study are shown in Table 5.

[0426] Table 4. Demographic information and relevant medical history for patients enrolled in PC025 TIFF0007645913000015.tif119159

[0427] Table 5. Baseline characteristics of subjects randomized in the double-blind phase of clinical trial PC025 TIFF0007645913000016.tif73159

[0428] dosage One subject with treated type 2 diabetes completed the open-label treatment period at a dose of 1.5 mg / kg. Of the remaining 10 subjects, one completed the open-label treatment period at a dose of 2.4 mg / kg, and three at a dose of 3.3 mg / kg. The final six subjects enrolled in the study completed the open-label treatment period at a dose of 4.2 mg / kg.

[0429] Changes in body composition, waist circumference, and weight Body fat and lean mass were measured by DEXA at ​​baseline and again at the end of open-label treatment. Because DEXA was not performed on Day 97, only body composition measurements were performed for subjects randomized in the double-blind phase performed between baseline and Day 69. Changes in body composition are summarized in Table 6. Changes in body composition by DEXA were assessed separately for growth hormone-treated and growth hormone-naive subjects. These results are shown in Table 6.

[0430] DEXA body weight was calculated as the sum of body fat and lean body mass. The ratio of lean body mass to body fat was also calculated.

[0431] Table 6. Change in body composition by DEXA from baseline to day 69 TIFF0007645913000017.tif87128

[0432] 10 weeks of DCCR treatment has a highly significant and clinically relevant effect on body composition, including a reduction in body fat, an increase in lean body mass, and a highly significant increase in the ratio of lean body mass to body fat.Because these patients have nearly equal lean body mass and fat mass at baseline, the parallel increase in lean body mass and the reduction in body fat do not result in a net change in body weight.In general, the changes in body composition are of similar magnitude in both growth hormone-treated and growth hormone-naive subjects.

[0433] Changes in body composition were dose-dependent: subjects who completed the open-label treatment phase at the 4.2 mg / kg dose experienced a 6.3% decrease in fat mass, a 9.2% increase in lean body mass, and a 16.6% increase in the ratio of lean body mass to fat mass.

[0434] Three subjects in the study showed an increase in lean body mass of more than 10%. All subjects showed an increase in the lean body mass / fat mass ratio. The majority of subjects in the study showed an increase in the lean body mass / fat mass ratio of more than 10%, with one showing an increase of more than 20%.

[0435] Figures 1-4 summarize the percent change in body fat, lean mass, and lean mass / fat mass ratio from baseline to day 69.

[0436] At each visit, weight and waist circumference were measured during physical examination. This data can be used to evaluate the change from baseline to day 69 for all subjects randomized in the double-blind phase, the change by treatment arm for the period from day 69 to day 97, and the change in subjects who continued on DCCR in the double-blind phase from baseline to day 97. The results from the period from baseline to day 69 inclusive are summarized in Table 7. The results from the period from day 69 to day 97 inclusive are summarized in Table 8. The results for subjects who continued on DCCR in the double-blind phase from baseline to day 97 are shown in Table 9.

[0437] Table 7. Changes in weight and waist circumference from baseline to day 69 TIFF0007645913000018.tif20128

[0438] Table 8. Changes in weight and waist circumference from day 69 to day 97 TIFF0007645913000019.tif30144

[0439] Table 9. Change in weight and waist circumference from baseline to day 97 for subjects treated with DCCR in the double-blind phase TIFF0007645913000020.tif20128

[0440] Interestingly, the change in body weight from baseline to day 69 by DEXA and by standard weight measurement yields nearly identical results (an increase of 0.67% by DEXA and 0.53% by standard methods). In contrast to the lack of change in body weight, there was a statistically significant reduction in waist circumference to day 69 in all subjects randomized in the double-blind phase; and to day 97 for subjects who continued on DCCR. Comparison of the change in waist circumference between treatment groups between days 69 and 97 shows that placebo-treated patients showed a gradual increase in waist circumference, while subjects who continued on DCCR showed a significant reduction. The reduction in waist circumference is consistent with the explanation that DCCR-treated subjects are losing visceral fat.

[0441] Changes in overeating Binge eating questions were administered at all visits. This data can be used to assess the change from baseline to day 69 for all subjects randomized in the double-blind phase, the change by treatment group for the period from day 69 to day 97, and the change in subjects who continued on DCCR in the double-blind phase from baseline to day 97. The results from the period from baseline to day 69 are summarized in Table 10. The results from the period from day 69 to day 97 are summarized in Table 11. The results for subjects who continued on DCCR in the double-blind phase from baseline to day 97 are shown in Table 12.

[0442] Table 10. Change in Binge Eating from Baseline to Day 69 TIFF0007645913000021.tif11128

[0443] Table 11. Changes in overeating from day 69 to day 97 TIFF0007645913000022.tif20135

[0444] Table 12. Change in Binge Eating from Baseline to Day 97 for Subjects Treated with DCCR in the Double-Blind Phase TIFF0007645913000023.tif15128

[0445] A statistically significant reduction in binge eating was seen in all subjects randomized in the double-blind phase from baseline to Day 69 and in subjects who continued on DCCR through the double-blind phase from baseline to Day 97.

[0446] DCCR-treated patients at the end of 97 days of treatment showed a 29.2% improvement in binge eating, whereas patients treated with DCCR for 69 days followed by placebo treatment for 28 days showed only a 13.9% improvement in binge eating at day 97. Thus, at the end of the double-blind phase, DCCR-treated patients showed more than twice the improvement in binge eating shown by patients randomized to placebo in the double-blind phase. When patients discontinue DCCR treatment, it takes approximately 7-10 days for DCCR to be completely removed from circulation, given its long half-life (28-32 hours). Verbatim testimonials were obtained from the parents of subjects in the study suggesting that their children's food-related behaviors were observed to worsen only during the final weeks of the study, suggesting that the longer double-blind phase may have resulted in further withdrawal of the treatment group. In general, the magnitude of the effect on how moody subjects became when denied food, on how easy it was to get them to think about other things once food was denied, and on how often they stole food, rummaged through garbage for food, and negotiated for food were equal to or greater than the overall effect on the binge eating scores. DCCR appeared to have a smaller effect on the extent to which subjects became crafty or quick with food, and how often they got up in the middle of the night looking for food.

[0447] Improvement in binge eating was observed in subjects with baseline binge eating ranging from 29 (-45%) to less than 5 (-33%) on a 0 to 34 point scale.

[0448] Approximately 25% of subjects completed the open-label phase with very low levels of binge eating (2 or 3 on a scale of 0 to 34). These subjects tended to be able to lose more body fat than average. Two such subjects, both female, one growth hormone treated and one growth hormone naïve, lost more than 10% of their initial body fat mass over the course of 10 weeks.

[0449] FIG. 1 shows the change in binge eating from baseline to day 69.

[0450] Lipid changes A lipid panel was assessed at baseline and again at days 69 and 97. This data can be used to assess the change from baseline to day 69 for all subjects randomized in the double-blind phase, the change by treatment group for the period from day 69 to day 97, and the change in subjects who continued on DCCR in the double-blind phase from baseline to day 97. The results from the period including baseline to day 69 are summarized in Table 13. The results for subjects who continued on DCCR in the double-blind phase from baseline to day 97 are shown in Table 14.

[0451] Table 13. Change in lipids from baseline to day 69 TIFF0007645913000024.tif30128

[0452] Table 14. Median percent lipid changes from baseline to day 97 for subjects treated with DCCR in the double-blind phase TIFF0007645913000025.tif34128

[0453] Consistent with previous studies involving DCCR, treatment of subjects randomized in the double-blind phase with DCCR from baseline to day 69 resulted in several statistically significant changes in lipids, including reductions in total cholesterol, LDL cholesterol and non-HDL cholesterol. Even though the magnitude of effect on triglycerides was larger, this did not reach significance due to smaller n and greater variability within the population. In general, greater reductions in triglycerides were seen in subjects with significant elevations in triglycerides at baseline. A similar pattern was observed in subjects treated with DCCR until the end of double-blind treatment. The reductions in total cholesterol, triglycerides, LDL-C and non-HDL-C were all greater in subjects treated with DCCR for longer.

[0454] Changes in leptin and ghrelin Leptin and ghrelin were measured at baseline and again on day 69. Results from baseline to day 69 for leptin and ghrelin are listed in Table 15.

[0455] Table 15. Changes in leptin and ghrelin from baseline to day 69 TIFF0007645913000026.tif15128

[0456] Further evidence of a reduction in body fat comes from the analysis of leptin, the results of which are consistent with the DEXA and waist circumference data: leptin was reduced by more than 20% from baseline, although this did not reach statistical significance.

[0457] Ghrelin may or may not contribute substantially to overeating in PWS, but reduction of ghrelin is beneficial in PWS patients.

[0458] Behavioral changes Using questions adapted from natural history studies of PWS, participants reported the presence or absence of 23 PWS-related behaviors at baseline and again at day 69. These behaviors generally fell into four categories: (1) Aggressive, threatening and disruptive behavior; (2) self-injurious behavior; (3) obsessive-compulsive behavior; and (4) Other actions. Questions were administered at baseline and again on day 69. Cessation rates for aggressive, threatening and disruptive behaviors, as well as all other behaviors, are presented in Table 16.

[0459] Table 16. Discontinuation rates for various classes of behaviors in clinical trial PC025 TIFF0007645913000027.tif15132

[0460] The effects on aggressive, threatening, and disruptive behavior were unrelated to the effects on binge eating.

[0461] Changes in resting energy expenditure and respiratory quotient Measurements of resting energy expenditure and respiratory quotient can be highly variable from visit to visit. Despite this variability, resting energy expenditure and respiratory quotient did not appear to change from baseline to day 69.

[0462] Changes in insulin sensitivity Treatment with DCCR in other clinical trials has been associated with improved insulin resistance as measured by changes in homeostatic model assessment of insulin resistance (HOMA-IR). Improvements in insulin sensitivity have been well documented in the diazoxide literature. Subjects enrolled in the double-blind phase of this study were highly insulin sensitive at baseline, which is typical for PWS patients in this age range. Consistent with previous DCCR clinical trials and the historically significant diazoxide literature, 10 weeks of treatment with DCCR resulted in an improvement in HOMA-IR from 2.61±1.85 at baseline to 1.46±1.36 at day 69. The difference did not reach statistical significance (p=0.095).

[0463] Example 4: Clinical Trial for Patients with Smith-Magenis Syndrome In a first example, a patient with Smith-Magenis syndrome is treated with an oral suspension of diazoxide. The initial dose is about 1 mg / kg and is administered in divided doses. After the patient has been stably treated with 1 mg / kg for a period of 1 to 2 weeks, the dose is titrated to about 1.5 mg / kg. After the patient has been stably treated with 1.5 mg / kg for a period of 1 to 2 weeks, the dose is titrated to about 2.0 mg / kg. This process of dose increments of about 0.5 mg / kg at each titration step and treatment periods of 1 to 2 weeks at each step is continued until the patient shows an adequate response to treatment or until a maximum dose of 5 mg / kg is reached. Possible responses to treatment may include a reduction in body fat, reduced hypotension, an increase in the ratio of lean body mass to fat mass, reduced overeating, reduced waist circumference, reduced body weight, reduced emotional outbursts and aggressive behavior, and improved cardiovascular risk factors. Treatment with the drug is long-term and may be continued for life.

[0464] In a second example, a patient with Smith-Magenis syndrome is treated with a controlled release tablet formulation of diazoxide choline. The initial dose is about 1.5 mg / kg and is administered once a day. After the patient has been stably treated with 1.5 mg / kg for a period of 1 to 2 weeks, the dose is titrated to about 2.1 mg / kg. After the patient has been stably treated with 2.1 mg / kg for a period of 1 to 2 weeks, the dose is titrated to about 2.7 mg / kg. This process of dose increments of about 0.6 mg / kg at each titration step and treatment periods of 1 to 2 weeks at each step is continued until the patient shows an adequate response to treatment or until a maximum dose of 5 mg / kg is reached. Possible responses to treatment may include loss of body fat, reduced hypotension, increased ratio of lean body mass to fat mass, reduced overeating, reduced waist circumference, weight loss, reduced emotional outbursts and aggressive behavior, and improved cardiovascular risk factors. Treatment with the drug is long-term and may be continued for life.

[0465] In a third example, a patient with Smith-Magenis syndrome is treated with a controlled release tablet formulation of diazoxide choline. The initial dose is about 1.5 mg / kg and is administered once a day. After the patient has been stably treated with 1.5 mg / kg for a period of 1 to 2 weeks, the dose is titrated to about 2.2 mg / kg. After the patient has been stably treated with 2.2 mg / kg for a period of 1 to 2 weeks, the dose is titrated to about 2.9 mg / kg. This process of dose increments of about 0.7 mg / kg at each titration step and treatment periods of 1 to 2 weeks at each step is continued until the patient shows an adequate response to treatment or a maximum dose of 5 mg / kg is reached. In parallel, the patient may be treated with beloranib. Possible responses to treatment may include a reduction in body fat, reduced hypotension, an increase in the ratio of lean body mass to fat mass, reduced overeating, reduced waist circumference, reduced body weight, reduced emotional outbursts and aggressive behavior, and improved cardiovascular risk factors. Drug treatment is long-term and can be continued for life.

[0466] In a fourth example, a patient with Smith-Magenis syndrome is treated with a controlled release tablet formulation of diazoxide choline. The initial dose is about 1.5 mg / kg, administered once daily. After the patient has been stably treated with 1.5 mg / kg for a period of 1 to 2 weeks, the dose is titrated to about 2.3 mg / kg. After the patient has been stably treated with 2.3 mg / kg for a period of 1 to 2 weeks, the dose is titrated to about 3.0 mg / kg. This process of dose increments of about 0.8 mg / kg at each titration step and treatment periods of 1 to 2 weeks at each step continues until the patient shows an adequate response to treatment or a maximum dose of 5 mg / kg is reached. In parallel, the patient may be treated with a non-acylated ghrelin analog. Possible responses to treatment may include loss of body fat, reduced hypotension, increased ratio of lean body mass to fat mass, reduced overeating, reduced waist circumference, reduced body weight, reduced emotional outbursts and aggressive behavior, and improved cardiovascular risk factors. Drug treatment is long-term and can be continued for life.

[0467] In a fifth example, a patient with Smith-Magenis syndrome is treated with a controlled release tablet formulation of diazoxide choline. The initial dose is about 1.5 mg / kg, administered once a day. After the patient has been stably treated with 1.5 mg / kg for a period of 1 to 2 weeks, the dose is titrated to about 2.4 mg / kg. After the patient has been stably treated with 2.4 mg / kg for a period of 1 to 2 weeks, the dose is titrated to about 3.3 mg / kg. This process of dose increments of about 0.9 mg / kg at each titration step and treatment periods of 1 to 2 weeks at each step continues until the patient shows an adequate response to treatment or a maximum dose of 5 mg / kg is reached. In parallel, the patient may be treated with an MC4 agonist. Possible responses to treatment may include loss of body fat, reduced hypotension, increased ratio of lean body mass to fat mass, reduced overeating, reduced waist circumference, reduced body weight, reduced emotional outbursts and aggressive behavior, and improved cardiovascular risk factors. Drug treatment is long-term and can be continued for life.

[0468] In a sixth example, a patient with Smith-Magenis syndrome is treated with a controlled release tablet formulation of diazoxide choline. The initial dose is about 1.5 mg / kg, administered once a day. After the patient has been stably treated with 1.5 mg / kg for a period of 1 to 2 weeks, the dose is titrated to about 2.5 mg / kg. After the patient has been stably treated with 2.5 mg / kg for a period of 1 to 2 weeks, the dose is titrated to about 3.5 mg / kg. This process of dose increments of about 1.0 mg / kg at each titration step and treatment periods of 1 to 2 weeks at each step is continued until the patient shows an adequate response to treatment or a maximum dose of 5 mg / kg is reached. In parallel, the patient may be treated with an MC4 agonist. Possible responses to treatment may include loss of body fat, reduced hypotension, increased ratio of lean body mass to fat mass, reduced overeating, reduced waist circumference, reduced body weight, reduced emotional outbursts and aggressive behavior, and improved cardiovascular risk factors. Drug treatment is long-term and can be continued for life.

[0469] All patents or other references cited in this specification are indicative of the level of skill of those skilled in the art to which this invention pertains and are incorporated by reference in their entirety, including any tables and figures, to the same extent as if each reference was individually incorporated by reference in its entirety.

[0470] Those skilled in the art will readily appreciate that the present invention is well adapted to obtain the ends and advantages mentioned, as well as those inherent therein. The methods, variables, and compositions described herein as presently representative of the preferred embodiments are illustrative and are not intended as limitations on the scope. Those skilled in the art will envision modifications thereof and other uses that are encompassed within the spirit of the invention, as defined by the scope of the claims.

[0471] The definitions set forth herein are not intended to be limiting to the meanings commonly understood by one of ordinary skill in the art, unless otherwise specified.

[0472] The invention illustratively described herein can be suitably practiced in the absence of any elements or limitations not specifically disclosed herein. Thus, for example, terms such as "comprises", "includes", "contains", etc., are to be interpreted expansively and without limitation. Furthermore, the terms and expressions used herein are used for explanatory purposes and not for limiting purposes, and there is no intention in the use of such terms and expressions to exclude any equivalents of the features shown and described or portions thereof, and it is recognized that various modifications are possible within the scope of the invention as claimed. Thus, although the present invention has been specifically disclosed by preferred embodiments and optional features, it should be understood that modifications and variations of the invention embodied herein may be used by those skilled in the art, and such modifications and variations are considered to be within the scope of the present invention.

[0473] The invention has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the general disclosure also form part of the invention. This includes the general description of the invention with a provisos or negative limitation excluding any subject matter from the genus, regardless of whether the excluded material is specifically recited herein.

[0474] Other embodiments are within the scope of the following claims. Furthermore, when features or aspects of the invention are described in terms of a Markush group, one of ordinary skill in the art will recognize that the invention is also thereby described in terms of any individual element or subgroup of elements of the Markush group.

Claims

1. A pharmaceutical formulation for increasing lower limb muscle mass in a subject with Prader-Willi syndrome, comprising an effective amount of diazoxide or a pharma- ceutically acceptable salt thereof.

2. 10. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation comprises diazoxide.

3. 3. The pharmaceutical formulation of claim 1 or 2, wherein the pharma- ceutically acceptable salt is diazoxide choline.

4. The pharmaceutical formulation of any one of claims 1 to 3, wherein diazoxide or a pharma- ceutically acceptable salt thereof is administered orally.

5. The pharmaceutical formulation of any one of claims 1 to 4, wherein the pharmaceutical formulation comprises at least one excipient that affects the release rate of diazoxide or a pharma- ceutically acceptable salt thereof.

6. 6. The pharmaceutical formulation of any one of claims 1 to 5, wherein the pharmaceutical formulation comprises at least one excipient that delays the release of diazoxide or a pharma- ceutically acceptable salt thereof.

7. The pharmaceutical formulation of any one of claims 1 to 6, wherein the pharmaceutical formulation further comprises at least one other active ingredient.

8. The pharmaceutical formulation of any one of claims 1 to 7, wherein following administration of the pharmaceutical formulation to the subject, the subject's lean body mass or lean body mass / fat mass ratio is increased by at least 2%.

9. 9. The pharmaceutical formulation of any one of claims 1 to 8, wherein following administration of the pharmaceutical formulation to the subject, the subject's lean body mass or lean body mass / fat mass ratio is increased by at least 3%.

10. 9. The pharmaceutical formulation of any one of claims 1 to 8, wherein following administration of the pharmaceutical formulation to the subject, the subject's lean body mass or lean body mass / fat mass ratio is increased by at least 4%.

11. 9. The pharmaceutical formulation of any one of claims 1 to 8, wherein following administration of the pharmaceutical formulation to the subject, the subject's lean body mass or lean body mass / fat mass ratio is increased by at least 5%.

12. The pharmaceutical formulation of any one of claims 1 to 11, wherein the pharmaceutical formulation is administered to the subject for one year or more.

13. The pharmaceutical formulation of any one of claims 1 to 12, wherein after administration of the pharmaceutical formulation to the subject, binge eating in the subject is reduced by at least 10%.

14. The pharmaceutical formulation of any one of claims 1 to 12, wherein after administration of the pharmaceutical formulation to the subject, binge eating in the subject is reduced by at least 20%.

15. The pharmaceutical formulation of any one of claims 1 to 12, wherein after administration of the pharmaceutical formulation to the subject, binge eating in the subject is reduced by at least 30%.

16. The pharmaceutical formulation of any one of claims 1 to 15, wherein there is no increase in circulating concentration of IGF-1 following administration of the pharmaceutical formulation to the subject.

17. The pharmaceutical formulation of any one of claims 1 to 16, wherein the pharmaceutical formulation is administered to the subject twice daily.

18. The pharmaceutical formulation of any one of claims 1 to 16, wherein the pharmaceutical formulation is administered to the subject once daily.

19. The pharmaceutical formulation of any one of claims 1 to 18, further comprising administering to the subject human growth hormone.

20. 20. The pharmaceutical formulation of claim 19, wherein the human growth hormone is administered by injection.

21. The pharmaceutical formulation of any one of claims 1 to 18, wherein the subject is not administered human growth hormone.

22. Use of diazoxide or a pharma- ceutically acceptable salt thereof in the manufacture of a pharmaceutical preparation for increasing lower limb muscle mass in a subject with Prader-Willi syndrome, the pharmaceutical preparation comprising an effective amount of diazoxide or a pharma- ceutically acceptable salt thereof.

23. 23. The use of claim 22, wherein the pharmaceutical formulation comprises diazoxide.

24. 24. The use according to claim 22 or 23, wherein the pharma- ceutically acceptable salt is diazoxide choline.

25. The use according to any one of claims 22 to 24, wherein the pharmaceutical formulation comprises at least one excipient that affects the release rate of diazoxide, or a pharma- ceutically acceptable salt thereof.

26. The use according to any one of claims 22 to 25, wherein the pharmaceutical formulation comprises at least one excipient that delays the release of diazoxide, or a pharma- ceutically acceptable salt thereof.

27. The use according to any one of claims 22 to 26, wherein the pharmaceutical formulation further comprises at least one other active ingredient.

28. The use according to any one of claims 22 to 27, wherein following administration of the pharmaceutical preparation to the subject, the subject's lean body mass or lean body mass / fat mass ratio is increased by at least 2%.

29. The use according to any one of claims 22 to 28, wherein after administration of the pharmaceutical formulation to the subject, binge eating in the subject is reduced by at least 10%.

30. The use according to any one of claims 22 to 29, wherein the subject is an adult.

31. The use according to any one of claims 22 to 30, wherein the subject is over 16 years of age.

32. The use according to any one of claims 22 to 31, wherein the subject is not administered human growth hormone.

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