Methods for treating a subject having prader-willi syndrome or smith-magenis syndrome

Abstract

The present invention provides for the immediate or chronic administration of certain potassium ATP (K ATP ) channel openers, optionally in combination with growth hormone, to subjects to achieve novel pharmacodynamic, pharmacokinetic, therapeutic, physiological, metabolic, and compositional outcomes in the treatment of diseases or conditions involving K ATP channels. Also provided are pharmaceutical formulations, methods of administration, and methods of dosing K ATP channel openers to achieve these outcomes and to reduce the incidence of adverse effects in treated individuals. Also provided are methods of co-administering K ATP channel openers with other drugs, e.g., in combination with growth hormone, to treat diseases in humans and animals, e.g., Prader-Willi Syndrome (PWS), Smith-Magenis Syndrome (SMS), etc.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201580072525.9 (Filing Date: November 12, 2015, Inventor Name: ARIANNA P. SCHIAVO, Title of Invention: Methods for treating subjects having Prader-Willi Syndrome or Smith-Magenis Syndrome). TECHNICAL FIELD

[0002] The present invention relates to pharmaceutical formulations of potassium ATP (K ATP ) channel openers and their use for treating various diseases and conditions such as Prader-Willi Syndrome (PWS), Smith-Magenis Syndrome (SMS), and the like. BACKGROUND

[0003] The following description of background of the invention is provided merely as an aid to understanding the invention and is not admitted to be prior art to the invention.

[0004] ATP-sensitive potassium (K ATP ) channels play an important role in many tissues by coupling cellular metabolism to electrical activity. K ATP Channels have been identified as octameric complexes of two unrelated proteins that assemble with a 4:4 stoichiometry. The first is a pore-forming subunit, Kir6.x, which forms an inwardly rectifying K + channel; the second is an ABC (ATP-binding cassette) transporter, also known as a sulfonylurea receptor (SURx) (Babenko et al., Annu. Rev. Physiol., 60:667-687 (1998)). The Kir6.x pore-forming subunit is common to many types of K ATP channels and has two putative transmembrane domains (identified as TM1 and TM2) connected by a pore loop (H5). The subunit containing the SUR receptor includes multiple transmembrane domains and two nucleotide-binding folds.

[0005] Depending on their tissue localization, K ATP channels exist in different isoforms or subtypes resulting from assembly of SUR subunits and Kir subunits in various combinations. The combination of SUR1 subunit and Kir6.2 subunit (SUR1 / Kir6.2) typically forms K ATP channels of the fat cell and pancreatic B cell types, while SUR2A / Kir6.2 and SUR2B / Kir6.2 or Kir6.1 combinations typically form K ATP channels of the cardiac and smooth muscle types, respectively.Channels (Babenko et al., Annu. Rev. Physiol., 60:667-687 (1998)). There is also evidence that the channels can include Kir2.x subunits. Such potassium channels are 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 in this way play a key role in regulating cellular activity. In most excitable cells, K ATP Channels are closed under normal physiological conditions and open when the tissue is metabolically compromised (e.g., when the (ATP:ADP) ratio falls). This causes K+to flow out and the cell to hyperpolarize, thereby preventing the opening of voltage-operated Ca2+channels (VOCs). (Prog Res Research, (2001) 31 :77-80).

[0006] Potassium channel openers (PCOs or KCOs) (also known as channel activators or channel agonists) are a structurally diverse group of compounds that do not share an obvious common pharmacophore in relation to their ability to antagonize the inhibition of K ATP Channels by intracellular nucleotides. Diazoxide is a PCO that stimulates K ATP Channels in pancreatic β cells (see Trube et al., Pfluegers Arch Eur J Physiol, 407, 493-99 (1986)). Pinacidil and chromakalim are PCOs that activate the potassium channels of the sarcolemma (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 demonstrated to exist in the 6thto 11thpredicted transmembrane domains (TMD6-11) of the SUR1 subunit as well as the first nucleotide binding fold (NBF1).

[0007] Diazoxide is a non- diuretic benzothiadiazide derivative having the formula 7-chloro-3-methyl-2H-l,2,4-benzothiadiazine 1.1-dioxide (empirical formula C8H7CIN2O2S) that is commercialized in three different formulations to treat two different disease indications: 1) hypertensive emergencies and 2) hyperinsulinemic hypoglycemic conditions. Hypertensive emergencies are treated with Hyperstat IV, which is an aqueous formulation of diazoxide for intravenous use adjusted to pH 11.6 with sodium hydroxide. Hyperstat IV is administered in a bolus dose into a peripheral vein to treat malignant hypertension or sulfonylurea overdoses. In this use, diazoxide acts to open potassium channels in vascular smooth muscle, stabilizing the membrane potential at resting levels and preventing vasoconstriction.

[0008] Hyperinsulinemic hypoglycemic conditions are treated with Proglycem, which is an oral pharmaceutical form of diazoxide that can be administered to infants, children, and adults. It is available as a chocolate mint flavored oral suspension that includes 7.25% alcohol, sorbitol, chocolate cream flavor, propylene glycol, magnesium aluminum silicate, sodium carboxymethylcellulose, peppermint flavor, sodium benzoate, methyl paraben, hydrochloric acid to adjust pH, poloxamer 188, propyl paraben, and water. Diazoxide is also available as a capsule that contains either 50 mg or 100 mg of diazoxide that includes lactose and magnesium stearate.

[0009] Several experimental formulations of diazoxide have been tested in humans and animals. These include oral solutions that were tested in pharmacodynamic and pharmacokinetic studies as well as tablet formulations that are being developed as antihypertensive agents but have never been commercialized (see Calesnick et al., J. Pharm. Sci. 54: 1277-1280 (1965); Reddy et al., AAPS Pharm SciTech 4(4): 1-98, 9 (2003); U.S. Patent 6,361,795).

[0010] Current oral formulations of diazoxide are labeled for twice or thrice daily dosing at 8 hour or 12 hour intervals. Most patients receiving diazoxide are dosed thrice daily. Commercial and experimental formulations of diazoxide are characterized by rapid drug release upon ingestion, with release being completed in about 2 hours.

[0011] Current oral diazoxide formulations cause a range of adverse side effects during therapeutic use, including indigestion, nausea, diarrhea, fluid retention, edema, decreased sodium, chloride, and uric acid excretion rates, hyperglycemia, vomiting, abdominal pain, intestinal obstruction, tachycardia, palpitations, and headache (see the current Proglycem packaging insert). Oral diazoxide treatment is used in individuals suffering from severe disease where failure to receive treatment would result in significant morbidity and mortality. The adverse side effects of oral administration are tolerable because the therapeutic benefits are significant. The adverse side effects of oral diazoxide limit the efficacy of the drug in treating obese patients at labeled doses ranging from 3 mg / kg to 8 mg / kg daily.

[0012] The effects of diazoxide in animal models of diabetes and obesity (e.g., obese and emaciated Zuckerrat rats) have 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)); Stanridge 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)).

[0013] The effects of diazoxide in humans with obesity or diabetes have been reported. See, e.g., Wigand and Blackard (Diabetes 28(4):287-291 (1979); Evaluation of diazoxide on insulin receptors); 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); Moderatedose diazoxide treatment on weight loss in obese patients); Alemzadeh et al. (J Clin Endocr Metab 83:1911-1915 (1998); Low dose diazoxide treatment on 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 clinical onset of type 1 diabetes); Bjork et al. (Diabetes Care 21(3):427-430 (1998); Diazoxide treatment in obese children with type 1 diabetes); and, Wajngot et al. (Diabetes 53(2):344-349 (2004); Diazoxide treatment in obese patients with type 2 diabetes)."Effect of diazoxide on residual insulin secretion in adult type I diabetes patients"; and Qvigstad et al. (Diabetic Medicine 21 :73-76 (2004)).

[0014] U.S. Patent No. 5,284,845 describes a method for normalizing blood glucose and insulin levels in individuals exhibiting normal fasting blood glucose and insulin levels and elevated glucose levels and at least one of the following abnormal insulin levels in an oral glucose tolerance test: delayed insulin peak, exaggerated insulin peak, and a secondary elevated insulin peak. According to this reference, the method comprises administering diazoxide in an amount of about 0.4 mg to about 0.8 mg per kg of body weight prior to each meal in an amount effective to normalize blood glucose and insulin levels.

[0015] U.S. Patent No. 6,197,765 describes the administration of diazoxide as a treatment for Syndrome X and resulting complications including hyperlipidemia, hypertension, central obesity, hyperinsulinemia, and impaired glucose intolerance. According to this reference, diazoxide interferes with pancreatic function by eliminating endogenous insulin secretion, thereby causing an insulin-deficient state and hyperglycemic levels comparable to diabetic patients dependent on exogenous insulin administration to normalize blood glucose levels.

[0016] U.S. Patent No. 2,986,573 describes diazoxide and alkali metal salts for the treatment of hypertension.

[0017] U.S. Patent No. 5,629,045 describes diazoxide for topical ophthalmic administration.

[0018] WO 98 / 10786 describes the use of diazoxide for the treatment of Syndrome X, including obesity associated therewith.

[0019] U.S. Patent Publication No. 2003 / 0035106 describes diazoxide-containing compounds for reducing consumption of fat-containing foods.

[0020] U.S. Patent Publication No. 2004 / 0204472 describes the use of a Cox-2 inhibitor plus diazoxide for the treatment of obesity.

[0021] U.S. Patent Publication No. 2002 / 0035106 describes K ATP Use of a channel opener for reducing consumption of fat-containing foods. SUMMARY

[0022] Provided herein are K ATP channel openers and their use, optionally in combination with growth hormone, for treating various diseases and conditions, including Prader-Willi Syndrome (PWS), Smith-Magenis Syndrome (SMS), and the like. These formulations are characterized as being bioavailable. As used herein, K ATP channel openers have any one or more of the following properties: (1) open SUR1 / Kir6.2 potassium channels; (2) bind to the SUR1 subunit of the channel; and (3) inhibit glucose-induced insulin release upon in vivo administration of the compound. Preferably, K ATP channel openers have all three properties. As defined above, K ATP channel openers are preferably of the structure of the compounds of Formulas I-VII, as shown below. ATP channel openers. As defined above, K ATP channel openers preferably have the structure of the compounds of Formulas I-VII, as shown below.

[0023] According to one aspect of the present invention, one or more K ATP channel openers, optionally in combination with growth hormone, are effective for treating subjects having Prader-Willi Syndrome (PWS), Smith-Magenis Syndrome (SMS), and the like, and are particularly effective for increasing lean body mass in such subjects. Thus, in one aspect of the present invention, there is provided a method of increasing lean body mass in a subject having Prader-Willi Syndrome (PWS), Smith-Magenis Syndrome (SMS), and the like, the method comprising administering to the subject an effective amount of a K ATP channel opener, optionally in combination with growth hormone, for at least 4 weeks.

[0024] 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%.

[0025] In some embodiments, in addition to increasing lean body mass in a subject, the methods of the present invention also reduce hyperphagia in the subject. In some embodiments, the subject's hyperphagia is reduced by at least 10%. In some embodiments, the subject's hyperphagia is reduced by at least 20%. In some embodiments, the subject's hyperphagia is reduced by at least 30%.

[0026] In some embodiments, the methods of the application reduce body fat in the subject in addition to increasing lean body mass in the subject. In some embodiments, the body fat of the subject is reduced by at least 1%. In some embodiments, the body fat of the subject is reduced by at least 3%. In some embodiments, the body fat of the subject is reduced by at least 5%.

[0027] In another aspect, the application provides a method of increasing lean body mass in a subject suffering from Prader-Willi Syndrome (PWS), Smith-Magenis Syndrome (SMS), or the like, wherein the subject has been treated by administering to the subject a growth hormone, the method comprising co-administering to the subject an effective amount of a K ATP channel opener in addition to the growth hormone.

[0028] In yet another aspect, the application provides a method of increasing lean body mass in a subject suffering from Prader-Willi Syndrome (PWS), Smith-Magenis Syndrome (SMS), or the like, wherein the subject has been treated by administering to the subject an effective amount of a K ATP channel opener, the method comprising co-administering to the subject an effective amount of a growth hormone in addition to the K ATP channel opener.

[0029] The K ATP channel openers of the application are defined by Formula I as follows:

[0030]

[0031] wherein:

[0032] R 1a and R 1b are, independently when present, selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, amino, and substituted amino;

[0033] R 2a and R 2b are, independently when present, selected from the group consisting of hydrogen and lower alkyl;

[0034] X is a 1-atom chain, a 2-atom chain, or a 3-atom chain, wherein each atom is independently selected from carbon, sulfur, or nitrogen, and each atom is optionally substituted with halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, cycloalkyl, substituted cycloalkyl, substituted lower alkoxy, amino, or substituted amino;

[0035] wherein each of ring A and ring B is independently saturated, mono-unsaturated, poly-unsaturated, or aromatic;

[0036] And all its biological equivalents, including salts, prodrugs, and isomers.

[0037] In a specific embodiment, the compound of formula I may include a double bond between position 1 and position 2 of ring A or between position 2 and position 3. When a double bond is present between position 1 and position 2 of ring A, R 2a It does not exist and R 1a and R 1b One of them does not exist. When the double bond exists between position 2 and position 3 of ring A, R 2b It does not exist and R 1a and R 1b One of them does not exist. In a preferred embodiment, R 1a and R 1b It is not an amino group. In another preferred embodiment, ring B does not contain any heteroatoms.

[0038] K is defined by Equation II as a subclass of Equation I. ATP The following are channel opening agents:

[0039]

[0040] in:

[0041] R 1 Choose from the group consisting of: hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, amino, and substituted amino;

[0042] R 2a Selected from the group consisting of hydrogen and lower alkyl groups;

[0043] X is a 1-atom chain, a 2-atom chain, or a 3-atom chain, wherein each atom is independently selected from carbon, sulfur, or nitrogen, and each atom is optionally substituted with a halogen, hydroxyl, lower alkyl, substituted lower alkyl, lower alkoxy, cycloalkyl, substituted cycloalkyl, substituted lower alkoxy, amino, or substituted amino.

[0044] Among them, ring B can be saturated, monounsaturated, polyunsaturated, or aromatic;

[0045] And all its biological equivalents, including salts, prodrugs, and isomers.

[0046] In a specific implementation of Equation II, X is C(R) a )C(R b ), where R a and R bindependently selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkoxy, substituted lower alkoxy, amino, sulfonamido, aminosulfonyl, sulfonyl, and the like. In further embodiments, R a and R b are independently selected from the group consisting of hydroxyl, substituted oxy, substituted thiol, alkylthio, substituted alkylthio, sulfinyl, sulfonyl, substituted sulfinyl, substituted sulfonyl, substituted sulfonamido, substituted amino, substituted amine, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamido, and the like. In a preferred embodiment, R 1 is not amino. In another preferred embodiment, ring B does not include any heteroatoms.

[0047] K is defined by formula III as a sub-class of formula I ATP Channel openers are as follows:

[0048]

[0049] wherein:

[0050] R 1 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, amino, and substituted amino;

[0051] R 2b is selected from the group consisting of hydrogen and lower alkyl;

[0052] X is a 1-atom chain, a 2-atom chain, or a 3-atom chain, wherein each atom is independently selected from carbon, sulfur, or nitrogen, and each atom is optionally substituted with halogen, hydroxyl, lower alkyl, substituted lower alkyl, lower alkoxy, cycloalkyl, substituted cycloalkyl, substituted lower alkoxy, amino, or substituted amino;

[0053] wherein ring B is saturated, mono-unsaturated, poly-unsaturated, or aromatic;

[0054] and all bioequivalents thereof, including salts, prodrugs, and isomers.

[0055] In specific embodiments of formula III, X is C(R a )C(R b ), wherein R a and R b are independently selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkoxy, substituted lower alkoxy, amino, sulfonamido, aminosulfonyl, sulfonyl, and the like. In further embodiments, R a and Rb independently selected from the group consisting of hydroxy, 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. In a preferred embodiment, R 1 is not amino. In another preferred embodiment, ring B does not include any heteroatoms.

[0056] K is defined by formula IV as a sub-class of formula I ATP Channel openers are as follows:

[0057]

[0058] wherein:

[0059] R 1 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, amino, and substituted lower amino;

[0060] R 2a is selected from the group consisting of hydrogen, lower alkyl, and substituted lower alkyl;

[0061] R 3 is selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, amino, and substituted amino;

[0062] R 4 is selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, amino, and substituted amino;

[0063] and all bioequivalents thereof, including salts, prodrugs, and isomers.

[0064] In a specific embodiment of formula IV, R 1 is lower alkyl (preferably ethyl or methyl); R 2a is hydrogen; and R 3 and R 4 are each independently halogen.

[0065] In a preferred embodiment of formula IV, R 1 is not amino.

[0066] In another embodiment of formula IV, R 1 is methyl; R 2a 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; and R4 It is chlorine.

[0067] K is defined by equation V, which is a subclass of equation I. ATP The following are channel opening agents:

[0068]

[0069] in:

[0070] R 1 Choose from the group consisting of: hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, amino, and substituted lower amino;

[0071] R 2b Choose from the group consisting of: hydrogen, lower alkyl groups, and substituted lower alkyl groups;

[0072] R 3 Choose from the group consisting of: hydrogen, halogens, lower alkyl groups, substituted lower alkyl groups, amino groups, and substituted amino groups;

[0073] R 4 Choose from the group consisting of: hydrogen, halogens, lower alkyl groups, substituted lower alkyl groups, amino groups, and substituted amino groups;

[0074] And all its biological equivalents, including salts, prodrugs, and isomers.

[0075] In a specific implementation scheme of formula V, R 1 It is a lower alkyl group (preferably ethyl or methyl); R 2b It is hydrogen; and R 3 and R 4 Each is a halogen on its own.

[0076] In a preferred embodiment of formula V, R 1 It is not amino.

[0077] In another embodiment of formula V, R 1 It is methyl; R 2b It is hydrogen; R 3 Choose from the group consisting of: hydrogen, halogens, lower alkyl groups, substituted lower alkyl groups, amino groups, substituted amino groups, cycloalkyl groups, and substituted cycloalkyl groups; and R 4 It is chlorine.

[0078] K as defined by equation VI ATP The following are channel opening agents:

[0079]

[0080] in:

[0081] R 1 Choose from the group consisting of: hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, amino, and substituted lower amino, or R 1 Can be used with R 5 or R 6 To combine and form another ring;

[0082] R 2a Choose from the group consisting of: hydrogen, lower alkyl groups, and substituted lower alkyl groups;

[0083] R 5 Choose from the group consisting of: hydrogen, halogen, hydroxyl, lower alkyl, substituted lower alkyl, amino, substituted amino, sulfonyl, aminosulfonyl, and sulfonylamino, or R 5 Can be used with R 1 or R 6 To combine and form another ring;

[0084] R 6 Choose from the group consisting of: hydrogen, halogen, lower alkyl, substituted lower alkyl, amino, substituted amino, sulfonyl, aminosulfonyl, and sulfonylamino, or R 6 Can be used with R 1 or R 5 To combine and form another ring;

[0085] Among them, R 1 and R 5 、or R 1 and R 6 、or R 5 and R 6 The rings formed by their coordination are saturated, monounsaturated, polyunsaturated, or aromatic.

[0086] Among them, R 1 and R 5 、or R 1 and R 6 、or R 5 and R 6 The ring formed by the coordination is optionally substituted with halogen, hydroxyl, lower alkyl, substituted lower alkyl, amino, substituted amino, sulfonyl, aminosulfonyl, or sulfonylamino.

[0087] And all its bioequivalents, including salts, prodrugs, and isomers.

[0088] In a preferred embodiment, R 1 It is not an amino substituent.

[0089] In another embodiment of formula VI, R 5 and R6 combined to form a 6-membered ring. In another embodiment, R 5 and R 6 combined to form a 6-membered ring, wherein there is at least one nitrogen present. Preferred is a ring formed by R 5 and R 6 formed rings do not include any heteroatoms.

[0090] K is defined by formula VII ATP Channel openers are as follows:

[0091]

[0092] wherein:

[0093] 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 may be coordinated with R 5 or R 6 to form an additional ring;

[0094] R 2b is selected from the group consisting of hydrogen, lower alkyl, and substituted lower alkyl;

[0095] R 5 is selected from the group consisting of hydrogen, halogen, hydroxy, lower alkyl, substituted lower alkyl, amino, substituted amino, sulfonyl, aminosulfonyl, and sulfonylamino, or R 5 may be coordinated with R 1 or R 6 to form an additional ring;

[0096] 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 may be coordinated with R 1 or R 5 to form an additional ring;

[0097] wherein the ring formed by coordination of R 1 and R 5 , or R 1 and R 6 , or R 5 and R 6 is saturated, mono-unsaturated, poly-unsaturated, or aromatic;

[0098] wherein the ring formed by coordination of R 1 and R 5 , or R 1and R 6 , or R 5 and R 6 together with the ring they form is optionally substituted with halogen, hydroxyl, lower alkyl, substituted lower alkyl, amino, substituted amino, sulfonyl, aminosulfonyl, or sulfonylamino;

[0099] and all biological equivalents thereof, including salts, prodrugs, and isomers.

[0100] In a preferred embodiment, R 1 is not an amino substituent.

[0101] In another embodiment of Formula VI, R 5 and R 6 are combined to form a 6-membered ring. In another embodiment, R 5 and R 6 are combined to form a 6-membered ring, wherein there is at least one nitrogen present. Preferred is a ring formed by R 5 and R 6 does not include any heteroatoms.

[0102] Unless otherwise indicated, references in this application to K ATP channel openers are to be understood as referring to one or more K ATP channel openers having one or more, and preferably all three, of the following properties: (1) opening SUR1 / Kir6.2 potassium channels; (2) binding to the SUR1 subunit of the K ATP channel; and (3) inhibiting glucose-induced insulin release upon in vivo administration of the compound. Such K ATP channel openers preferably have the structure of any one of the compounds of Formulae I-VII; or more preferably, the structure of any one of the compounds of Formulae I-VII, wherein R 1 is not an amino group and, in addition, wherein ring B or its equivalent does not include any heteroatoms; or more preferably, any one of the compounds of Formula II or III; or more preferably, any one of the compounds of Formula II or III, wherein R 1 is not an amino group, and in addition, wherein ring B or its equivalent does not include any heteroatoms, or more preferably, the structure is diazoxide. Structural variants or biological equivalents of the compounds of any one of Formulae I-VII are also contemplated, such as derivatives, salts, prodrugs, or isomers. Other K ATP channel openers contemplated for use herein include BPDZ62, BPDZ 73, NN414, BPDZ 154.

[0103] References in this application to K ATPIn vitro analysis of glucose-induced insulin release in the presence of a channel opener can be determined using rat islets as provided by DeTullio et al., J. Med. Chem., 46:3342-3353 (2003) or by using human islets as provided by DeTullio et al., J. Med. Chem., 46:3342-3353 (2003) or by using human islets as provided by

[0104] Provided herein are K ATP Formulations of a channel opener and its bioequivalents, such as controlled release pharmaceutical formulations. In one embodiment, the controlled release formulation is formulated for oral administration. Such formulations contain 10 mg to 100 mg, 25 mg to 100 mg, 100 mg to 200 mg, 200 mg to 300 mg, 300 mg to 500 mg, or 500 mg to 2000 mg of K ATP channel opener per single administration dose. ATP The dose of a channel opener can be determined based on the body weight of the patient to which it is to be administered, i.e., the formulation can contain 0.1 mg to 20 mg of K ATP channel opener per kilogram of patient body weight; or 0.1 mg to 0.5 mg of K ATP channel opener per kilogram of patient body weight; or 0.5 mg to 1 mg of K ATP channel opener per kilogram of patient body weight; or 1 mg to 2 mg of K ATP channel opener per kilogram of patient body weight; or 2 mg to 5 mg of K ATP channel opener per kilogram of patient body weight; or 5 mg to 10 mg of K ATP channel opener per kilogram of patient body weight; or 10 mg to 15 mg of K ATP channel opener per kilogram of patient body weight; or 15 mg to 20 mg of K ATP channel opener per kilogram of patient body weight.

[0105] Also provided herein are controlled release pharmaceutical formulations containing K ATP channel opener obtained by at least one of the following: (a) particle size reduction involving comminution, spray drying, or other micronization techniques; (b) use of a pharmaceutical salt of K ATP channel opener; (c) use of ion exchange resins; (d) use of clathrates, e.g., cyclodextrins; (e) compression of K ATP channel opener with a solubilizing agent including low viscosity hydroxypropyl methylcellulose, low viscosity methylcellulose, or an excipient that functions similarly or a combination thereof; (f) association of K ATP channel opener with a salt; (g) use of KATP (h) Solid dispersions of channel openers; (i) the use of self-emulsifying systems; (j) the addition of one or more surfactants to the formulation; (k) the use of nanoparticles; or (k) a combination of these methods.

[0106] This article also provides information containing K. ATP Controlled-release drug formulations of channel openers, the formulations comprising substantially inhibiting K ATP The channel activator is released from the formulation of at least one component up to the point of gastric passage. "Substantially inhibited" as used herein means that less than 15% of the drug is released from the formulation during gastric transit, more preferably less than 10%, or even more preferably less than 5%. Release can be measured in a standard USP-based in vitro gastric dissolution assay in a calibrated dissolution apparatus (see, for example, Chapter 711 (2005) of the United States Pharmacopeia).

[0107] It also provides K ATP Oral pharmaceutical formulations of channel openers, the formulation comprising substantially inhibiting K ATP The channel opener is at least one component released from the formulation up to the point of gastric passage. Essentially inhibiting drug release during gastric passage is achieved by including in the formulation 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 film on a tablet; (c) a pH-sensitive polymer or copolymer applied as a film to an encapsulation system; (d) a pH-sensitive polymer or copolymer applied to encapsulated microparticles; (e) a non-water-soluble polymer or copolymer applied as a compression coating on a tablet; (f) a non-water-soluble polymer or copolymer applied as a film on a tablet; (g) a non-water-soluble polymer applied as a film to an encapsulation system; (h) a non-water-soluble polymer applied to microparticles; (i) incorporating the formulation into an osmotic pump system; (j) using a system controlled by an ion exchange resin; and (k) a combination of these methods, wherein the pH-sensitive polymer or copolymer is resistant to degradation under acidic conditions.

[0108] This article also provides K ATP A controlled-release drug formulation of a channel opener, wherein the formulation comprises at least one component that facilitates K ATPSustained release of the channel opener over a period of 2-4 hours after administration, or over a period of 4-8 hours after administration, or over a period of more than 8-24 hours after administration. 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 matrix of the coating; (d) a erodible matrix that controls the rate of drug release; (e) polymer coated drug pellets, granules or microparticles that can be further encapsulated or compressed into tablets; (f) an osmotic pump system containing the drug; (g) a compressed coated tablet form of the drug; or (h) a combination of these methods.

[0109] An erodible matrix as used herein is the tablet core of a tablet formulation that initiates a disintegration process upon exposure to an aqueous environment that facilitates the release of the drug from the matrix. The rate of release of the drug from the tablet is controlled by both the solubility of the drug and the rate of disintegration of the matrix.

[0110] The above formulations can also contain one or more additional pharmaceutically active agents useful in treating a condition selected from the group consisting of obesity, prediabetes, diabetes, hypertension, depression, elevated cholesterol, fluid retention, other obesity related co-morbidities, ischemia and reperfusion injury, epilepsy, schizophrenia, mania, or other psychiatric disorders (in addition to the K ATP channel opener).

[0111] Also provided is a controlled release pharmaceutical formulation of a K ATP channel opener, wherein administration to an obese, overweight, or obesity-prone individual causes at least one of: (a) suppression of fasting insulin secretion; (b) suppression of glucose-stimulated insulin secretion; (c) increased energy expenditure; (d) increased beta oxidation of fat; (e) suppression of hyperphagia over about 18 hours; or (f) increased lean body mass.

[0112] Further provided is a controlled release pharmaceutical formulation of a K ATP channel opener, wherein administration to an obese, overweight, or obesity-prone individual causes at least one of: (a) suppression of fasting insulin secretion; (b) suppression of glucose-stimulated insulin secretion; (c) increased energy expenditure; (d) increased beta oxidation of fat; (e) suppression of hyperphagia over about 18 hours; or (f) increased lean body mass.

[0113] Still further provided is a controlled release pharmaceutical formulation of a K ATPA controlled release pharmaceutical formulation of a channel opener that, when administered to an obese, overweight, or obesity-prone individual, causes at least one of the following: (a) suppression of fasting insulin secretion; (b) suppression of glucose-stimulated insulin secretion; (c) increased energy expenditure; (d) increased beta oxidation of fat; (e) suppression of hyperphagia for about 24 hours; or (f) increased lean body mass.

[0114] Also provided is a K ATP A controlled release pharmaceutical formulation of a channel opener that, when administered to an obese, overweight, or obesity-prone individual, causes at least one of the following: (a) suppression of fasting insulin secretion; (b) suppression of glucose-stimulated insulin secretion; (c) increased energy expenditure; (d) increased beta oxidation of fat; (e) suppression of hyperphagia for about 18 hours; or (f) increased lean body mass.

[0115] Provided herein is a method of treating hypoglycemia, comprising orally administering a K ATP A controlled release formulation of a channel opener, optionally in combination with growth hormone.

[0116] Also provided herein is a method of treating an obesity-related comorbidity in an obese, overweight, or obesity-prone individual, comprising administering a therapeutically effective amount of a K ATP A solid oral dosage form of a channel opener, or a K ATP A controlled release pharmaceutical formulation of a channel opener, optionally in combination with growth hormone. In a preferred embodiment, administration is no more than twice per 24 hours, or once per 24 hours.

[0117] Still further provided herein is a method of effecting weight loss in an obese, overweight, or obesity-prone individual, comprising administering a therapeutically effective amount of a K ATP A solid oral dosage form of a channel opener, or a K ATP A controlled release pharmaceutical formulation of a channel opener, optionally in combination with growth hormone. In a preferred embodiment, administration is no more than twice per 24 hours, or once per 24 hours. The daily dose administered is preferably 50 mg to 180 mg. In certain embodiments, the obese individual has a body mass index greater than 30 kg / m 2 , or greater than 35 kg / m 2 , or greater than 40 kg / m 2 , or greater than 50 kg / m 2 , or greater than 60 kg / m 2 at the start of the method.

[0118] Also provided is a method of maintaining weight loss in an obese, overweight, or obesity- susceptible individual, the method comprising administering a therapeutically effective amount of a K ATP a solid oral dosage form of a channel opener or a K ATP a controlled release pharmaceutical formulation of a channel opener, optionally in combination with growth hormone. Once a certain weight loss has occurred, another option is to re-gain weight, and it is then preferred to maintain the weight of an obese individual. In a preferred embodiment, administration is no more than twice per 24 hours, or once per 24 hours.

[0119] Also provided is a method of increasing energy expenditure in an overweight, obese, or obesity- susceptible individual, the method comprising administering an effective amount of a K ATP a solid oral dosage form of a channel opener or a K ATP a controlled release pharmaceutical formulation of a channel opener, optionally in combination with growth hormone. In a preferred embodiment, administration is no more than twice per 24 hours, or once per 24 hours. In certain embodiments, the individual has a body mass index greater than 20 kg / m 2 , or greater than 25 kg / m 2 , or greater than 30 kg / m 2 , or greater than 35 kg / m 2 , or greater than 40 kg / m 2 , or greater than 50 kg / m 2 , or greater than 60 kg / m 2 at the start of the method.

[0120] Also provided is a method of increasing β-oxidation of fat in an overweight, obese, or obesity- susceptible individual, the method comprising administering an effective amount of a K ATP a solid oral dosage form of a channel opener or a K ATP a controlled release pharmaceutical formulation of a channel opener, optionally in combination with growth hormone. In a preferred embodiment, administration is no more than twice per 24 hours, or once per 24 hours. In certain embodiments, the individual has a body mass index greater than 20 kg / m 2 , or greater than 25 kg / m 2 , or greater than 30 kg / m 2 , or greater than 35 kg / m 2 , or greater than 40 kg / m 2 , or greater than 50 kg / m 2 , or greater than 60 kg / m 2 at the start of the method.

[0121] Furthermore, a method for reducing visceral fat in overweight, obese, or obesity-prone individuals is provided, the method comprising administering an effective amount of potassium (K). ATP Solid oral dosage form of channel opener or K ATP A controlled-release formulation of a channel opener, optionally in combination with growth hormone. In a preferred embodiment, administration is performed no more than twice every 24 hours, or once every 24 hours.

[0122] Furthermore, a method for delaying or preventing the progression of prediabetes to diabetes is provided, the method comprising administering an effective amount of K ATP Channel opener or K ATP A controlled-release formulation of a channel opener, optionally in combination with growth hormone. In a preferred embodiment, administration is performed no more than twice every 24 hours, or once every 24 hours.

[0123] Another method for restoring normal glucose tolerance in individuals with prediabetes is provided, the method comprising administering an effective amount of potassium (K). ATP Channel opener or K ATP A controlled-release formulation of a channel opener, optionally in combination with growth hormone. In a preferred embodiment, administration is performed no more than twice every 24 hours, or once every 24 hours.

[0124] A method for restoring normal glucose tolerance in individuals with diabetes is also provided, the method comprising administering an effective amount of potassium (K). ATP Channel opener or K ATP A controlled-release formulation of a channel opener, optionally in combination with growth hormone. In a preferred embodiment, administration is performed no more than twice every 24 hours, or once every 24 hours.

[0125] Furthermore, a method for delaying or preventing the progression of diabetes in an individual is provided, the method comprising administering an effective amount of K ATP Channel opener or K ATP A controlled-release formulation of a channel opener, optionally in combination with growth hormone. In a preferred embodiment, administration is performed no more than twice every 24 hours, or once every 24 hours.

[0126] A method for preventing or treating weight gain, impaired glucose tolerance, or dyslipidemia associated with the use of antipsychotic medications is also provided, the method comprising co-administering an effective amount of K ATP Channel opener or K ATP A controlled-release formulation of a channel opener, optionally in combination with growth hormone. In a preferred embodiment, administration is performed no more than twice every 24 hours, or once every 24 hours.

[0127] Also provided is a method of increasing lean body mass in a Prader-Willi Syndrome patient, a Smith-Magenis Syndrome patient, a Froelich's Syndrome patient, a Cohen Syndrome patient, a Summit Syndrome patient, an Alstrom Syndrome patient, a Borjeson Syndrome patient, or a Bardet-Biedl Syndrome patient, the method comprising administering an effective amount of K ATP a channel opener, optionally in combination with growth hormone, or K ATP a controlled release pharmaceutical formulation of a channel opener, optionally in combination with growth hormone. In a preferred embodiment, administration is no more than twice per 24 hours, or once per 24 hours.

[0128] Further still provided is a method of treating obesity or elevated triglycerides in a patient having Type I, Type II, Type III, or Type IV hyperlipoproteinemia, the method comprising administering an effective amount of K ATP a channel opener, or K ATP a controlled release pharmaceutical formulation of a channel opener, optionally in combination with growth hormone. In a preferred embodiment, administration is no more than twice per 24 hours, or once per 24 hours.

[0129] Also provided is a method of reducing the incidence of adverse effects caused by administration of K ATP a channel opener in the treatment of a disease in a subject, by any of: (a) using a dosage form that reduces C max adverse side effects associated with peak drug levels; (b) using 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) starting dosing at sub-therapeutic levels and increasing the dose daily in a stepwise fashion until a therapeutic dose is reached, where the number of steps is 2 to 10 to reduce the incidence of adverse side effects that occur transiently at the start of treatment; (d) using the lowest effective dose to achieve the desired therapeutic effect to reduce the incidence of dose-dependent adverse side effects; or (e) optimizing the time of day and relative to meals that the dose is administered.

[0130] Also provided is a method of preventing weight gain, dyslipidemia, or impaired glucose tolerance in a subject receiving treatment with an antipsychotic drug, the method comprising administering K ATPPharmaceutical formulations of a channel opener, optionally in combination with growth hormone.

[0131] Further provided is a method of treating weight gain, dyslipidemia, or impaired glucose tolerance in a subject receiving antipsychotic therapy, the method comprising administering a K ATP Pharmaceutical formulations of a channel opener, optionally in combination with growth hormone.

[0132] Further provided is a method of treating a disease characterized by obesity, hyperphagia, dyslipidemia, or reduced energy expenditure, the disease comprising (a) Prader-Willi Syndrome; (b) Frohlich's Syndrome; (c) Cohen Syndrome; (d) Summit Syndrome; (e) Alstrom Syndrome; (f) Borjeson Syndrome; (g) Bardet-Biedl Syndrome; (h) hyperlipoproteinemia type I, type II, type III, and type IV; or (i) Smith-Magenis Syndrome (SMS), the method comprising administering a K ATP Pharmaceutical formulations of a channel opener, optionally in combination with growth hormone.

[0133] Further provided is a K ATP Pharmaceutical formulations of a channel opener, the formulation further comprising a pharmaceutically active agent other than the K ATP Pharmaceutical formulations of a channel opener, the formulation further comprising a pharmaceutically active agent other than the K

[0134] The K ATP Formulations of a channel opener described herein provide improved compliance, efficacy, and safety, and provide co-formulation with other pharmaceutical agents. Included are K ATP Co-formulations of a channel opener with one or more additional pharmaceutically active agents having complementary or analogous activity or targets. Can be combined with K ATP Other pharmaceutically active agents that can be combined with a channel opener to treat obesity or maintain weight loss in an obesity-susceptible individual include, but are not limited to, sibutramine, orlistat, phentermine, rimonabant, diuretics, anti-epileptics, or other pharmaceutically active agents whose therapeutic utility includes weight loss. Once a certain weight loss has occurred, it is preferable to maintain the weight of an obese individual, as another option is to re-gain weight. Can be combined with K ATPOther pharmaceutically active agents with which the channel opener is combined to treat type II diabetes or pre-diabetes include acarbose, miglitol, metformin, repaglinide, nateglinide, rosiglitizone, proglitizone, ramipril, metaglidasen, or any other pharmaceutically active agent that improves insulin sensitivity or glucose utilization or glycemic control whose mode of action is not to enhance insulin secretion. K ATP Other pharmaceutically active agents with which the channel opener is combined to treat obesity-related co-morbidities include pharmaceutically active agents for lowering cholesterol, pharmaceutically active agents for lowering blood pressure, anti-inflammatory agents that are not cox-2 inhibitors, agents that are antidepressants, agents for treating urinary incontinence, or other agents that are routinely used to treat disease conditions that have an increased incidence in overweight or obese patients compared to normal weight individuals, including but not limited to agents that treat atherosclerosis, osteoarthritis, herniated spinal discs, degeneration of the knee and hip joints, 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 hernias, menstrual irregularities, infertility, and the like.

[0135] In the context of the present application, the term "therapeutically effective" or "effective amount" means an amount of a material or a quantity of a material effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or medical condition in a subject being treated, and / or to prolong the survival of the subject.

[0136] The term "pharmaceutically acceptable" means that the identified material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient taking into consideration the disease or condition to be treated and the corresponding route of administration. For example, it is generally desirable that such a material be substantially sterile, e.g., for injectables.

[0137] The term "composition" as used herein refers to a preparation suitable for administration to an intended animal subject for therapeutic purposes; an exemplary composition contains at least one pharmaceutically active compound and at least one pharmaceutically acceptable carrier or excipient. Other terms as used herein are defined below.

[0138] Adipocyte: an animal connective tissue cell specialized for fat synthesis and storage.

[0139] Agonist: A compound that has an affinity for a cellular receptor and stimulates a physiological activity at that cellular receptor that is normally stimulated by a naturally occurring substance, thereby triggering a chemical reaction. An agonist of a receptor can also be considered an activator of a receptor.

[0140] About: Used herein to mean plus or minus 10% in quantity.

[0141] Adipose tissue: Tissue that contains primarily adipocytes.

[0142] Adolescent: A person between the ages of 10 and 19.

[0143] Adiponectin: A protein hormone that regulates metabolism of lipids and glucose, produced and secreted only by adipocytes. Adiponectin influences the body's response to insulin. Adiponectin also has an anti-inflammatory effect on cells lining the walls of blood vessels.

[0144] Improving symptoms of a particular condition by administration of a particular pharmaceutical composition: refers to any alleviation, whether permanent or temporary, continuous or transitory, that can be attributed to or is associated with the administration of the composition.

[0145] Analog: A compound that is structurally similar to another compound, but differs in at least one atom.

[0146] Antagonist: A substance that tends to eliminate the effect of another substance as a result of binding to a cellular receptor without eliciting a biological response.

[0147] Atherosclerotic plaque: Accumulation of cholesterol and fatty substances within blood vessels as a result of the effects of atherosclerosis.

[0148] Bariatric surgery: A variety of surgical procedures designed to assist in the management or treatment of obesity and related diseases.

[0149] Beta cell rest: Temporarily placing beta cells in a state in which metabolic stress is reduced due to suppression of insulin secretion.

[0150] Bi-layer laminate: A component of a pharmaceutical dosage form composed of a laminate of two different materials.

[0151] Bioavailability: Refers to the amount or extent of a therapeutically active substance that is released from a pharmaceutical product and becomes available at the intended site of action of the drug in the body. The amount or extent of drug released can be determined by pharmacokinetic parameters of the drug, such as area under the blood or plasma drug concentration-time curve (AUC) and peak blood or plasma concentration (C max ).

[0152] Bioequivalent: Two formulations of the same active substance are bioequivalent when there is no significant difference in the rate and extent of availability of the active substance at the site of drug action when administered under similar conditions at the same molar dose. In this definition "formulation" can include the free base of the active substance or different salts of the active substance. Bioequivalence can be demonstrated via several in vivo and in vitro methods. These methods include, in order of decreasing preference, pharmacokinetic studies, pharmacodynamic studies, clinical studies, and in vitro studies. Specifically, bioequivalence is demonstrated using pharmacokinetic measures of the drug, such as the area under the blood or plasma drug concentration-time curve (AUC) and peak blood or plasma concentration (Cmax) using statistical criteria. max

[0153] Cannabinoid receptor: Receptor in the endocannabinoid (EC) system that is associated with food intake and tobacco dependence. Blocking the cannabinoid receptor can reduce dependence on tobacco and cravings for food.

[0154] Combination: Refers to any association between or among two or more items. The combination can be two or more separate items, such as two compositions or two sets. It can be a mixture thereof, such as a single mixture of two or more items, or any variation thereof.

[0155] Composition: Refers to any mixture. It can be a solution, suspension, liquid, powder, paste, aqueous, non-aqueous, or any combination thereof.

[0156] Compressed tablet: A tablet formed by applying pressure to a volume of tablet matrix in a die.

[0157] Compressed coated tablet: A tablet formed by compression of a coating added to a compressed tablet core containing a pharmaceutically active agent.

[0158] Derivative: A chemical substance derived from another substance by modification or substitution.

[0159] Daily dose: The total amount of a drug taken in a 24 hour period, whether taken as a single dose or divided into multiple doses.

[0160] Diazoxide: 7-chloro-3-methyl-2-H-l,2,4-benzothiadiazine 1,1-dioxide, having the empirical formula C8H7CIN2O2S and a molecular weight of 230.7.

[0161] Encapsulated system: Structural features that contain a drug within a structure such as a drug capsule. Gels containing a drug in the middle are also considered encapsulated systems.

[0162] ​Equivalent amount: the amount of a drug derivative that produces the same effect as a defined amount of the non-derivatized drug in an assay or when administered to a subject.

[0163] Fatty acid synthase: central enzyme of a multi-enzyme complex that catalyzes the formation of palmitate from acetyl-CoA, malonyl-CoA, and NADPH.

[0164] Gastric lipase: an enzyme secreted into the gastrointestinal tract that catalyzes the hydrolysis of dietary triglycerides.

[0165] Glidant: an inactive ingredient in a pharmaceutical formulation that prevents the matrix from caking during processing steps.

[0166] Growth hormone: also known as somatotropin or somatotropic hormone, is a peptide hormone that stimulates growth, cell reproduction, and regeneration in humans and other animals. It is a type of mitogen that is specific to only certain kinds of cells. Growth hormone is a single-chain polypeptide of 191 amino acids that is synthesized, stored, and secreted by growth hormone cells in the pars distalis of the anterior pituitary. GH is a stress hormone that raises concentrations of glucose and free fatty acids. It also stimulates the production of IGF-1.

[0167] Hyperinsulinemia: an excessively high level of insulin in the blood, which is distinguished from hyperinsulinism, which is the overproduction of insulin by the islets of Langerhans. Hyperinsulinemia can be the result of various conditions such as obesity and pregnancy.

[0168] Hyperinsulinism: overproduction of insulin by the islets of Langerhans.

[0169] Hyperlipidemia: a general term for an elevated concentration of any or all of the lipids in the plasma, such as cholesterol, triglycerides, and lipoproteins.

[0170] Hyperphagia: the ingestion of more food than is optimal.

[0171] Ingredient of a pharmaceutical composition: refers to one or more materials used in the manufacture of a pharmaceutical composition. Ingredient can refer to an active ingredient (pharmaceutical agent) or other material in a composition. Ingredients can include water and other solvents, salts, buffers, surfactants, water, non-aqueous solvents, and flavorings.

[0172] IGF-1 is also known as somatomedin C, is a protein that in humans is encoded by the IGF1 gene. IGF-1 is a hormone that is similar in molecular structure to insulin. It plays an important role in childhood growth and continues to have an anabolic effect 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.

[0173] Insulin resistance: A condition in which the body's tissues respond poorly to insulin.

[0174] Ischemic injury: Damage to tissue caused by a state of hypoxia, usually due to an occlusion of arterial blood supply or insufficient blood flow, resulting in a lack of oxygen in the tissue.

[0175] Ketotic acidosis: Acidosis accompanied by the accumulation of ketone bodies in body tissues and fluids (ketosis), as in diabetic acidosis.

[0176] Kit: Refers to a packaged combination. The packaged combination can optionally include one or more labels, instructions, and / or reagents for use with the combination.

[0177] Kir: K ATP Pore-forming subunit of the channel. Also known as K ATP Inwardly rectifying subunit of the channel. Usually in the form of Kir6.x and occasionally in the form of Kir2.x subtypes.

[0178] K ATP Channel: ATP-sensitive potassium ion channel across the cell membrane, formed by the association of 4 copies of the sulfonylurea receptor and 4 copies of the pore-forming subunit Kir. Agonizing the channel can cause membrane hyperpolarization.

[0179] Lean body mass: Lean body mass is a component of body composition, calculated by subtracting the body fat weight from the total body weight, which is lean body weight plus fat weight. In the equation:

[0180] Lean body mass equals body weight minus body fat (LBM = BW - BF)

[0181] Lean body mass plus body fat equals body weight (LBM + BF = BW)

[0182] The percentage of total lean body mass is not usually quoted, it will usually be 60-90%. Instead, the percentage of body fat is calculated as a supplement, and it is usually 10-40%. Lean body mass (LBM) has been described as a better index than total body weight in prescribing appropriate drug levels and assessing metabolic disorders, because body fat is less relevant to metabolism.

[0183] Leptin: Product of the ob (obesity) locus (16 kD). It is present in the plasma of mammals and exerts a hormone action that decreases food intake and increases energy expenditure.

[0184] Lipogenesis: The production of new lipids, primarily triacylglycerols. It depends on the action of a variety of different enzymes and transport molecules.

[0185] Lipolysis: The breakdown of fats by the concerted action of a variety of enzymes.

[0186] Lipoprotein lipase: An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to produce diacylglycerol and a fatty acid anion. The enzyme hydrolyzes triacylglycerol to chylomicrons, very low density lipoproteins, low density lipoproteins, and diacylglycerol.

[0187] Lubricants: Inactive ingredients in pharmaceutical formulations that allow materials to flow during various processing steps, especially tableting.

[0188] Microparticles: Small particles that are formed during the process of open pharmaceutical formulation that can be coated before the production of the final dosage form.

[0189] Obesity: An increase in body weight beyond the range required for body growth and maintenance, resulting from an excessive accumulation of fat in the body. It is formally defined as having a body mass index greater than 30 kg / m 2 .

[0190] Obesity susceptibility: An individual who has a higher than average risk of becoming obese due to genetic susceptibility or previous history of obesity.

[0191] Obesity-related comorbidities: Any disease or condition in an animal or human that has an increased incidence in individuals who are obese or overweight. Examples of such conditions include hypertension, prediabetes, type 2 diabetes, osteoarthritis, and cardiovascular conditions.

[0192] Osmotic controlled release: A drug dosage form in which the release of active drug is achieved primarily through the hydration of a swellable component of the formulation.

[0193] Overweight: An individual whose body weight is higher than the ideal body weight for their height, but does not meet the criteria for classification as obese. In humans using the body mass index (kg / m 2 ), an overweight individual has a BMI of 25 to 30.

[0194] Oxidation of fats: A series of reactions involving acyl CoA compounds, whereby these compounds undergo beta oxidation and thiolytic cleavage, with the formation of acetyl CoA; the main pathway for the catabolism of fatty acids in living tissue.

[0195] Pharmaceutical composition: Refers to a composition containing a pharmaceutical agent and one or more other ingredients that is formulated for administration to a subject. A pharmaceutical agent refers to the active ingredient of a pharmaceutical composition. Typically, the active ingredient is active in treating a disease or condition. For example, pharmaceutical agents that can be included in a pharmaceutical composition include agents for treating obesity or diabetes. A pharmaceutical active agent can be referred to as a "pharmaceutical active."

[0196] Pharmacodynamic: refers to the effect mediated by the pharmacological action.

[0197] Pharmacodynamics: refers to the effect mediated by the pharmacological action.

[0198] Pharmacokinetics: refers to the absorption, distribution, metabolism, and elimination of a drug in the body.

[0199] Polymorph: a compound that shares the same chemical properties but has a different crystal structure.

[0200] Prader-Willi Syndrome (PWS): a complex neurobehavioral / metabolic disorder attributed to the absence of normally active paternally expressed genes in the 15ql 1-q13 region of chromosome 15. PWS is an imprinting condition in which 70-75% of cases are attributed to de novo deletion of the 11-q13 region of chromosome 15 inherited paternally, 20-30% are attributed to maternal uniparental disomy 15 (UPD), and the remaining 2-5% are attributed to microdeletions or epimutations at the imprinting center (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)).

[0201] Clinical manifestations of the condition begin with decreased fetal activity in utero (Miller Am J Med Genet A 155A(5): 1-10 (2011)). Low lean mass and hypotonia are universal in PWS and 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 variety of behavioral comorbidities, including autism spectrum disorder-like behaviors, obsessive-compulsive behaviors, self-injurious behaviors, and aggressive, threatening, and destructive behaviors. About 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 (ibid)). Almost all PWS patients are hypogonadal, requiring sex hormone supplementation (Goldstone, 2004 (ibid); Davies et al., 2008 (ibid); Cassidy and Driscoll, 2009 (ibid)). These patients have hypothalamic insufficiency / dysfunction (Goldstone Am J Clin Nutr 75(3): 468-475 (2002)).

[0202] Excessive body fat accumulation can begin at about 2 years of age and can persist into adulthood (Miller 2011 (ibid)). The vast majority of body fat in PWS is subcutaneous (Brambilla 1997 (ibid); 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 universal in PWS, unlike the universality of low lean mass and hypotonia. For example, Sode-Carlson et al. (2010) (ibid) evaluated 46 adult PWS patients, 25 females and 21 males. The average BMI of these adult PWS patients was 27.2 kg / m2, which is within the normal range for BMI. The average subcutaneous fat mass was 17.6 kg, which is within the normal range for subcutaneous fat mass. The average lean mass was 32.6 kg, which is below the normal range for lean mass. 2Therefore, on average, these patients are overweight rather than obese, suggesting that in fact, more than half are not obese according to the best measure. Similarly, Brambilla et al., Nutr Metab Cardiovasc Dis 21(4):269-276 (2011) studied a population of 109 children with PWS. They found that 54% of the children were classified as obese by the best measure. No Therefore, in both adults and children with PWS, obesity is not only not common, but in fact can occur in less than half of the population. The percentage of subcutaneous fat to total fat in PWS is greater than the percentage it occupies in obese controls of all ages (Sode-Carlson 2010 (supra)).

[0203] Binge eating, with associated problematic food-related behaviors, begins at an average age of about 8 years (Miller 2011 (supra)). These patients feel hungry when they are not. At the onset of binge eating, PWS patients will eat anything within view Any food, eat at night, dig through trash for food, steal food, eat frozen foods, pet foods, spoiled foods, and even non-food items (Miller 2011 (supra)). If denied food, they will become angry or tantrum. Throughout life, after this stage, access to food is strictly limited, with cabinets and refrigerators locked. To limit food-related anxiety, meal times and meal composition are strictly controlled.

[0204] The mortality rate of PWS patients is three times that of the general population of all ages (Cassidy Genet Med 14(1): 10-26 (2012)), with the average age at death being about 29 years (PWSUSA mortality database, n=488). In contrast, obesity, but not morbid obesity, 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, eds, National Academies Press).

[0205] 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 energy expenditure and total work in a group of 48 PWS patients to a group of 24 obese controls. PWS patients had significantly lower total energy expenditure (-20%), resting energy expenditure (-16%), and mechanical work (-35%) than controls. The difference in mechanical work remained significant after adjusting for group differences in lean body mass.

[0206] 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. The PWS group had significantly lower ADMR, AEE, and PAL than the control group (P < 0.01) (-28.2%, -58.2%, and -14.2%, respectively).

[0207] 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 confirmed that 63% of infants with PWS and 73% of prepubertal children with PWS had at least one cardiovascular risk factor, defined as dyslipidemia or hypertension. Thus, the cardiometabolic risk in PWS is elevated even in younger children.

[0208] Pre-adipocyte: a progenitor cell of an adipocyte.

[0209] Prediabetes: a condition prior to the diagnosis of type II diabetes. Type II diabetes is a form of diabetes characterized by insulin insensitivity or insulin resistance.

[0210] Prodrug: refers to a compound that, when metabolized, produces the desired active compound. Typically, prodrugs are inactive, or less active than the active compound, but can provide advantageous handling, administration, or metabolic properties. For example, some prodrugs are esters of the active compound; during metabolic cleavage, the ester group is cleaved to produce the active drug. In addition, some prodrugs are enzymatically activated to produce the active compound or a compound that, upon further chemical reaction, produces the active compound.

[0211] Long-term administration (long-term basis): A pharmaceutically acceptable formulation of a drug administered over 7 days or more. Typically, long-term administration lasts for at least two weeks, preferably at least one month, and even more preferably at least two months (i.e., at least 8 weeks).

[0212] Rapidly dissolving formulations: Pharmaceutical formulations that release substantially all of the active pharmaceutical ingredient from the formulation within 10 minutes when administered orally.

[0213] Sustained-release formulations (or “continuous-release formulations”): Formulations of pharmaceutical products that, when administered to animals, provide the release of the active pharmaceutical ingredient over a prolonged period of time compared to the release provided by formulations of the same active pharmaceutical ingredient that cause rapid absorption. Similar terms are prolonged-release, long-acting-release, and slow-release. In all cases, by definition, the formulation has a reduced rate of release of the active substance.

[0214] Delayed-release formulations (or “delayed-release formulations”): Delayed-release products are improved release, but not prolonged release. They involve the release of a discrete amount of drug after a certain period of time following drug administration, such as enteric-coated products, and exhibit a lag time during which little or no absorption occurs.

[0215] Controlled-release formulations (or "controlled-release formulations") may include formulations of pharmaceutical products that delay the release of a pharmaceutical active agent upon administration and control the release of both in a manner consistent with sustained release.

[0216] Salt: A neutral, basic, or acidic compound formed by the combination of an acid or acid group and a base or base group.

[0217] Smith-Mageli syndrome (SMS; OMIM#182290, *607642): a complex, generally sporadic, inherited disorder caused by haploinadequacy of the retinoic acid-inducible protein 1 (RAI1) gene, which is caused by deletion of 17p11.2 of the gene covering retinoic acid-inducible protein 1 (RAI1) or mutation of RAI1 (see, for example, Burns et al., Human Molecular Genetics, 2010, Vol. 19, No. 20, pp. 4026-4042).

[0218] Smith-Magenis syndrome is characterized by a clinically recognizable phenotype, including physical, developmental, neurological, and behavioral features. Short stature (<5th percentile) is observed in approximately 67% of young patients. Over time, short stature resolves, with most individuals reaching the 10th-25th percentile by adulthood (see, e.g., Burns et al. (supra)). Most children with SMS also have significant early-onset obesity (see, e.g., European Journal of Human Genetics (2008) 16, 412-421). Obesity is common in adolescents and adults, often with broad chest and truncal obesity. RAI1 haploinsufficiency represents a monogenic model of obesity with hyperphagia, abnormal fat distribution, and altered hypothalamic gene expression related to satiety, food intake, behavior, and obesity.

[0219] Hearing loss is variable and often associated with chronic ear infections. Ophthalmologic features are present in >60% of SMS patients and include myopia, iris abnormalities, strabismus, small corneas, and rarely retinal detachment (often caused by aggressive behavior).

[0220] A prenatal SMS history is notable for significantly reduced fetal movement in 50% of pregnancies. Early infancy is complicated by feeding difficulties leading to failure to thrive, significant oromotor dysfunction with poor sucking reflex, gastroesophageal reflux, and hypotonia.

[0221] Most SMS individuals have mild to moderate mental retardation. IQ decreases with increasing age of the child, such that individuals ultimately fall in the mild mental retardation range by adulthood. Language delay, with or without hearing loss, occurs in 96% of SMS patients. Additionally, fine motor / gross motor delays, sensory integration problems, and poor adaptive functioning are seen. Other neurological features include pes cavus or flat feet, abnormal 'fidgety' gait, balance problems, and decreased sensitivity to pain, which is often observed in relation to self-injurious behavior in this disorder.

[0222] Sleep disturbances have been reported in 75-100% of SMS cases. Infants often experience excessive sleepiness during the first year of life. Sleep disturbances in older children include difficulty falling asleep, decreased REM sleep, decreased 24-hour and nighttime sleep, sleep cycle fragmentation and shortening with frequent nighttime and early morning awakenings, and daytime excessive sleepiness.

[0223] Behavioral problems are one of the unique and characteristic features of SMS. Maladaptive behaviors are of primary concern and include frequent irritability / temper tantrums, seeking attention, aggressive behavior, noncompliance, distractibility, and self-injurious behavior. Self-injurious behavior includes head banging, skin picking, wrist biting, onychotillomania, and polyembolokoilamania. The behavioral phenotype of SMS escalates with age, often with the onset of puberty. Age, degree of developmental delay, severity of any associated systemic disorder, and degree of sleep disturbance all have a strong influence on maladaptive behavior. Individuals also lack respect for personal space during conversations and have mood swings.

[0224] SMS patients share many features in common with PWS patients. These include: (1) reduced fetal activity; (2) hypotonia; (3) feeding difficulties in early infancy; (4) short stature; (5) early onset obesity, possibly including hyperphagia; (6) developmental delay; (7) mental retardation; (8) irritability; (9) aggressive behavior; (10) self-injurious behavior; (11) excessive sleepiness in infancy and similar sleep disturbances 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 presentation and natural history of the disease are quite similar.

[0225] Solid oral dosage form: A pharmaceutical preparation designed for oral administration, including capsules and tablets.

[0226] Subject: Refers to an animal, including mammals, such as humans.

[0227] Sulfonylurea receptor: K ATP Channels responsible for interaction with sulfonylureas, other K ATP Channel antagonists, diazoxide, and other K ATP Channel agonists.

[0228] Tablet: A pharmaceutical dosage form produced by bringing a volume of a matrix containing a pharmaceutically active agent and excipients into a size and shape suitable for oral administration.

[0229] Thermogenesis: The physiological process of heat production in the body.

[0230] Threshold concentration: The minimum circulating concentration of a drug required to produce a specific metabolic, physiological, or compositional change in a human or animal receiving treatment.

[0231] Treatment: Means any manner in which the symptoms of a condition, disorder, or disease or other indication are ameliorated or otherwise beneficially altered.

[0232] Triglyceride: The storage fat of animal and human adipose tissue consisting primarily of glycerol esters of saturated fatty acids.

[0233] Type I diabetes: A chronic condition in which the pancreas produces little or no insulin because beta cells have been destroyed.

[0234] Uncoupling protein: A family of proteins that allow oxidation to proceed in mitochondria without the phosphorylation that normally accompanies it to produce ATP.

[0235] Visceral fat: Human adipose tissue that is primarily present in subcutaneous fat and under the muscle layer in the body. BRIEF DESCRIPTION OF DRAWINGS

[0236] Figure 1 Changes in binge eating score for all subjects participating in clinical study PC025 are summarized.

[0237] Figure 2 Percent change in lean body mass for all subjects participating in clinical study PC025 are summarized.

[0238] Figure 3 Percent change in body fat mass for all subjects participating in clinical study PC025 are summarized.

[0239] Figure 4 Percent change in lean body mass / fat mass ratio for all subjects participating in clinical study PC025 are summarized. DETAILED DESCRIPTION

[0240] Provided herein are specific K ATP Pharmaceutical formulations of channel openers that achieve novel pharmacodynamic, pharmacokinetic, therapeutic, physiological, and metabolic outcomes when administered to a subject. Also provided are specific K ATP Pharmaceutical formulations, methods of administration, and methods of dosing of channel openers, optionally in combination with growth hormone, that achieve therapeutic outcomes while reducing the incidence of adverse effects.

[0241] Specifically, pharmaceutical formulations formulated for oral administration exhibit advantageous properties, including: promoting uniformity of absorption, pharmacokinetic, and pharmacodynamic responses among treated patients, facilitating patient compliance, and enhancing the safety profile of the product, such as by reducing the incidence of serious adverse effects. Also provided are methods of treating metabolic and other diseases in humans and animals by administering the formulations.

[0242] Compounds of Formula II and Formula III, Formula IV and Formula V, and Formula VI and Formula VII, such as, for example, diazoxide (shown below), can be prototropic tautomers. Prototropic tautomers are isomers that differ from each other only in the position of a hydrogen atom and a double bond. The hydrogen atom and double bond switch places between a carbon atom and a heteroatom such as, for example, N. Thus, when the nitrogen substituent is hydrogen, the two isomeric chemical structures can be used interchangeably.

[0243]

[0244] Particular K ATP Channel openers include any of those within Formula I through Formula VII. Exemplary such compounds include diazoxide, BPDZ 62, BPDZ 73, NN414, and BPDZ 154 (see, e.g., Schou et al., Bioorg. Med. Chem., 13, 141-155 (2005)). Compound BPDZ 154 is also an effective K ATP Channel activators. Synthesis of BPDZ compounds is provided in Cosgrove et al., J. Clin. Endocrinol. Metab., 87, 4860-4868 (2002).

[0245] Analogues of diazoxide include 3-isopropylamino-7-methoxy-4H-l,2,4,- benzothiadiazine 1,1-dioxide, which is a selective Kir6.2 / SURl 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. In addition, 2-alkyl substituted diazoxides generally do not act as traditional potassium channel activators, but rather show potential as Ca 2+ Blockers.

[0246] Other diazoxide analogues are described in Schou et al., Bioorg. Med. Chem., 13, 141-155 (2005), and are shown below.

[0247]

[0248] R 1 , R 2 , and R 3 are

[0249] a) H, Cl, NHCH(CH3)2

[0250] b) CF3, H, NHCH(CH3)2

[0251] c) H, Cl, NHCH2CH2CH(CH3)2

[0252] d)H,Cl,NH-cyclobutyl

[0253] At position 3 of the molecule (labeled as R below) 3 Diazine analogs with different alkyl substituents are described in Bertolino et al., Receptors and Channels, 1, 267-278 (1993).

[0254]

[0255]

[0256] K of Formulas I-VII and related compounds ATP Channel activity can be measured by membrane potential studies, as described in Schou et al., Bioorg. Med. Chem., 13, 141-155 (2005); and Dabrowski et al., Diabetes, 51, 1896-1906 (2002).

[0257] Measurements of inhibition of glucose-stimulated insulin release from βTC6 cells are described in Schou et al., Bioorg. Med. Chem., 13, 141-155 (2005). Specific K ATP The ability of channel openers to inhibit insulin release from incubated rat islets can be demonstrated as described by Ouedraogo et al., Biol. Chem., 383, 1759-1768 (2002).

[0258] K ATP Channel openers for recombinant K ATP Activation of the channel can be studied by monitoring macroscopic currents in the inner-outward membranes of Xenopus oocytes co-expressing Kir6.2 and SUR1, SUR2A, or SUR2B. Membranes expressing SUR can be prepared using known methods. See, for example, Dabrowski et al., Diabetes, 51, 1896–1906 (2002).

[0259] K can be determined by combining experiments. ATPChannel openers bind to SURl, SUR2A, and SUR2B. See, e.g., Schwanstecher et al., EMBO J., 17, 5529-5535 (1998).

[0260] The preparation of SURl and SUR2A chimeras as described by Babenko et al. allowed for a comparison of the pharmacological characteristics (i.e., sulfonyl sensitivity and responsiveness to diazoxide or other potassium channel openers) of the SURl / Kir6.2 potassium channel and the SUR2A / Kir6.2 potassium channel. See Babenko et al., J. Biol. Chem., 275(2), 717-720 (2000). Sulfonylurea receptors and inward 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).

[0261] Differences between the human SURl gene and the human SUR2 gene are described and illustrated in Aguilar-Bryan et al., Physiological Review, 78(1), 227-245 (1998).

[0262] "Halo" and "halogen" refer to all halogens, i.e., chlorine (CI), fluorine (F), bromine (Br), or iodine (I).

[0263] "Hetero" and "hetero" refer to an atom of any element other than carbon or hydrogen.

[0264] "Substituted oxy" refers to the group -OR f where R f is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl.

[0265] "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.

[0266] "Alkyl" refers to an alkane-derived group containing from 1 to 10, preferably 1 to 6 carbon atoms. Alkyl groups include straight chain alkyl, branched chain alkyl, and cyclic alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and the like. Straight chain or branched chain alkyl groups contain from 1 to 10, preferably 1 to 6, more preferably 1 to 4, still more preferably 1 to 2 carbon atoms. Alkyl groups are attached at any available point to produce a stable compound.

[0267] "Substituted alkyl" is alkyl independently substituted with 1 or more, for example 1, 2, or 3 groups or substituents such as halo, hydroxy, optionally substituted alkoxy, optionally substituted alkylthio, alkylsulfinyl, alkylsulfonyl, optionally substituted amino, optionally substituted amido, amidino, optionally alkyl substituted urea, optionally alkyl N-mono- or N,N-disubstituted aminosulfonyl, alkylsulfonylamino, carboxy, heterocycle, substituted heterocycle, nitro, cyano, thiol, sulfonylamido, and the like, the alkyl groups being attached at any available point to produce a stable compound. Specifically, "fluoro-substituted" means substituted with 1 or more, for example 1, 2, or 3 fluorine atoms. "Optionally fluoro-substituted" means that the substitution, if present, is fluorine.

[0268] "Lower alkyl" refers to an alkyl group having from 1 to 6 carbon atoms.

[0269] "Substituted lower alkyl" is lower alkyl substituted with 1 or more, for example 1, 2, or 3 groups or substituents as defined above, the alkyl groups being attached at any available point to produce a stable compound.

[0270] "Cycloalkyl" refers to a saturated or unsaturated, non-aromatic, monocyclic, bicyclic, or tricyclic carbocyclic ring system having from 3 to 8, more preferably 3 to 6 ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, and the like. "Cycloalkylene" is a divalent cycloalkyl group.

[0271] "Alkoxy" represents the group -OR f where R f is lower alkyl.

[0272] "Substituted alkoxy" represents the group -OR f where R f is substituted lower alkyl.

[0273] "Alkylthio" or "thioalkoxy" refers to the group -S-R where R is lower alkyl.

[0274] "Substituted alkylthio" or "substituted thioalkoxy" refers to the group -S-R where R is substituted lower alkyl.

[0275] "Carboxy" or "carboxyl" denotes the -C(O)OH group.

[0276] "Sulfonyl" denotes the group -S(O)2-.

[0277] "Substituted sulfonyl" denotes 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.

[0278] "Substituted sulfonyl" denotes 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.

[0279] "Sulfonylamido" denotes the group -NRS(O)2-, where R is hydrogen or lower alkyl.

[0280] "Substituted sulfonylamido" denotes the group -NR a S(O)2-R b where R a is hydrogen or lower alkyl and 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.

[0281] "Amino" or "amine" denotes the group -NH2. "Divalent amine" denotes the group -NH-. "Substituted divalent amine" denotes the group -NR-, where R is lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl, substituted acyl, sulfonyl, or substituted sulfonyl.

[0282] "Substituted amino" or "substituted amine" denotes the group -NR i R j where R i and R j are independently hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl, substituted acyl, sulfonyl, substituted sulfonyl, or cycloalkyl, with the proviso, however, that at least one of R i and R j is not hydrogen. R i Rj In combination with nitrogen can form an optionally substituted heterocyclic or heteroaromatic ring.

[0283] "Alkylsulfinyl" denotes the group -S(O)R p where R p is optionally substituted alkyl.

[0284] "Alkylsulfonyl" denotes the group -S(O)2R p where R p is optionally substituted alkyl.

[0285] "Alkylsulfonylamido" denotes the group -NR q S(O)2R p where R p is optionally substituted alkyl and R q is hydrogen or lower alkyl.

[0286] Pharmaceutical formulations containing a K ATP channel opener 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 to make tablet formulations; (4) quantitatively produce K ATP channel openers when exposed to simulated or actual gastric and duodenal conditions; (5) release K ATP channel openers from sufficiently small particles that are readily dissolved and absorbed; (6) provide greater than 80% absorption of the administered dose when incorporated into a pharmaceutical formulation; (7) do not pose an elevated toxicological risk compared to the free base of the K ATP channel opener; (8) can be formulated into acceptable pharmaceutical formulations to treat obesity and other diseases in humans; (9) are acceptable to the FDA as the basis for a drug product; (10) can be recrystallized to improve purity; (11) can be used to form co-crystals of two or more salts of the K ATP channel opener; (12) have limited hygroscopicity to improve stability; or (13) the conditions for synthesis and crystallization of the salt can be varied so that different crystal structures (polymorphs) can be controlled in the synthesis of the salt.

[0287] K ATP channel openers can be formulated as pharmaceutically acceptable salts. Pharmaceutically acceptable salts are salts that are not toxic at their administered amounts and concentrations. The preparation of such salts can facilitate pharmacological use by altering the physical characteristics of the compound without impeding its physiological action. Useful alterations in physical characteristics include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administration of lower effective doses of the drug.

[0288] 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 obtained from acids such as hydrochloric, fumaric, sulfuric, phosphoric, sulfamic, acetic, citric, lactic, tartaric, malonic, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexylsulfamic, fumaric, and quinic.

[0289] In the presence of acidic functional groups such as carboxylic acid or phenol, pharmaceutically acceptable salts also include base addition salts, such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamines, and zinc. See, e.g., Remington: The Science and Practice of Pharmacy, 19th Ed., Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995. Such salts can be prepared using the appropriate corresponding base. Remington's Pharmaceutical Sciences Table 1: Controlled release formulation characteristics and properties , 19th Ed., Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995. Such salts can be prepared using the appropriate corresponding base.

[0290] Pharmaceutically acceptable salts can be prepared, for example, by dissolving the free base form of the compound in a suitable solvent, such as aqueous solution containing the appropriate acid or an aqueous alcohol solution containing the appropriate acid, and then separating the salt by evaporation of the solution. In another embodiment, the salt is prepared by reacting the free base with the acid in an organic solvent.

[0291] Pharmaceutically acceptable salts of different compounds can exist as complexes. Examples of complexes include 8-chlorotheophylline complexes (similar to, e.g., dimenhydrinate: diphenhydramine 8-chlorotheophylline (1:1) complex; Dramamine) and various cyclodextrin inclusion complexes.

[0292] K ATPSpecific salts of the channel opener and of the diazoxide can include, but are not limited to, acetate, acetonide, acetyl, adipate, aspartate, besylate, bis-acetylate, bitartrate, bromide, butanol, butyrate, calcium, camsylate, caproate, carbonate, citrate, cyclamate, decanoate, diacetate, digluconate, dinitrate, diphosphate, disodium, di-pyruvate, disulfide, edisylate, enanthate, estolate, esylate, ethylsuccinate, furoate, gluceptate, gluconate, hexacetonide, hippurate, hydrabamine, hydrobromide, hydrochloride, isethionate, lactobionate, malate, maleate, meglumine, methylbromide, methylsulfate, metrizoate, nafate, napsylate, nitrate, oleate, palmitate, pamoate, phenylpropionate, phosphate, pivalate, polistirex, polygalacturonate, propionate, propylbenzylhydroxybenzoate, saccharate, sodium glycinate, sodium phosphate, sodium succinate, stearate, suberate, sulfate, sulfonate, sulfosalicylate, tartrate, tetrabasic, terephthalate, tosylate, trifluoroacetate, trihydrate, trisilicate, tromethamine, valerate, xinafoate, and the like.

[0293] The formulations provided herein exhibit some or all of the following characteristics: (1) they remain stable at ambient temperature for at least one year; (2) they provide the convenience of oral administration; (3) they promote patient compliance with dosing; (4) they consistently promote high levels of absorption of the pharmaceutically active agent at the time of administration; (5) they allow K ATP The channel opener is released over a sustained time range such that K ATP The circulating concentration of the channel opener or its metabolically active metabolite does not fall below the therapeutically effective concentration; (6) they achieve these results independent of the pH of the gastrointestinal tract of the individual receiving treatment; and (7) they delay release until gastric transit is complete or nearly complete.

[0294] Formulations designed for oral administration can be provided, for example, as capsules or tablets. Capsule or tablet formulations include a number of distinct components. One is a component that enhances the absorption of the K ATP The channel opener. Another maintains the release of the drug over more than 2 hours. A third delays the significant release of the drug until gastric transit is complete.

[0295] The formulations disclosed herein exhibit improved K ATPSolubility and absorption of channel openers. These advantageous properties are achieved by one or more of the following methods: (1) reducing the particle size of the formulation by pulverization, spray drying, or other micronization techniques; (2) using K ATP (3) Pharmaceutical salts of channel openers; (4) Use of ion exchange resins in formulations; (5) Use of inclusion complexes, such as cyclodextrins; ATP The channel opener is pressed together with a solubilizer, the solubilizer comprising low-viscosity hydroxypropyl methylcellulose, low-viscosity methylcellulose or excipients that perform similar functions, and combinations thereof; (6) K is made prior to formulation. ATP Channel openers associate with salts; (7) Use K ATP (7) Solid dispersions of channel openers; (8) Use of self-emulsifying systems; (9) Addition of one or more surfactants to the formulation; (10) Use of nanoparticles in the formulation; or (11) Combinations of these methods. Preferably, when K ATP When the channel opener is a salt of diazine, the salt is not a sodium salt.

[0296] K ATP The release of the channel opener over a sustained period of time (2 hours to 24 hours) is achieved by using one or more methods, including but not limited to: (1) using a pH-sensitive polymer coating; (2) using a hydrogel; (3) using a membrane coating that controls the diffusion rate of the drug from the coated matrix; (4) using a soluble matrix that controls the drug release rate; (5) using polymer-coated pellets, granules, or microparticles that can be further encapsulated or compressed into tablets; (6) using an osmotic pump system; or (7) using compressed coated tablets; or (8) a combination of these methods.

[0297] Delay K ATPRelease of the channel opener from the formulation until gastric transit is complete is achieved in the formulations provided herein by any of several mechanisms. Use of a pH sensitive polymer or copolymer that acts as an effective barrier to release of the active agent at a pH of 3.0 or lower and is unstable at a pH of 5.5 and above when applied around the drug matrix. This provides control over release of the active compound in the stomach, but once the dosage form has passed into the small intestine, release is rapidly allowed. An alternative to a pH sensitive polymer or copolymer is a non-water soluble polymer or copolymer. The degree of resistance to release in the stomach environment can be controlled by coating with a blend of non-water soluble and water soluble polymers. In this approach, neither of the blended polymers or copolymers is 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.

[0298] The delayed release polymer can be applied to the tablet by spray coating (as a thin film) or by compression coating. If a capsule is used, one or more polymers can be applied to the surface of the capsule or to the drug particles, which can then be encapsulated in, for example, a capsule or gel. If the capsule is coated, it will resist disintegration until after gastric transit. If the particles are coated, the capsule can disintegrate in the stomach, but little to no drug will be released until the free particles complete gastric transit. Finally, an osmotic pump system using, for example, a swelling hydrogel can be used to delay release of the drug in the stomach. The swelling hydrogel absorbs water after administration. Swelling of the gel causes the drug to be displaced from the system for absorption. The time and rate of drug release depends on the gel used and the rate of water reaching the gel, which can be controlled by the size of the opening in the system for fluid entry. See the online article by Dong et al., "Osmotic Pump Systems for Controlled Release of Non-Aqueous Liquid Formulations," Drug Delivery Technology. SOFTCAP TM ( SOFTCAP TM for Controlled Release of Non-Aqueous Liquid Formulations."

[0299] Thus, delayed K ATPRelease of the channel opener from the formulations of the present application until after gastric transit is complete is achieved in the formulations provided herein by any of several mechanisms, including but not limited to: (a) pH sensitive polymers or copolymers applied as a compression coating on the tablet; (b) pH sensitive polymers or copolymers applied as a film on the tablet; (c) pH sensitive polymers or copolymers applied as a film to the encapsulation system; (d) pH sensitive polymers or copolymers applied to the encapsulated microparticles; (e) non-water soluble polymers or copolymers applied as a compression coating on the tablet; (f) non-water soluble polymers or copolymers applied as a film on the tablet; (g) non-water soluble polymers applied as a film to the encapsulation system; (h) non-water soluble polymers applied to the microparticles; (i) incorporation of the formulation into an osmotic pump system; or (j) use of a system controlled by ion exchange resins; or (k) combinations of these methods, wherein the pH sensitive polymers or copolymers are resistant to degradation under acidic conditions.

[0300] Formulations designed for administration once a day (every 24 hours) are provided. These can contain 25 mg to 500 mg of K ATP Channel openers. Formulations intended for administration twice a day (every 24 hours) are also provided. These can contain 25 mg to 250 mg of K ATP Channel openers.

[0301] The formulations provided herein exhibit improved safety of the administered drug product. This improvement in safety occurs through at least two mechanisms. First, delaying release of the active drug until after gastric transit is complete can reduce the incidence of a variety of gastrointestinal adverse side effects, including nausea, vomiting, indigestion, abdominal pain, diarrhea, and ileus. Second, by maintaining release of the active drug over 2 hours or more up to 24 hours, peak drug levels are reduced relative to those 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 a reduction in adverse effects that are determined in part or in whole by peak drug levels. These adverse effects include: fluid retention with associated decreased rates of sodium, chloride, and uric acid excretion, edema, hyperglycemia and associated potential for progression to ketoacidosis, cataracts, and non-ketotic hyperosmolar coma, headache, tachycardia, and palpitations.

[0302] K ATP Channel openers. Formulations intended for administration twice a day (every 24 hours) are also provided. These can contain 25 mg to 250 mg of K

[0303] Example 1: Formulations containing potassium ATP channel activators

[0304] A. Unit form: tablet or capsule

[0305] B. Dose / unit: 10 mg - 100 mg

[0306] 100 mg - 200 mg

[0307] 200 mg - 300 mg

[0308] 300 mg - 500 mg

[0309] 500 mg - 2000 mg

[0310] C. Administration once per day (24 hours)

[0311] twice per day (24 hours)

[0312] D. Release time: 2 hours - 4 hours

[0313] 4 hours - 8 hours

[0314] 8 hours - 24 hours

[0315] For example, the controlled release composition can be a tablet containing 25 mg - 100 mg of a K ATP channel opener, such tablet being administered once per day to achieve a controlled release time of 2 hours - 4 hours. All of these formulations can further include features that substantially delay release of the drug active until after gastric transit is complete.

[0316] In addition, any of the above formulations from Table 1 can include at least one feature that enhances solubility or absorption of the K ATP channel opener.

[0317] The controlled release formulations provided herein comprise an active compound (e.g., a K ATP channel opener, optionally in combination with growth hormone) and a matrix comprising a gelling agent that swells upon contact with an aqueous fluid. The active compound(s) encapsulated within the gel are slowly released into the body upon dissolution of the gel. The active compound(s) can be uniformly dispersed within the matrix or can exist as drug pockets within the matrix. For example, the drug can be formulated as small particles dispersed within the matrix. In addition, the particles of drug can also include a matrix, thereby providing a primary matrix and a secondary matrix, as described in U.S. Patent No. 4,880,830 to Rhodes.

[0318] The gelling agent is preferably a polymeric material and can include, for example, any pharmaceutically acceptable water-soluble or water-insoluble slow release polymer such as xanthan gum, gelatin, cellulose ethers, gum arabic, locust bean gum, guar gum, carboxyvinyl polymers, agar, gum arabic, gum tragacanth, Veegum®, magnesium aluminum silicate, 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 acid resins or mixtures of the above (see, e.g., U.S. Patent No. 5,415,871).

[0319] The gelling agent of the matrix can also be a heterogeneous dispersion gel comprising a heteropolysaccharide component and a homopolysaccharide component which produces a rapid forming and rigid gel, as described in U.S. Patent No. 5,399,359. The matrix can also include a cross-linking agent, such as a monovalent or multivalent metal cation to further add rigidity and reduce dissolution of the matrix, thereby further slowing the release of the drug. The amount of cross-linking agent to add can be determined using methods routine to one of ordinary skill in the art.

[0320] The matrix of the controlled release composition can also include one or more pharmaceutically acceptable excipients, i.e., formulation excipients, recognized by those skilled in the art. Such excipients include, for example, binding agents: polyvinylpyrrolidone, gelatin, starch paste, microcrystalline cellulose; diluents (or fillers): starch, sucrose, dextrose, lactose, fructose, xylitol, sorbitol, sodium chloride, dextrin, calcium phosphate, calcium sulfate; and lubricating agents: stearic acid, magnesium stearate, calcium stearate, Precirol® TM ; and glidants: e.g., talc or colloidal silicon dioxide.

[0321] The matrix of the controlled release composition can also include a hydrophobic material which slows the hydration of the gelling agent without destroying the hydrophilicity of the matrix, as described in U.S. Patent No. 5,399,359. The hydrophobic polymer can include, for example, alkylcelluloses such as ethylcellulose, other hydrophobic cellulose materials, polymers or copolymers derived from acrylate or methacrylate esters, copolymers of acrylate and methacrylate esters, zein, waxes, shellac, hydrogenated vegetable oils, waxes and wax-like substances such as carnauba wax, whale wax, candelilla wax, cocoa butter, cetylstearyl alcohol, beeswax, ozocerite, paraffin wax, myristyl alcohol, stearyl alcohol, cetyl alcohol and stearic acid, and any other pharmaceutically acceptable hydrophobic material known to one of ordinary skill in the art.

[0322] The amount of hydrophobic material incorporated into the controlled release composition is an amount effective to slow the hydration of the gelling agent without destroying the hydrophilic matrix formed upon exposure to environmental fluids. In certain preferred embodiments, the hydrophobic material is included in the matrix in an amount of about 1% to about 20% by weight and replaces a corresponding amount of formulation excipient. The solvent for the hydrophobic material can be an aqueous solvent or an organic solvent, or a mixture thereof.

[0323] Examples of commercially available alkyl celluloses are AQUACOAT® E (an aqueous dispersion of ethyl cellulose available from FMC Corporation) and EUDRAGIT® RL (an aqueous dispersion of ethyl cellulose available from Colorcon Corporation). Examples of commercially available acrylic polymers suitable for use as the hydrophobic material include EPODRIAN® RS and RL (copolymers of acrylates and methacrylates with low content (e.g., 1 :20 or 1 :40) of quaternary ammonium compounds).

[0324] The controlled release composition can also be coated to delay liquid access to the active compound and / or to delay release of the active compound via a film coating. The film coating can provide the features of resistance to gastric fluid and enteric solubility by resisting rapid dissolution of the composition in the digestive tract. The film coating generally comprises about 5-15% by weight of the controlled release composition. Preferably, the core comprises about 90% by weight of the composition, with the remaining 10% provided by the coating. Such coatings can be film coatings, as are well known in the art, and include gels, waxes, fats, emulsifiers, combinations of fats and emulsifiers, polymers, starches, and the like.

[0325] Polymers and copolymers can be used as film coatings. Solution coatings and dispersion coatings can be used to coat the active compound alone or the active compound in combination with the matrix. The coating is preferably applied to the drug or the combination of the drug and the matrix as a solid core of material, as is well known in the art.

[0326] Solutions for coating can include polymers in both organic solvent systems and aqueous solvent systems, and generally also include one or more compounds used as plasticizers. Polymers that can be used in the coating composition include, for example, methyl cellulose (METHOCEL® A; Dow Chemical Co.), hydroxypropyl methyl cellulose (KLUCEL® HPMC; Ashland Inc.) with a molecular weight of 1,000 to 4,000,000, A; Dow Chemical Co.), hydroxypropyl methyl cellulose (KLUCEL® HPMC; Ashland Inc.) with a molecular weight of 1,000 to 4,000,000, E; Dow Chemical Co. or Shin Etsu), hydroxypropyl cellulose with a molecular weight of 2,000 to 2,000,000, ethyl cellulose, cellulose acetate, cellulose triacetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate (Eastman Kodak), carboxymethyl ethyl cellulose hydroxypropyl methyl cellulose phthalate, ethyl cellulose, methyl cellulose and in general cellulose derivatives, polymethacrylic acid-methacrylic acid copolymers (type A 1 : 1 Eudragit L100; type B 1 :2 Eudragit S100; and type C 1 : 1 Eudragit L100-55; aqueous dispersion 30% solids, Eudragit L30D), poly(meth)acrylate: poly(ethyl acrylate-methyl methacrylate) (2: 1), Eudragit NE30D aqueous dispersion 30% solids, polyaminomethacrylate Eudragit E100, poly(trimethyl quaternary aminoethyl methacrylate chloride) quaternary aminomethacrylate copolymer, Eudragit RL30D and Eudragit RS30D, carboxyvinyl polymers, polyvinyl alcohol, dextran, scleroglucan, mannan, and xanthan gum.

[0327] Aqueous polymer dispersions include Eudragit L30D and RS / RL30D, and NE30D, Aquacoat brand ethyl cellulose, Surelease brand ethyl cellulose, EC brand N-10F ethyl cellulose, Aquateric brand cellulose acetate phthalate, Coateric brand poly(vinyl acetate phthalate), and Aqacoat brand hydroxypropyl methyl cellulose acetate succinate. Most of these dispersions are latex, pseudolatex, powder or micronized powder media.

[0328] A plasticizer can be included in the coating to increase the flexibility and stability of the polymer film and to prevent changes in polymer permeability over long periods of storage. Such changes can affect the drug release rate. Suitable conventional plasticizers include, for example, diethyl phthalate, triacetin, acetylated monoglycerides, acetyl tri-butyl citrate, acetyl tri-ethyl 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 alcohols, petrolatum and lanolin alcohols, phthalate esters, polyethylene glycol, propylene glycol, rapeseed oil, sesame oil, triacetin, tri-butyl citrate, tri-ethyl citrate, and acetyl tri-ethyl citrate, or a mixture of any two or more of the foregoing. Plasticizers that can be used in aqueous coatings include, for example, propylene glycol, polyethylene glycol (PEG 400), triacetin, polysorbate 80, tri-ethyl citrate, and di-ethyl d-tartrate.

[0329] A coating solution comprising a mixture of hydroxypropyl methylcellulose and aqueous ethylcellulose (e.g., Aquacoat brand) as the polymer and dibutyl sebacate as the plasticizer can be used to coat the microparticles. (Aquacoat is an aqueous polymer dispersion of ethylcellulose and contains sodium lauryl sulfate and cetyl alcohol). Preferably, the plasticizer comprises about 1-2% of the composition.

[0330] In addition to the polymer, the coating layer can also include an excipient to aid in formulating the coating solution. Such an excipient can include a lubricant or a wetting agent. Suitable lubricants for use as an excipient in film coating include, for example, talc, calcium stearate, colloidal silicon dioxide, glycerin, magnesium stearate, mineral oil, polyethylene glycol, and zinc stearate, aluminum stearate, or a mixture of any two or more of the foregoing. Suitable wetting agents include, for example, sodium lauryl sulfate, acacia, benzalkonium chloride, cetomacrogol emulsifying wax, cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolamine, docusate sodium, sodium stearates, emulsifying wax, glyceryl monostearate, hydroxypropyl cellulose, lanolin alcohols, lecithin, mineral oil, monoethanolamine, poloxamer, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene stearates, propylene glycol alginate, sorbitol esters, stearyl alcohol, and triethanolamine, or a mixture of any two or more of the foregoing.

[0331] The specified tablet or capsule formulations of Table 1 can include an obesity treatment drug (in addition to K ATPThe obesity treatment drug can be co-formulated with the channel opener. Obesity treatment drugs that can be used include, but are not limited to, sibutramine hydrochloride (5 mg / unit - 30 mg / unit), orlistat (50 mg / unit - 360 mg / unit), phentermine hydrochloride or phentermine resin complex (15 mg / unit to 40 mg / unit), zonisamide (100 mg / unit to 600 mg / unit), topiramate (64 mg / unit to 400 mg / unit), naltrexone hydrochloride (50 mg / unit to 600 mg / unit), rimonabant (5 mg / unit to 20 mg / unit), ADP356 (5 mg / unit to 25 mg / unit), ATL962 (20 mg / unit to 400 mg / unit), or AOD9604 (1 mg / unit to 10 mg / unit). These formulations are preferably used once a day. For twice a day dosing, K ATP The amount of the channel opener is half the amount included in the once a day formulation and the co-formulated obesity treatment drug is half the specified amount. Alternative obesity treatment drugs can include: selective serotonin 2c receptor agonists, dopamine antagonists, cannabinoid-1 receptor antagonists, leptin analogs, leptin transport and / or leptin receptor promoters, neuropeptide Y and peptide YY antagonists, proopiomelanocortin and cocaine and amphetamine regulated transcript promoters, melanocyte stimulating hormone analogs, melanocortin-4 receptor agonists, and agents that affect insulin metabolism / activity including protein tyrosine phosphatase-1B inhibitors, peroxisome proliferator-activated receptor-gamma receptor antagonists, short acting bromocriptine (ergoset), somatostatin agonists (octreotide), and adiponectin; agents that affect the gastrointestinal neural pathways including those that increase cholecystokinin activity, increase glucagon-like peptide-1 activity (extendin 4, liraglutide, dipeptidyl peptidase IV inhibitors), and increase protein YY3-36 activity as well as those that decrease ghrelin activity; and amylin analogs, agents that can increase resting metabolic rate ("selective" beta-3 stimulators / agonists, uncoupling protein homologs, and thyroid receptor agonists), melanin concentrating hormone antagonists, phytostanol analogs, amylase inhibitors, growth hormone fragments, synthetic analogs of dehydroepiandrosterone sulfate, antagonists of fatty acid type 1 1 B hydroxysteroid dehydrogenase activity, corticotropin-releasing hormone agonists, fatty acid synthesis inhibitors, carboxypeptidase inhibitors, indanones / indanols, aminosterols, and other agents that inhibit gastric and pancreatic lipases.

[0332] The specified tablet or capsule formulations in Table 1 may include those used with diabetes treatment drugs (except K). ATP Common formulations other than channel openers. Suitable diabetes treatments include, but are not limited to, acarbose (50 mg / unit to 300 mg / unit), miglitol (25 mg / unit to 300 mg / unit), metformin hydrochloride (300 mg / unit to 2000 mg / unit), repaglinide (1 mg / unit to 16 mg / unit), nateglinide (200 mg / unit to 400 mg / unit), rosiglitazone (5 mg / unit to 50 mg / unit), metadextrin (100 mg / unit to 400 mg / unit), or any medication that improves insulin sensitivity or improves glucose utilization and absorption. These formulations are preferably used once daily. For twice-daily dosing, K ATP The amount of the channel opener is half the amount included in the once-daily formulation, and for co-formulated diabetes treatments, it is half the quantification.

[0333] The specified tablet or capsule formulations in Table 1 may include co-preparations with cholesterol-lowering drugs. Cholesterol-lowering drugs that may be used include, but are not limited to, pravastatin, simvastatin, atorvastatin, fluvastatin, rosuvastatin, or lovastatin (all from 10 mg / unit to 80 mg / unit). These formulations are preferably used once daily. For twice-daily dosing, K ATP The amount of the channel opener is preferably 25 mg / unit to 200 mg / unit, and the cholesterol-lowering drug formulated together refers to half of the quantification.

[0334] The specified tablet or capsule formulations of Table 1 can include coformulation with a depression treatment drug. Depression treatment drugs that can be used include, but are not limited to, citalopram hydrobromide (10 mg / unit to 80 mg / unit), escitalopram hydrobromide (5 mg / unit to 40 mg / unit), fluvoxamine maleate (25 mg / unit to 300 mg / unit), paroxetine hydrochloride (12.5 mg / unit to 75 mg / unit), fluoxetine hydrochloride (30 mg / unit to 100 mg / unit), setraline hydrochloride (25 mg / unit to 200 mg / unit), amitriptyline hydrochloride (10 mg / unit to 200 mg / unit), desipramine hydrochloride (10 mg / unit to 300 mg / unit), nortriptyline hydrochloride (10 mg / unit to 150 mg / unit), duloxetine hydrochloride (20 mg / unit to 210 mg / unit), venlafaxine hydrochloride (37.5 mg / unit to 150 mg / unit), phenelzine sulfate (10 mg / unit to 30 mg / unit), bupropion hydrochloride (200 mg / unit to 400 mg / unit), or mirtazapine (7.5 mg / unit to 90 mg / unit). 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 included in the once-a-day formulation and the coformulated depression treatment drug is half the specified amount.

[0335] The specified tablet or capsule formulations of Table 1 can include co-formulations with a hypertension treating drug. Hypertension treating drugs that can be used include, but are not limited to, enalapril maleate (2.5 mg / unit to 40 mg / unit), captopril (2.5 mg / unit to 150 mg / unit), lisinopril (10 mg / unit to 40 mg / unit), benazepril hydrochloride (10 mg / unit to 80 mg / unit), quinapril hydrochloride (10 mg / unit to 80 mg / unit), peridopril erbumine (4 mg / unit to 8 mg / unit), ramipril (1.25 mg / unit to 20 mg / unit), trandolapril (1 mg / unit to 8 mg / unit), fosinoprilsodium (10 mg / unit to 80 mg / unit), moexipril hydrochloride (5 mg / unit to 20 mg / unit), losartan potassium (25 mg / unit to 200 mg / unit), irbesartan (75 mg / unit to 600 mg / unit), valsartan (40 mg / unit to 600 mg / unit), candesartan cilexetil (4 mg / unit to 64 mg / unit), olmesartan medoxamil (5 mg / unit to 80 mg / unit), telmisartan (20 mg / unit to 160 mg / unit), eprosartan mesylate (75 mg / unit to 600 mg / unit), atenolol (25 mg / unit to 200 mg / unit), propranolol hydrochloride (10 mg / unit to 180 mg / unit), metoprolol tartrate, metoprolol succinate or metoprolol fumarate (all 25 mg / unit to 400 mg / unit), nadolol (20 mg / unit to 160 mg / unit), betaxolol hydrochloride (10 mg / unit to 40 mg / unit), acebutolol hydrochloride (200 mg / unit to 800 mg / unit), pindolol (5 mg / unit to 20 mg / unit), bisoprolol fumarate (5 mg / unit to 20 mg / unit), nifedipine (15 mg / unit to 100 mg / unit), felodipine (2.5 mg / unit to 20 mg / unit), amlodipine besylate (2.5 mg / unit to 20 mg / unit), nicardipine (10 mg / unit to 40 mg / unit), nisoldipine (10 mg / unit to 80 mg / unit), terazosin hydrochloride (1 mg / unit to 20 mg / unit), doxasoxin mesylate (4 mg / unit to 16 mg / unit), prazosin hydrochloride (25 mg / unit to 10 mg / unit), or alfuzosin (10 mg / unit to 20 mg / unit). These formulations are preferably used once a day. For twice a day dosing, K. ATP The amount of the channel opener is preferably half the amount included in the once a day formulation and the co-formulated hypertension treatment drug is half the specified amount.

[0336] The specified tablet or capsule formulations of Table 1 can include co-formulation with a diuretic to treat edema. Diuretics that can be used include, but are not limited to, amiloride hydrochloride (1 mg / unit to 10 mg / unit), spironolactone (10 mg / unit to 100 mg / unit), triamterene (25 mg / unit to 200 mg / unit), bumetanide (0.5 mg / unit to 4 mg / unit), furosemide (10 mg / unit to 160 mg / unit), ethacrynic acid or sodium ethacrynic acid (both 10 mg / unit to 50 mg / unit), tosemide (5 mg / unit to 100 mg / unit), chlorthalidone (10 mg / unit to 200 mg / unit), indapamide (1 mg / unit to 5 mg / unit), hydrochlorothiazide (10 mg / unit to 100 mg / unit), chlorothiazide (50 mg / unit to 500 mg / unit), bendroflumethiazide (5 mg / unit to 25 mg / unit), hydroflumethiazide (10 mg / unit to 50 mg / unit), mythyclothiazide (1 mg / unit to 5 mg / unit), or polythiazide (1 mg / unit to 10 mg / unit). These formulations are preferably used once a day. For twice a day dosing, K ATP The amount of the channel opener is preferably half the amount included in the once a day formulation and the co-formulated diuretic is half the specified amount.

[0337] The specified tablet or capsule formulations of Table 1 can include coformulation with a drug that treats inflammation or pain. Drugs that can be used to treat inflammation or pain include, but are not limited to, aspirin (100 mg / unit to 1000 mg / unit), tramadol hydrochloride (25 mg / unit to 150 mg / unit), gabapentin (100 mg / unit to 800 mg / unit), acetominophen (100 mg / unit to 1000 mg / unit), carbamazepine (100 mg / unit to 400 mg / unit), ibuprofen (100 mg / unit to 1600 mg / unit), ketoprofen (12 mg / unit to 200 mg / unit), fenprofen sodium (100 mg / unit to 600 mg / unit), flurbiprofen sodium or flurbiprofen (both 50 mg / unit to 200 mg / unit), or a combination of any of these 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 included in the once-a-day formulation and the coformulated diuretic is half the specified amount.

[0338] The specified tablet or capsule formulations of Table 1 can include coformulation with a drug that treats obesity-related co-morbidities, including those specified above for treating diabetes, cholesterol, depression, high blood pressure, and edema, or a drug that treats atherosclerosis, osteoarthritis, herniated spinal disc, degeneration of the knee and hip joints, 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 hiatal hernia, menstrual irregularities, and infertility.

[0339] The specified tablet or capsule formulations of Table 1 can include coformulation with an antipsychotic drug, the combination used to treat a psychotic condition and to treat or prevent weight gain, dyslipidemia, or impaired glucose tolerance in the individual receiving treatment. Drugs that can be used to treat various psychotic conditions include, but are not limited to, lithium or a salt thereof (250 mg / unit to 2500 mg / unit), carbamazepine or a salt thereof (50 mg / unit to 1200 mg / unit), valproate, valproic acid, or divalproex (125 mg / unit to 2500 mg / unit), lamotrigine (12.5 mg / unit to 200 mg / unit), olanzapine (5 mg / unit to 20 mg / unit), clozapine (12.5 mg / unit to 450 mg / unit), or risperidone (0.25 mg / unit to 4 mg / unit). These coformulations are preferably intended for once-a-day administration. For twice-a-day dosing, K ATP The amount of channel opener is preferably half the amount included in the once-a-day formulation and the coformulated antipsychotic drug is half the specified amount.

[0340] The specified tablet or capsule formulations of Table 1 can include coformulation with a drug that treats or prevents ischemic or reperfusion injury. Drugs that can be used to treat or prevent ischemic or reperfusion injury include, but are not limited to, low molecular weight heparin (dalteparin, enoxaparin, nadroparin, tinzaparin, or danaparoid), ancrd, pentoxifylline, nimodipine, flunarizine, ebselen, tirilazad, clomethiazole, AMPA agonists (GYKI 52466, NBQX, YM90K, zonampanel, or MPQX), SYM 2081, selfotel, cerestat, CP-101,606, dextrophan, dextromethorphan, MK-801, NPS 1502, remacemide, ACEA 1021, GV150526, eliprodil, ifenprodil, lubeluzole, naloxone, nalfemene, citicoline, acetyl-l-carnitine, nifedipine, resveratrol, nitrone derivatives, clopidogrel, dabigatram, prasugrel, troxoprodil, AGY-94806, or KAI-9803.

[0341] Provided is the continuous once or twice daily administration of a formulation of a K ATP channel opener to an obese or overweight subject to produce a K

[0342] Provided is the continuous once or twice daily administration of a formulation of a K ATP channel opener to an obese, overweight, or obesity-prone subject to produce a K

[0343] Provided is the continuous once or twice daily administration of a formulation of a K ATPFormulations of a channel opener that are administered as a single dose to an obese, overweight, or obesity-prone subject, such that energy expenditure is elevated for about 24 hours or for about 18 hours.

[0344] Provided are K ATP Formulations of a channel opener that are administered as a single dose to an obese, overweight, or obesity-prone subject, such that beta oxidation of fat is elevated for about 24 hours or for about 18 hours.

[0345] Provided are K ATP Formulations of a channel opener that are administered as a single dose to an obesity-prone subject, such that hyperphagia is inhibited for about 24 hours or for about 18 hours.

[0346] Provided are formulations that are administered to a subject once or twice per day (every 24 hours) to produce a circulating concentration of a K ATP channel opener sufficient to induce beta cell rest or improved insulin sensitivity or both. Such beta cell rest and improvement in insulin sensitivity can be useful in the effective treatment of Type I diabetes, Type II diabetes, and pre-diabetes. Such beta cell rest and improvement in insulin sensitivity can be useful in the effective restoration of normal glucose tolerance in Type II diabetic and pre-diabetic subjects.

[0347] Various pharmaceutical K ATP channel opener formulations have a variety of applications, including but not limited to: (1) treatment of obesity; (2) prevention of weight gain in individuals predisposed to obesity; (3) treatment of hyperinsulinemia or hyperinsulinism; (4) treatment of hypoglycemia; (5) treatment of hyperlipidemia; (6) treatment of Type II diabetes; (7) preservation of pancreatic function in Type I diabetics; (8) treatment of metabolic syndrome (or Syndrome X); (9) prevention of the progression of pre-diabetes to diabetes; (10) correction of defects in insulin secretion and insulin sensitivity that lead to pre-diabetes and Type II diabetes; (11) treatment of polycystic ovary syndrome; (12) prevention of ischemic or reperfusion injury; (13) treatment of weight gain, dyslipidemia, or impaired glucose tolerance in subjects receiving antipsychotic drug therapy; (14) prevention of weight gain, dyslipidemia, or impaired glucose tolerance in subjects receiving antipsychotic drug therapy; and (15) treatment of any disease in which hyperlipidemia, hyperinsulinemia, hyperinsulinism, hyperlipidemia, hyperphagia, or obesity is a contributing factor in the severity or progression of the disease, including but not limited to Prader-Willi syndrome, Smith-Magenis syndrome, Frohlich's syndrome, Cohen syndrome, Summit syndrome, Alstrom syndrome, Borjeson syndrome, Bardet-Biedl syndrome, Type I, Type II, Type III, and Type IV hyperlipoproteinemia, and the like.

[0348] In one embodiment, K ATP A channel opener is administered as a solid oral dosage form once every 24 hours to an overweight or obese individual, optionally in combination with growth hormone, to cause weight loss. In further embodiments, the individual (a) is not a Type I diabetic; (b) is not a Type II diabetic; (c) is not experiencing chronic, recurrent, or drug-induced hypoglycemia; (d) does not have metabolic syndrome; or (e) is not experiencing malignant hypertension.

[0349] In one embodiment, K ATP A channel opener is administered as a solid oral dosage form twice every 24 hours to an overweight or obese individual, optionally in combination with growth hormone, to cause weight loss. The treatment can be the only treatment to cause weight loss. In further embodiments, the overweight or obese individual (a) does not have an insulin secreting tumor; (b) does not have polycystic ovary syndrome; (c) is not a Type I diabetic; (d) is not a Type II diabetic; (e) does not have metabolic syndrome; (f) is not experiencing chronic, recurrent, or drug-induced hypoglycemia; (g) is not being treated with haloperidol for schizophrenia; or (h) is not experiencing malignant hypertension. In further embodiments, the overweight or obese adolescent (a) is not diagnosed as being a Type I or Type II diabetic; (b) is not experiencing chronic, recurrent, or drug-induced hypoglycemia; or (c) is not diagnosed as having metabolic syndrome.

[0350] In one embodiment, K ATP A channel opener is administered as a solid oral dosage form three times every 24 hours to an overweight or obese individual, optionally in combination with growth hormone, to cause weight loss. The treatment can be the only treatment to cause weight loss. In further embodiments, the overweight or obese individual (a) does not have an insulin secreting tumor; (b) does not have polycystic ovary syndrome; (c) is not a Type I diabetic; (d) is not a Type II diabetic; (e) does not have metabolic syndrome; or (f) is not experiencing chronic, recurrent, or drug-induced hypoglycemia.

[0351] In one embodiment, K ATP A channel opener is administered as a solid oral dosage form three times every 24 hours to an overweight or obese adolescent, optionally in combination with growth hormone, to cause weight loss. The treatment can be the only treatment to cause weight loss. In further embodiments, the overweight or obese adolescent (a) is a Type I or Type II diabetic; (b) is not experiencing chronic, recurrent, or drug-induced hypoglycemia; or (c) does not have metabolic syndrome.

[0352] In one embodiment, KATP A channel opener is administered as a solid oral dosage form three times per 24 hours to an overweight or obese adult, optionally in combination with growth hormone, to induce weight loss, said adult (a) not concurrently receiving glucagon injections, triiodothyronine, or furosemide; (b) not receiving haloperidol treatment for schizophrenia; or (c) not experiencing malignant hypertension.

[0353] In another embodiment, K ATP A channel opener is administered as a solid oral dosage form four times per 24 hours to an overweight or obese individual, optionally in combination with growth hormone, to induce weight loss.

[0354] In another embodiment, K ATP A channel opener is administered as a solid oral dosage form once, twice, three times, or four times per 24 hours to an overweight or obese individual at a daily dose of 50 mg to 275 mg, optionally in combination with growth hormone, to induce weight loss. In another embodiment, the overweight or obese individual (a) is not a Type I diabetic; (b) is not a Type II diabetic; (c) is not suffering from chronic, recurrent, or drug-induced hypoglycemia; or (d) does not have metabolic syndrome.

[0355] In another embodiment, K ATP A channel opener is administered as a solid oral dosage form once, twice, three times, or four times per 24 hours to an overweight or obese individual at a daily dose of 130 mg to 275 mg, optionally in combination with growth hormone, to induce weight loss. In another embodiment, the overweight or obese individual (a) is not a Type I diabetic; (b) is not a Type II diabetic; (c) is not suffering from chronic, recurrent, or drug-induced hypoglycemia; or (d) does not have metabolic syndrome.

[0356] In another embodiment, K ATP A channel opener is administered as a solid oral dosage form once, twice, three times, or four times per 24 hours to an overweight or obese individual, optionally in combination with growth hormone, to maintain weight loss, since once a certain weight loss has occurred, another option is to re-gain weight, and it is preferable to maintain the weight of an obese individual. In another embodiment, the K ATP The daily dose of the channel opener is 50 mg to 275 mg.

[0357] In other embodiments, K ATP A channel opener is administered as a solid oral dosage form to an overweight, obese, or obesity-prone individual, optionally in combination with growth hormone, to (a) elevate energy expenditure; (b) elevate fat beta oxidation; or (c) reduce circulating triglyceride concentration.

[0358] In other embodiments, the solid oral dosage of K ATP The channel opener is administered on a chronic basis to an individual in need thereof to cause a 25%, 50%, or 75% reduction in initial body fat.

[0359] In another embodiment, the solid oral dosage of K ATP The channel opener is administered on a chronic basis to an individual in need thereof, optionally in combination with growth hormone, to cause (a) preferential reduction in body fat; or (b) preferential reduction in visceral body fat.

[0360] In further embodiments, the solid oral dosage of K ATP The channel opener is administered on a chronic basis to an individual in need thereof, optionally in combination with growth hormone, to cause (a) a 25%, 50%, or 75% reduction in initial body fat; (b) preferential reduction in body fat; or (c) preferential reduction in visceral fat.

[0361] In another embodiment, the solid oral dosage of K ATP The channel opener is administered to an individual, optionally in combination with growth hormone, to cause preferential reduction in body fat and to cause a reduction in circulating triglycerides.

[0362] In another embodiment, the solid oral dosage of K ATP The channel opener is co-administered with growth hormone.

[0363] In yet another embodiment, the solid oral dosage of K ATP The channel opener is co-administered with growth hormone and optionally one or more of the following: sibutramine, orlistat, rimonabant, an appetite suppressant, an antidepressant, an antiepileptic, a diuretic other than furosemide, a drug that causes weight loss by a mechanism other than K ATP The channel opener is co-administered with a drug that causes weight loss by a mechanism other than K ATP The channel opener is co-administered with a drug that causes weight loss by a mechanism other than K ATP The channel opener is co-administered with a drug that causes weight loss by a mechanism other than K

[0364] In another embodiment, the solid oral dosage of K ATPA channel opener is co-administered with growth hormone and optionally one or more of an anti-depressant, a blood pressure lowering drug, a cholesterol lowering drug, an HDL raising drug, an anti-inflammatory agent that is not a Cox-2 inhibitor, a circulating triglyceride lowering drug to induce weight loss and / or treat obesity related co-morbidities in an overweight, obese, or obesity prone individual. In further embodiments, the overweight, obese, or obesity prone individual (a) is not a Type I diabetic; (b) is not a Type II diabetic; (c) is not suffering from chronic, recurrent, or drug induced hypoglycemia; or (d) does not have metabolic syndrome.

[0365] In another embodiment, a solid oral dosage of K ATP A channel opener is co-administered with growth hormone and optionally one or more of a blood pressure lowering drug, a cholesterol lowering drug, an HDL raising drug, an anti-inflammatory agent that is not a Cox-2 inhibitor, a circulating triglyceride lowering drug to maintain weight and / or treat obesity related co-morbidities in an overweight, obese, or obesity prone individual because once a certain weight loss has occurred, another option is to re-gain weight and it is preferable to maintain the weight of an obese individual. In further embodiments, the overweight, obese, or obesity prone individual (a) is not a Type I diabetic; (b) is not a Type II diabetic; (c) is not suffering from chronic, recurrent, or drug induced hypoglycemia; or (d) does not have metabolic syndrome.

[0366] In further embodiments, K ATP A tablet formulation of a channel opener is used to administer a therapeutically effective dose of K ATP A channel opener to (a) provide beta cell rest; (b) treat Type I or Type II diabetes; or (c) prevent the onset of diabetes.

[0367] In further embodiments, K ATP A solid oral dosage form or tablet formulation of a channel opener is co-administered with growth hormone and optionally one or more of phentermine or a derivative thereof to an obese adult or adolescent to induce weight loss and / or treat obesity and obesity related co-morbidities. In further embodiments, K ATP A solid oral dosage form or tablet formulation of a channel opener is co-administered with phentermine or a derivative thereof to an obese adult or adolescent, optionally in combination with growth hormone, to treat metabolic syndrome in a patient in need thereof.

[0368] In further embodiments, K ATPA pharmaceutically acceptable formulation of a channel opener is co-administered with growth hormone and optionally one or more of 15 mg to 37.5 mg daily dose 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 co-morbidities. 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.

[0369] In another embodiment, K ATP A rapidly dissolving formulation of a channel opener, optionally in combination with growth hormone, is used to provide a therapeutically effective dose to a patient in need thereof.

[0370] In another embodiment, K ATP A channel opener is administered once every 24 hours at a dose of 125 mg to 275 mg to an overweight or obese individual, optionally in combination with growth hormone, who is not a type II diabetic and is not being treated for nocturnal hypoglycemia.

[0371] In another embodiment, K ATP A channel opener is formulated into a tablet or capsule for oral administration. The tablet or capsule can be co-formulated with metformin. In another embodiment, K ATP A channel opener is formulated into an oral suspension, and in another embodiment, the oral suspension can be further encapsulated.

[0372] In another embodiment, K ATP A pharmaceutically acceptable salt of a channel opener is formulated into a tablet or capsule for oral administration, or an oral suspension or oral solution, or an encapsulated oral solution. If the opener is diazoxide, the salt is preferably not the sodium salt.

[0373] In another embodiment, K ATP A channel opener is co-formulated with hydrochlorothiazide, chlorothiazide, cyclothiazide, benzthiazide, chlorthalidone, bendroflumethiazide, hydroflumethiazide, trichlormethiazide, or polythiazide into a pharmaceutical formulation suitable for oral administration.

[0374] When the formulations provided herein are administered to a human or animal, some or all of the following effects are observed: (1) reduced production of lipoprotein lipase by adipocytes; (2) enhanced lipolysis by adipocytes; (3) reduced expression of fatty acid synthase by adipocytes; (4) reduced glycerol phosphate dehydrogenase activity by adipocytes; (5) little or no new triglyceride synthesis and storage by adipocytes; (6) enhanced expression of beta3 adrenergic receptors (β3ARs), improved adrenergic function in adipocytes; (7) reduced glucose-stimulated insulin secretion by pancreatic B cells; (8) reduced insulinemia; (9) elevated blood glucose levels; (10) increased expression of uncoupling protein 1 in adipocytes; (11) enhanced thermogenesis in white and brown adipose tissue; (12) reduced plasma triglyceride concentration; (13) reduced circulating leptin concentration; (14) up-regulation of insulin receptors; (15) enhanced glucose uptake; (16) reduced adipocyte hyperplasia; (17) reduced adipocyte hypertrophy; (18) reduced rate of conversion of preadipocytes to adipocytes; (19) reduced rate of obesity; (20) increased protection against ischemic or reperfusion injury in the CNS, heart, and other tissues; (21) improved insulin sensitivity; (22) elevated CSF insulin concentration; (23) elevated circulating adiponectin concentration; (25) reduced circulating triglyceride concentration; (26) enhanced β cell rest; and / or (27) increased lean body mass.

[0375] Threshold concentrations of the present application include K ATP Those circulating concentrations of the channel opener, optionally in combination with growth hormone, which result in (1) a measurable suppression of fasting insulin levels; (2) at least a 10% reduction in fasting insulin levels relative to baseline measurements in the same individual prior to treatment with K ATP at least a 20% suppression of fasting insulin levels relative to baseline measurements in the same individual prior to treatment with K ATP at least a 30% suppression of fasting insulin levels relative to baseline measurements in the same individual prior to treatment with K ATP at least a 40% suppression of fasting insulin levels relative to baseline measurements in the same individual prior to treatment with K ATP at least a 50% suppression of fasting insulin levels relative to baseline measurements in the same individual prior to treatment with K ATP at least a 60% suppression of fasting insulin levels relative to baseline measurements in the same individual prior to treatment with K ATPBaseline measurements of the same individual prior to treatment with a channel opener showed that fasting insulin levels were suppressed by at least 70%; (8) relative to those on K-line therapy. ATP Baseline measurements of the same individual prior to treatment with a channel opener showed that fasting insulin levels were suppressed by at least 80%; (9) weight loss; (10) increased resting energy expenditure; or (11) increased oxidation of fats or fatty acids.

[0376] The threshold effect of the present invention includes K produced by intravenous formulations of drugs administered to individuals susceptible to obesity, or immediately released oral formulations of drugs, or controlled-release formulations of drugs, or sustained-release formulations of drugs, or transdermal formulations, or intranasal formulations. ATP The circulating concentrations of the channel opener cause (1) weight loss; and (2) weight maintenance.

[0377] The threshold effect of the present invention includes the K-effect generated by intravenous formulations of drugs administered to individuals with prediabetes, or immediate-release oral formulations of drugs, or controlled-release formulations of drugs, or sustained-release formulations of drugs, or transdermal formulations, or intranasal formulations. ATP The circulating concentrations of the channel opener enable the prevention of diabetes.

[0378] The threshold effect of the present invention includes K produced by intravenous formulations of drugs administered to individuals with type 1 diabetes, or immediately released oral formulations of drugs, or controlled-release formulations of drugs, or sustained-release formulations of drugs, or transdermal formulations, or intranasal formulations. ATP The circulating concentrations of channel openers that induce β-cell quiescence.

[0379] As described in this article, long-term administration of K to overweight, obese, or obesity-prone individuals... ATP Channel openers induce weight maintenance or reduction through one or more of the following mechanisms, including but not limited to: (1) increased energy expenditure; (2) increased oxidation of fats and fatty acids; (3) increased lipolysis in adipose tissue; (4) increased tissue glucose uptake and insulin sensitivity; (5) improved β-adrenergic response; and (6) increased lean body mass. As described herein, long-term administration of K to obese or obesity-prone individuals... ATP Channel openers can also cause weight maintenance or reduction by suppressing appetite.

[0380] Long-term administration of K to overweight or obese humans or animals ATPThe pharmaceutical formulation of a channel opener, optionally in combination with growth hormone, will result in significant and sustained weight loss, including some or all of the following effects: (1) preferential reduction of body fat; (2) greater than 25% reduction of initial body fat mass; (3) greater than 50% reduction of initial body fat mass; (4) greater than 75% reduction of initial body fat mass; (5) significant increase in resting energy expenditure; (6) increased oxidation of fat and fatty acids; (7) reduction in blood pressure; (8) reduction in production of lipoprotein lipase by adipocytes; (9) enhanced lipolysis by adipocytes; (10) reduction in expression of fatty acid synthase by adipocytes; (11) reduction in glycerol phosphate dehydrogenase activity by adipocytes; (12) little or no new triglyceride synthesis and storage by adipocytes; (13) enhanced expression of beta3 adrenergic receptors (β3AR) and improved adrenergic function in adipocytes; (14) reduction in glucose-stimulated insulin secretion by pancreatic B cells; (15) reduction in insulinemia; (16) elevated blood glucose levels; (17) increased expression of uncoupling protein 1 in adipocytes; (18) enhanced thermogenesis in white and brown adipose tissue; (19) reduction in plasma triglyceride concentration; (20) reduction in circulating leptin concentration; (21) upregulation of insulin receptors; (22) enhanced glucose uptake; (23) reduction in adipocyte hyperplasia; (24) reduction in adipocyte hypertrophy; (25) reduction in the rate of conversion of preadipocytes to adipocytes; (26) reduction in the rate of obesity; (27) reduction in metabolic most active adipose tissue (visceral) first, followed by less metabolically active adipose tissue; (28) elevated circulating adiponectin concentration; (29) elevated cerebrospinal fluid insulin levels; (30) elevated pancreatic islet insulin mRNA and insulin content; (31) improved metabolic efficiency of insulin; or (32) increased lean body mass.

[0381] K ATPFormulations of a channel opener, optionally in combination with growth hormone, will result in sustained maintenance of body weight, including some or all of the following effects: (1) an increase in resting energy expenditure; (2) an increase in oxidation of fat and fatty acids; (3) a decrease in blood pressure; (4) a decrease in production of lipoprotein lipase by adipocytes; (5) an increase in lipolysis by adipocytes; (6) a decrease in expression of fatty acid synthase by adipocytes; (7) a decrease in glycerol phosphate dehydrogenase activity by adipocytes; (8) little or no new triglycerides synthesized and stored by adipocytes; (9) an increase in expression of beta3 adrenergic receptors (β3AR) and improved adrenergic function in adipocytes; (10) a decrease in glucose-stimulated insulin secretion by pancreatic B cells; (11) a decrease in insulinemia; (12) an increase in blood glucose levels; (13) an increase in expression of uncoupling protein 1 in adipocytes; (14) an increase in thermogenesis in white and brown adipose tissue; (15) a decrease in plasma triglyceride concentration; (16) a decrease in circulating leptin concentration; (17) an upregulation of insulin receptors; (18) an increase in glucose uptake; (19) a decrease in adipocyte hyperplasia; (20) a decrease in adipocyte hypertrophy; (21) a decrease in the rate of conversion of preadipocytes to adipocytes; and (22) a decrease in the rate of obesity; (23) an increase in circulating adiponectin concentration; (24) an increase in cerebrospinal fluid insulin levels; (25) an increase in pancreatic islet insulin mRNA and insulin content; or (26) an increase in metabolic efficiency of insulin.

[0382] immediately or chronically administering K ATPFormulations of a channel opener, optionally in combination with growth hormone, will result in prevention of beta cell failure, improved glycemic control, and prevention of progression from prediabetes to diabetes, including some or all of the following effects: (1) increased resting energy expenditure; (2) increased oxidation of fat and fatty acids; (3) decreased blood pressure; (4) decreased production of lipoprotein lipase by adipocytes; (5) increased lipolysis by adipocytes; (6) decreased expression of fatty acid synthase by adipocytes; (7) decreased glycerol phosphate dehydrogenase activity by adipocytes; (8) little or no new triglyceride synthesis and storage by adipocytes; (9) increased expression of beta3 adrenergic receptors (β3AR) and improved adrenergic function in adipocytes; (10) decreased glucose-stimulated insulin secretion by pancreatic B cells; (11) decreased insulinemia; (12) increased blood glucose levels; (13) increased expression of uncoupling protein 1 in adipocytes; (14) increased thermogenesis in white and brown adipose tissue; (15) decreased plasma triglyceride concentration; (16) decreased circulating leptin concentration; (17) upregulation of insulin receptors; (18) increased glucose uptake; (19) decreased adipocyte hyperplasia; (20) decreased adipocyte hypertrophy; (21) decreased rate of conversion of preadipocytes to adipocytes; (22) decreased rate of obesity; (23) increased circulating adiponectin concentration; (24) increased cerebrospinal fluid insulin levels; (25) increased pancreatic islet insulin mRNA and insulin content; or (26) increased metabolic efficiency of insulin.

[0383] K is administered immediately or chronically to a human or animal at risk of myocardial infarction or stroke or undergoing a surgical procedure to restore blood flow to the heart or brain. ATP Formulations of a channel opener, optionally in combination with growth hormone, will result in improved outcomes from surgery or after myocardial infarction or stroke by improving survival of tissue after blood flow is restored, reducing tissue stun, and changing the nature of the inflammatory response.

[0384] Pharmaceutical formulations as provided herein are designed to treat obesity, hyperlipidemia, hypertension, weight maintenance, type I diabetes, prediabetes, type II diabetes, or any condition in which weight loss, reduction of circulating triglycerides, or beta cell rest contribute to the outcome, providing a dose of K ATPMultiple key changes in the pharmacodynamics and pharmacokinetic response of the channel opener (optionally in combination with growth hormone) including one or more of the following: (1) extending the pharmacodynamic effect of the administered dose for greater than 24 hours as measured by inhibition of insulin secretion; (2) providing significant absorption of the active pharmaceutical ingredient in the small intestine; (3) providing significant absorption of the active pharmaceutical ingredient in the large intestine; (4) producing a reduced Cmax compared to the current oral suspension or capsule product of the active pharmaceutical ingredient at the same administered dose; (5) providing circulating concentrations of unbound active pharmaceutical ingredient above a threshold concentration for 24 hours or more from a single administered dose; and (6) providing more consistent drug absorption in the treated individuals compared to the existing capsule formulation.

[0385] The pharmaceutical co-formulation of the present invention is designed to treat multiple conditions in humans and animals including K ATP The channel opener in combination with growth hormone and optionally one or more of the following: (1) a diuretic; (2) a blood pressure lowering drug; (3) an appetite suppressing drug; (4) a cannabinoid receptor antagonist; (5) a drug that suppresses the action of gastric lipase; (6) any drug used to induce weight loss; (7) a cholesterol lowering drug; (8) a drug that lowers LDL bound cholesterol; (9) a drug that improves insulin sensitivity; (10) a drug that improves glucose utilization or absorption; (11) a drug that reduces the incidence of atherosclerotic plaques; (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.

[0386] The present invention uses K ATP The pharmaceutical formulation of the channel opener (optionally in combination with growth hormone) treating humans or animals results in a reduced incidence of adverse side effects including but not limited to edema, fluid retention, reduced excretion of sodium, chloride and uric acid, hyperglycemia, ketoacidosis, nausea, vomiting, dyspepsia, ileus and headache. The reduction in the incidence of these adverse side effects is achieved by: (1) starting the administration of the drug to the individual at a sub-therapeutic dose and increasing the dose daily in a stepwise fashion until the therapeutic dose is reached, wherein the number of days over which the stepwise increase in dose is achieved is from 2 to 10 days; (2) using the lowest effective dose to achieve the desired therapeutic effect; (3) using a pharmaceutical formulation that delays the release of the active agent until gastric transit is complete; (4) using a pharmaceutical formulation that delays the release of the active agent until gastric transit is complete; (5) using a pharmaceutical formulation that produces lower circulating peak drug levels compared to an immediate release oral suspension or capsule formulation at the same administered dose; and (6) optimizing the time of the administered dose within the day and relative to meals.

[0387] Use of K ATP Treatment of patients with Prader-Willi Syndrome, Smith-Magenis Syndrome, Frohlich's Syndrome, Cohen Syndrome, Summit Syndrome, Alström Syndrome, Borjeson Syndrome, Prader-Willi-Labat Syndrome, and hyperlipoproteinemia types I, II, III, and IV with a pharmaceutical formulation of a channel opener (optionally in combination with growth hormone) will produce some or all of the following therapeutic outcomes: (1) weight loss; (2) reduction in the rate of weight gain; (3) suppression of hyperphagia; (4) reduction in the incidence of impaired glucose tolerance, prediabetes, or diabetes; (5) reduction in the incidence of congestive heart failure; (6) reduction in hypertension; and (7) reduction in all-cause mortality.

[0388] Use of K ATP Treatment of prediabetic subjects with a pharmaceutical formulation of a channel opener (optionally in combination with growth hormone) will produce some or all of the following therapeutic outcomes: (1) weight loss; (2) restoration of normal glucose tolerance; (3) reduction in the rate of progression to diabetes; (4) reduction in hypertension; and (5) reduction in all-cause mortality.

[0389] Use of K ATP Treatment of diabetic subjects with a pharmaceutical formulation of a channel opener (optionally in combination with growth hormone) will produce some or all of the following therapeutic outcomes: (1) weight loss; (2) restoration of normal glucose tolerance; (3) reduction in the rate of progression of diabetes; (4) improvement in glucose tolerance; (5) reduction in hypertension; and (6) reduction in all-cause mortality.

[0390] Co-administration of a drug with K ATP Formulations of a channel opener to treat diseases in overweight, obese, or obesity-prone human and animal subjects involve co-administration of K ATP A pharmaceutically acceptable formulation of a channel opener with an acceptable formulation of growth hormone and optionally one or more of the following: (1) sibutramine; (2) orlistat; (3) rimonabant; (4) a drug that is an appetite suppressant; (5) any drug that is 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 absorption; (14) a drug that is an antiepileptic agent; (15) a drug that is an anti-inflammatory agent; or (16) a drug that lowers circulating triglycerides.

[0391] Co-administration of a drug with K ATPFormulations of the channel opener are co-administered with K ATP Pharmaceutically acceptable formulations of the channel opener with acceptable formulations of growth hormone and optionally one or more of the following: lithium, carbamazepine, valproic acid and divalproex sodium, and lamotrigine; antidepressants generally classified as monoamine oxidase inhibitors, including isocarboxazid, phenelzine sulfate, and tranylcypromine sulfate; tricyclic antidepressants, including doxepin, clomipramine, amitriptyline, maproiline, desipromine, nortriptyline, desipramine, doxepin, trimipramine, imipramine, and protryptyline; tetracyclic antidepressants, including mianserin, mirtazapine, maprotiline, oxaprotline, delequamine, levoprotline, triflucarbine, setiptiline, lortalaline, azipramine, aptazapine, and pirlindole; and major tranquilizers and atypical antipsychotic agents, including paloproxidol, perphenazine, thioridazine, risperidone, clozapine, olanzapine, and chlorpromazine.

[0392] In one embodiment, K ATP The channel opener (optionally in combination with growth hormone) is administered to an overweight or obese individual as an oral suspension, or immediate release capsule or tablet or controlled release formulation or transdermal formulation or intranasal formulation to achieve and maintain for a prolonged period of time a threshold concentration necessary to measurably reduce fasting insulin levels. Preferably, K 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%, and more preferably at least 80%. Fasting insulin levels are typically measured using an oral glucose tolerance test (OGTT). After an overnight fast, the patient ingests a known amount of glucose. The initial glucose level is determined by measuring the glucose level in the blood and urine prior to the test. Blood insulin levels are measured by drawing blood every hour for up to three hours after the glucose is taken. In the fasting glucose determination, individuals with a plasma glucose value greater than 200 mg / dl at 2 hours after the glucose load indicate impaired glucose tolerance.

[0393] In another embodiment, K ATP The channel opener (optionally in combination with growth hormone) is administered to an overweight or obese individual as an oral suspension, or immediate release capsule or tablet or controlled release formulation or transdermal formulation or intranasal formulation to achieve and maintain for a prolonged period of time a threshold concentration required to cause weight loss.

[0394] In another embodiment, K ATP The channel opener (optionally in combination with growth hormone) is administered to an overweight or obese individual as an oral suspension, or immediate release capsule or tablet or controlled release formulation or transdermal formulation or intranasal formulation to achieve and maintain for a prolonged period of time a threshold concentration required to elevate resting energy expenditure.

[0395] In another embodiment, K ATP The channel opener (optionally in combination with growth hormone) is administered to an overweight or obese individual as an oral suspension, or immediate release capsule or tablet or controlled release formulation or transdermal formulation or intranasal formulation to achieve and maintain for a prolonged period of time a threshold concentration required to elevate fat and fatty acid oxidation.

[0396] In another embodiment, K ATP The channel opener (optionally in combination with growth hormone) is administered to an obesity-prone individual as an oral suspension, or immediate release capsule or tablet or controlled release formulation or transdermal formulation or intranasal formulation to achieve and maintain for a prolonged period of time a threshold concentration required to cause weight loss.

[0397] In another embodiment, K ATP The channel opener (optionally in combination with growth hormone) is administered to an obesity-prone individual as an oral suspension, or immediate release capsule or tablet or controlled release formulation or transdermal formulation or intranasal formulation to achieve and maintain for a prolonged period of time a threshold concentration required to maintain weight.

[0398] In another embodiment, K ATP A channel opener (optionally in combination with growth hormone) is administered to an overweight or obese individual as an oral suspension, or immediate release capsule or tablet or controlled release formulation or transdermal formulation or intranasal formulation to achieve and maintain for a prolonged period of time a drug concentration above a threshold concentration required to cause weight loss.

[0399] In another embodiment, K ATP A channel opener (optionally in combination with growth hormone) is administered to an overweight or obese individual as an oral suspension, or immediate release capsule or tablet or controlled release formulation or transdermal formulation or intranasal formulation to achieve and maintain for a prolonged period of time a drug concentration above a threshold concentration required to cause weight loss.

[0400] In another embodiment, K ATP A channel opener (optionally in combination with growth hormone) is administered to an overweight or obese individual as an oral suspension, or immediate release capsule or tablet or controlled release formulation or transdermal formulation or intranasal formulation to achieve and maintain for a prolonged period of time a drug concentration above a threshold concentration required to cause weight loss.

[0401] In another embodiment, K ATP A channel opener (optionally in combination with growth hormone) is administered to an overweight or obese individual as an oral suspension, or immediate release capsule or tablet or controlled release formulation or transdermal formulation or intranasal formulation to achieve and maintain for a prolonged period of time a drug concentration above a threshold concentration required to cause weight loss.

[0402] In another embodiment, K ATP A channel opener (optionally in combination with growth hormone) is administered to an overweight or obese individual as an oral suspension, or immediate release capsule or tablet or controlled release formulation or transdermal formulation or intranasal formulation to achieve and maintain for a prolonged period of time a drug concentration above a threshold concentration required to cause weight loss.

[0403] In another embodiment, K ATP A channel opener (optionally in combination with growth hormone) is administered to an overweight or obese individual as an oral suspension, or immediate release capsule or tablet or controlled release formulation or transdermal formulation or intranasal formulation to achieve and maintain for a prolonged period of time a drug concentration above a threshold concentration required to cause weight loss.

[0404] In another embodiment, K ATPA channel opener (optionally in combination with growth hormone) is administered to a Type 1 diabetic individual as an oral suspension, or immediate release capsule or tablet or controlled release formulation or transdermal formulation or intranasal formulation to achieve and maintain for a prolonged period of time a drug concentration above the threshold concentration required to cause beta cell rest.

[0405] In another embodiment, a single dose of K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) that results in circulating concentrations of active drug sufficient to reduce insulin secretion for 24 hours or more.

[0406] In another embodiment, a single dose of K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) that results in circulating concentrations of active drug sufficient to reduce insulin secretion on a sustained basis.

[0407] In another embodiment, a single dose of K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) that results in circulating concentrations of active drug sufficient to elevate non-esterified fatty acids in the circulation for 24 hours or more.

[0408] In another embodiment, a single dose of K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) that results in circulating concentrations of active drug sufficient to elevate non-esterified fatty acids in the circulation on a sustained basis.

[0409] In another embodiment, a single dose of K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) that results in circulating concentrations of active drug sufficient to treat hypoglycemia in the circulation for 24 hours or more.

[0410] In another embodiment, a single dose of K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) that results in circulating concentrations of active drug sufficient to treat hypoglycemia on a sustained basis.

[0411] In another embodiment, a single dose of K ATPpharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) that produces circulating concentrations of the active drug sufficient to cause weight loss on a sustained basis.

[0412] In another embodiment, K ATP pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) that produces circulating concentrations of the active drug sufficient to maintain weight on a sustained basis, since once a certain weight loss has occurred, the alternative is to re-gain weight, and it is preferable to maintain the weight of an obese individual.

[0413] In another embodiment, K ATP pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) that produces circulating concentrations of the active drug sufficient to reduce circulating triglyceride levels on a sustained basis.

[0414] In another embodiment, a single dose of K ATP pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) that produces circulating concentrations of the active drug sufficient to reduce or prevent ischemic or reperfusion injury in the circulation for 24 hours or more.

[0415] In another embodiment, K ATP pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) that produces circulating concentrations of the active drug sufficient to reduce or prevent ischemic or reperfusion injury on a sustained basis.

[0416] In another embodiment, K ATP An adverse effect of frequent treatment with a channel opener (optionally in combination with growth hormone) is reduced using a pharmaceutically acceptable formulation of diazoxide or its derivatives administered to an individual in need thereof on a daily basis, where the first dose is known to be a sub-therapeutic dose, and the daily dose is subsequently escalated until a therapeutic dose is reached.

[0417] In another embodiment, K ATP An adverse effect of frequent treatment with a channel opener (optionally in combination with growth hormone) is reduced using K ATP pharmaceutically acceptable formulation of a channel opener, where the active ingredient is not released from the formulation until gastric transit is complete.

[0418] In another embodiment, KATP The adverse effects of frequent treatment with a channel opener (optionally in combination with growth hormone) is the use of K ATP The adverse effects of frequent treatment with a channel opener (optionally in combination with growth hormone) is the use of K

[0419] In another embodiment, the use of K ATP The adverse effects of frequent treatment with a channel opener (optionally in combination with growth hormone) is the use of K ATP The adverse effects of frequent treatment with a channel opener (optionally in combination with growth hormone) is the use of K

[0420] In another embodiment, the use of K ATP The adverse effects of frequent treatment with a channel opener (optionally in combination with growth hormone) is the use of K ATP The adverse effects of frequent treatment with a channel opener (optionally in combination with growth hormone) is the use of K

[0421] In another embodiment, the use of K ATP The adverse effects of frequent treatment with a channel opener (optionally in combination with growth hormone) is the use of K ATP The adverse effects of frequent treatment with a channel opener (optionally in combination with growth hormone) is the use of K

[0422] In another embodiment, the use of K ATP The adverse effects of frequent treatment with a channel opener (optionally in combination with growth hormone) is the use of K ATPA pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is optimized for weight loss, wherein the release of the active ingredient from the formulation has been modified to provide near zero order release over at least 12 hours.

[0423] In another embodiment, the treatment of an overweight or obese individual is by administration of K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is optimized for weight loss, wherein the release of the active ingredient from the formulation has been modified to provide near zero order release over at least 18 hours.

[0424] In another embodiment, the treatment of an overweight or obese individual is by administration of K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is optimized for weight loss, wherein the release of the active ingredient from the formulation has been modified to provide near zero order release over at least 18 hours.

[0425] In another embodiment, the treatment of an overweight or obese individual is by administration of K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is optimized for weight loss, wherein the release of the active ingredient from the formulation has been modified to provide rising drug concentrations in the circulation over at least 12 hours.

[0426] In another embodiment, the treatment of an overweight or obese individual is by administration of K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is optimized for weight loss, wherein the release of the active ingredient from the formulation has been modified to provide rising drug concentrations in the circulation over at least 18 hours.

[0427] In another embodiment, the treatment of an overweight or obese individual is by administration of K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is optimized for weight loss, wherein the release of the active ingredient from the formulation has been modified to match the basal insulin secretion pattern.

[0428] In another embodiment, the treatment of an overweight or obese individual is by administration of K ATPThe incidence of adverse effects upon treatment with a chann el opener (optionally in combination with growth hormone) is reduced using K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is optimized for weight maintenance, wherein the release of the active ingredient from the formulation has been modified to provide near zero order release over at least 12 hours.

[0429] In another embodiment, treatment of an obesity susceptible individual is by administration of K ATP The incidence of adverse effects upon treatment with a chann el opener (optionally in combination with growth hormone) is reduced using K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is optimized for weight maintenance, wherein the release of the active ingredient from the formulation has been modified to provide near zero order release over at least 12 hours.

[0430] In another embodiment, treatment of an obesity susceptible individual is by administration of K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is optimized for weight maintenance, wherein the release of the active ingredient from the formulation has been modified to provide near zero order release over at least 12 hours.

[0431] In another embodiment, treatment of an obesity susceptible individual is by administration of K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is optimized for weight maintenance, wherein the release of the active ingredient from the formulation has been modified to provide near zero order release over at least 12 hours.

[0432] In another embodiment, treatment of an obesity susceptible individual is by administration of K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is optimized for weight maintenance, wherein the release of the active ingredient from the formulation has been modified to provide near zero order release over at least 12 hours.

[0433] In another embodiment, the treatment of an obesity-susceptible individual is by administration of K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is optimized for weight maintenance, wherein the release of the active ingredient from the formulation has been modified to provide an ascending drug concentration in the circulation over at least 18 hours.

[0434] In another embodiment, the treatment of an obesity-susceptible individual is by administration of K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is optimized for weight maintenance, wherein the release of the active ingredient from the formulation has been modified to match the basal insulin secretion pattern.

[0435] In another embodiment, K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is co-administered with sibutramine to an overweight or obese individual to cause weight loss.

[0436] In another embodiment, K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is co-administered with orlistat to an overweight or obese individual to cause weight loss.

[0437] In another embodiment, K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is co-administered with rimonabant to an overweight or obese individual to cause weight loss.

[0438] In another embodiment, K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is co-administered with an appetite suppressant to an overweight or obese individual to cause weight loss.

[0439] In another embodiment, K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is co-administered with an antidepressant to an overweight or obese individual to cause weight loss.

[0440] In another embodiment, K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is co-administered with an antiepileptic drug to an overweight or obese individual to cause weight loss.

[0441] In another embodiment, K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is co-administered with a non-thiazide diuretic to an overweight or obese individual to cause weight loss.

[0442] In another embodiment, K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is co-administered to an overweight or obese individual with a drug that causes weight loss by a mechanism different from diazoxide to cause weight loss.

[0443] In another embodiment, K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is co-administered to an overweight, obesity-prone, or obese individual with a drug that lowers blood pressure to cause weight loss and treat obesity-related co-morbidities.

[0444] In another embodiment, K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is co-administered to an overweight, obesity-prone, or obese individual with a drug that lowers cholesterol to cause weight loss and treat obesity-related co-morbidities.

[0445] In another embodiment, K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is co-administered to an overweight, obesity-prone, or obese individual with a drug that raises HDL-associated cholesterol to cause weight loss and treat obesity-related co-morbidities.

[0446] In another embodiment, K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is co-administered to an overweight, obesity-prone, or obese individual with a drug that improves insulin sensitivity to cause weight loss and treat obesity-related co-morbidities.

[0447] In another embodiment, K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is co-administered to an overweight, obesity-prone, or obese individual with an anti-inflammatory agent to cause weight loss and treat obesity-related co-morbidities.

[0448] In another embodiment, K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is co-administered to an overweight, obesity-prone, or obese individual with a drug that lowers circulating triglycerides to cause weight loss and treat obesity-related co-morbidities.

[0449] In another embodiment, K ATP A pharmaceutically acceptable formulation of a channel opener (optionally in combination with growth hormone) is co-formulated with sibutramine for administration to an overweight, obesity-prone, or obese individual to cause weight loss and treat obesity-related co-morbidities.

[0450] In another embodiment, K ATP A channel opener (optionally in combination with growth hormone) is co-formulated with orlistat or other active agents that inhibit the action of gastric lipases into a pharmaceutically acceptable formulation for administration to an overweight, obesity-prone or obese individual to cause weight loss and treat obesity-related co-morbidities.

[0451] In another embodiment, K ATP A channel opener (optionally in combination with growth hormone) is co-formulated with a non-thiazide diuretic into a pharmaceutically acceptable formulation for administration to an overweight, obesity-prone or obese individual to cause weight loss and treat obesity-related co-morbidities.

[0452] In another embodiment, K ATP A channel opener (optionally in combination with growth hormone) is co-formulated with an appetite suppressant into a pharmaceutically acceptable formulation for administration to an overweight, obesity-prone or obese individual to cause weight loss and treat obesity-related co-morbidities.

[0453] In another embodiment, K ATP A channel opener (optionally in combination with growth hormone) is co-formulated with a cannabinoid receptor antagonist into a pharmaceutically acceptable formulation for administration to an overweight, obesity-prone or obese individual to cause weight loss and treat obesity-related co-morbidities.

[0454] In another embodiment, K ATP A channel opener (optionally in combination with growth hormone) is co-formulated with an anti-cholesterolemic active into a pharmaceutically acceptable formulation for administration to an overweight, obesity-prone or obese individual to cause weight loss and treat obesity-related co-morbidities.

[0455] In another embodiment, K ATP A channel opener (optionally in combination with growth hormone) is co-formulated with an anti-hypertensive active into a pharmaceutically acceptable formulation for administration to an overweight, obesity-prone or obese individual to cause weight loss and treat obesity-related co-morbidities.

[0456] In another embodiment, K ATP A channel opener (optionally in combination with growth hormone) is co-formulated with an insulin sensitizing active into a pharmaceutically acceptable formulation for administration to an overweight, obesity-prone or obese individual to cause weight loss and treat obesity-related co-morbidities.

[0457] In another embodiment, K ATPA channel opener (optionally in combination with growth hormone) is co-formulated with an anti-inflammatory active agent into a pharmaceutically acceptable formulation for administration to an overweight, obesity-prone, or obese individual to cause weight loss and treat obesity-related co-morbidities.

[0458] In another embodiment, K ATP A channel opener (optionally in combination with growth hormone) is co-formulated with an anti-depressive active agent into a pharmaceutically acceptable formulation for administration to an overweight, obesity-prone, or obese individual to cause weight loss and treat obesity-related co-morbidities.

[0459] In another embodiment, K ATP A channel opener (optionally in combination with growth hormone) is co-formulated with an anti-epileptic active agent into a pharmaceutically acceptable formulation for administration to an overweight, obesity-prone, or obese individual to cause weight loss and treat obesity-related co-morbidities.

[0460] In another embodiment, K ATP A channel opener (optionally in combination with growth hormone) is co-formulated with an active agent that reduces the incidence of atherosclerotic plaques into a pharmaceutically acceptable formulation for administration to an overweight, obesity-prone, or obese individual to cause weight loss and treat obesity-related co-morbidities.

[0461] In another embodiment, K ATP A channel opener (optionally in combination with growth hormone) is co-formulated with an active agent that reduces circulating concentrations of triglycerides into a pharmaceutically acceptable formulation for administration to an overweight, obesity-prone, or obese individual to cause weight loss and treat obesity-related co-morbidities.

[0462] Reduction of circulating triglycerides in an overweight, obese, or obesity-prone individual is achieved by administration of an effective amount of K ATP A solid oral dosage form of a channel opener (optionally in combination with growth hormone).

[0463] K ATP A solid oral dosage form of a channel opener can be used to administer a therapeutically effective dose of K ATP A channel opener is used to maintain body weight, since once a certain amount of weight loss has occurred, another option is to re-gain weight, and it is preferred to maintain the body weight of an obese individual.

[0464] A method of causing an overweight or obese individual to reduce their initial body fat by greater than 25% can be achieved by long-term administration of K ATP A solid oral dosage form of a channel opener (optionally in combination with growth hormone).

[0465] Methods of causing an overweight or obese individual to reduce initial body fat by greater than 50% can be achieved by chronic administration of K ATP Solid oral dosage forms of a channel opener, optionally in combination with growth hormone, are used to achieve this.

[0466] Methods of causing an overweight or obese individual to reduce initial body fat by greater than 75% can be achieved by chronic administration of K ATP Solid oral dosage forms of a channel opener, optionally in combination with growth hormone, are used to achieve this.

[0467] Methods of causing an overweight or obese individual to preferentially reduce visceral fat can be achieved by chronic administration of K ATP Solid oral dosage forms of a channel opener, optionally in combination with growth hormone, are used to achieve this.

[0468] Methods of causing an overweight or obese individual to reduce body fat and lower circulating triglycerides can be achieved by chronic administration of K ATP Solid oral dosage forms of a channel opener, optionally in combination with growth hormone, are used to achieve this.

[0469] The application will now be described with reference to the following non-limiting examples.

[0470] Example

[0471] Example 2: In vivo obesity testing

[0472] 1. Compressed tablet formulation

[0473] About 15-30% by weight of diazoxide or a derivative thereof is mixed with about 55-80% by weight of hydroxypropyl methylcellulose, about 3-10% by weight / volume of ethyl cellulose, and less than 3% 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 can be film-coated as described below for the microparticles.

[0474] A tablet containing 100 mg of diazoxide or a derivative thereof will also contain about 400 mg of hydroxypropyl cellulose and 10 mg of ethyl cellulose. A tablet containing 50 mg of diazoxide or a derivative thereof will also contain about 200 mg of hydroxypropyl cellulose and 5 mg of ethyl cellulose. A tablet containing 25 mg of diazoxide or a derivative thereof will also contain about 100 mg of hydroxypropyl cellulose and 2.5 mg of ethyl cellulose.

[0475] 2. Encapsulated coated microparticle formulation of diazoxide

[0476] Diazoxide or its derivatives are encapsulated into microparticles according to known methods (see, e.g., U.S. Patent No. 6,022,562). With the help of a granulator, microparticles having a diameter of 100 microns to 500 microns containing either diazoxide or derivatives alone or a combination of diazoxide or derivatives with one or more suitable excipients are formed, which are then sieved to isolate microparticles having the appropriate size. The microparticles are coated with a film by spray drying using a commercial instrument (e.g., Uniglatt spray coater). The film comprises ethyl cellulose, cellulose acetate, polyvinyl pyrrolidone, and / or polyacrylamide. The coating solution for the film can include a plasticizer, which can be castor oil, diethyl phthalate, triethyl citrate, and salicylic acid. The coating solution can also include a lubricant, which can be magnesium stearate, sodium oleate, or polyoxyethylenated sorbitan laurate. The coating solution can also include an excipient, such as talc, colloidal silicon dioxide, or a mixture of the two, added at 1.5% to 3% by weight to prevent the film-coated particles from clumping.

[0477] 3. Formulations of diazoxide or derivatives in tablet form for controlled release

[0478] Both the active ingredient and the hydroxypropyl methylcellulose (Dow Methocel K4M P) are passed through an ASTM 80 mesh screen before mixing. A mixture is formed from 1 part diazoxide or its derivatives / 4 parts hydroxypropyl methylcellulose. After thorough mixing, a sufficient volume of an ethyl cellulose solution in ethanol is added slowly as a granulating agent. The amount of ethyl cellulose in the final formulation is about 1 / 10 part per tablet. The material obtained by mixing the granulating agent is sieved through a 22 / 44 mesh screen. The resulting granules are dried at 40°C for 12 hours and then kept in a desiccator at room temperature for 12 hours. Once dried, the granules retained on the 44 mesh are mixed with 15% fine powder (granules passing through the 44 mesh). Each 2% by weight of talc and magnesium stearate are added as a glidant and lubricant. A colorant is also added. The tablets are compressed using a single punch tablet machine.

[0479] 4. Formulations of diazoxide or its derivatives in compressed tablet form for controlled release

[0480] A mixture of 20-40% by weight of diazoxide or its derivative and 30% by weight of hydroxypropyl methylcellulose (Dow Methocel K100LV P) and 20-40% by weight of finely divided lactose is granulated by the addition of water. The granulated mixture is wet milled and then dried at 110°C for 12 hours. The dried mixture is dry milled. After milling, 25% by weight of ethyl cellulose resin (Dow Ethocel 10FP or Ethocel 100FP) is added, followed by 0.5% by weight of magnesium stearate. A colorant is also added. The tablets are compressed using a single punch tablet press (Dasbach et al., poster at the AAPS Annual Meeting, November 10-14 (2002)).

[0481] 5. Formulations of diazoxide or its derivative in the form of compressed coated tablets providing controlled release

[0482] A tablet core is prepared by mixing 100 mg of diazoxide or its derivative with 10 mg of ethyl cellulose (Dow Ethocel 10FP), or by mixing 75 mg of diazoxide or its derivative with 25 mg of lactose and 10 mg of ethyl cellulose (Dow Ethocel 10FP), or by mixing 50 mg of diazoxide or its derivative with 50 mg of lactose and 10 mg of ethyl cellulose (Dow Ethocel 10FP). The tablet core is formed on an automated press using a concave tool. A compressed coating consisting of 400 mg of polyethylene oxide (Union Carbide POLYOX WSR Coagulant) is applied and compressed to 3000 psi (Dasbach et al., poster at the AAPS Annual Meeting, October 26-30 (2003)).

[0483] 6. Controlled release dosage forms of diazoxide or its derivative using an osmotic controlled release system

[0484] Diazoxide or its derivative is formulated into an osmotic modulated release system. In general, two components, a swellable hydrogel that drives the release of the active drug and diazoxide or its derivative, are assembled into a semi-permeable bilayer laminated shell. Upon assembly, a hole is drilled in the shell to facilitate the release of the active agent as the hydrogel hydrates.

[0485] The dosage form is manufactured to be adjusted, designed and shaped into an osmotic delivery system as follows: The diazoxide or its derivative composition is first provided by blending together polyethylene oxide, diazoxide or its derivative and hydroxypropyl methylcellulose into a uniform blend. Then, a volume of denatured absolute ethanol equal to 70% of the dry mass is slowly added under continuous mixing for 5 minutes. The freshly prepared wet granules are sieved through a 20 mesh screen, dried at room temperature for 16 hours and sieved again through a 20 mesh screen. Finally, the sieved granules are mixed with 0.5% by weight of magnesium stearate for 5 minutes.

[0486] 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 sieved separately through a 40 mesh screen. Then, all sieved ingredients are mixed with 5% by weight of hydroxypropyl methylcellulose to produce a uniform blend. Subsequently, a volume of denatured absolute alcohol equal to 50% of the dry mass is slowly added to the blend under continuous mixing for 5 minutes. The freshly prepared wet granules are passed through a 20 mesh screen, dried at room temperature for 16 hours and again through a 20 mesh screen. The sieved granules are mixed with 0.5% by weight of magnesium stearate for 5 minutes (see U.S. Patent No. 6,361,795 to Kuczynski et al.).

[0487] The diazoxide or its derivative composition and the hydrogel composition are compressed into a bilayered laminated tablet. First, the diazoxide or its derivative composition is added and tamped, then the hydrogel composition is added and the thin layers are laminated into a contact laminated arrangement under a 2 ton press head.

[0488] The bilayered laminated arrangement is coated with a semipermeable wall (i.e. a membrane). 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 bilayered laminate.

[0489] Finally, an exit channel is drilled through the semipermeable wall to connect the diazoxide or its derivative drug thin layer with the outside of the delivery system. Residual solvents are removed by drying at 50°C and 50% humidity. Subsequently, the osmotic system is dried at 50°C to remove excess moisture (see U.S. Patent No. 6,361,795 to Kuczynski et al.).

[0490] 7. Preparation of a salt of diazoxide

[0491] A hydrochloride salt of diazoxide is prepared by dissolving 1 mole of diazoxide (230.7 g) in 500 ml of Et2O. Dry HCl is passed into the solution until the weight of the container increases by 36 g. During the addition of HCl, the hydrochloride salt of diazoxide precipitates as a powder. The salt is filtered off and washed with anhydrous Et2O.

[0492] Example 3: Clinical study in obese pediatric and adult PWS patients

[0493] 1. Animal model of obesity

[0494] The efficacy of a formulation of diazoxide or derivative prepared as described herein can be tested in an animal model of obesity as described by Surwit et al. (Endocrinology 141 :3630-3637 (2000)). Briefly, 4-week-old B6 male mice (5 / cage) are housed in a temperature-controlled (22°C) room with a 12-h light, 12-h dark cycle. High fat (HF) and low fat (LF) experimental diets contain 58% and 11% of calories from fat, respectively. One group of mice is fed the HF diet for the first 4 weeks of the study; the remaining 15 mice are fed the LF diet. Mice assigned to the LF diet maintain this diet throughout the study as a lean control group of reference. At 4 weeks, all HF-fed mice are reassigned to 2 groups of mice. The first group remains on the HF diet throughout the study as an obese control group. The remaining 3 groups of mice are fed the HF diet and administered a controlled release formulation of diazoxide or derivative, which is administered by oral gavage as a single dose of approximately 150 mg of active agent per kilogram per day. Animals are weighed once per week, and food consumption is measured twice per week on a per cage basis until the diet is changed at 4 weeks, at which time body weight and food intake are determined daily. Feed efficiency (grams of body weight gained per unit of calories consumed) is calculated on a per cage basis. Samples for analysis of insulin, glucose, and leptin are collected on day 24 (4 days before the diet change), on day 32 (4 days after the change), and then every two weeks thereafter. In all cases, food is removed 8 hours prior to sample collection. Glucose is analyzed by the glucose oxidase method. Concentrations of insulin and leptin 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 concentrations of triglycerides and non-esterified fatty acids. After 4 weeks of drug treatment, a subset of 10 animals from each group is killed. Epididymal white adipose tissue (EWAT), retroperitoneal (RP) fat, interscapular brown adipose tissue (IBAT) fat pads, and gastrocnemius muscle are removed, trimmed, and weighed. Percent body fat is estimated from the weight of the epididymal fat pads. A subset of five animals from each group is injected intraperitoneally with 0.5 g / kg of glucose. At 30 minutes after injection, plasma samples are collected and analyzed for glucose content by the glucose oxidase method.

[0495] 2. Treatment of obesity in humans

[0496] Formulations of diazoxide or derivatives prepared as described herein can be tested for efficacy in obese humans. The study is performed as described by Alemzadeh (Alemzadeh et al., J Clin Endocr Metab 83: 1911-1915 (1998)). Subjects consist of moderately to morbidly obese adults with a body mass index (BMI) greater than or equal to 30 kg / m2. 2 Each subject receives a complete physical examination at the initial evaluation, body weight is measured on a standard electronic scale, and body composition is measured by DEXA.

[0497] All subjects are placed on a low-calorie diet for a 1-week run-in period prior to the start of the study. This is designed to exclude individuals who are unlikely to comply and to ensure pre-treatment weight stabilization. A maximum of 50 patients are tested at each dose of drug. Daily doses are set at 100 mg / day, 200 mg / day, and 300 mg / day. Daily doses are administered in 2 doses. At each administration, the dose is administered in one, two, or three 50 mg capsules or tablets. Individual patients are dosed once daily for up to 12 months. Patients are seen once a week, weighed, and questioned about any side effects or concurrent illnesses.

[0498] A twenty-four hour dietary recall is obtained from each patient. Dietary recalls are analyzed using standard computer software programs. All patients are placed on a low-calorie diet and are encouraged to participate in regular exercise.

[0499] The following laboratory tests are obtained before the study begins and after it is completed: blood pressure, fasting plasma glucose, insulin, cholesterol, triglycerides, free fatty acids (FFA), and glycosylated hemoglobin, as well as measurements of plasma-derived fatty acid appearance and oxidation rates. In addition, routine chemistry profiles and fasting plasma glucose are obtained once a week to identify those subjects with evidence of glucose intolerance and / or electrolyte abnormalities. Glucose is analyzed in plasma by a glucose oxidase method.

[0500] Insulin concentrations were determined by RIA using a double antibody kit. Cholesterol and triglyceride concentrations were measured enzymatically. Plasma FFA was determined by enzymatic colorimetry. SI was assessed by an intravenous glucose tolerance test (IVGTT) using a modified minimal model. After an overnight fast, a glucose bolus (300 mg / kg) was administered intravenously, followed (20 minutes later) by a bolus of insulin. Blood for determination of glucose and insulin was obtained from a contralateral vein at -30 minutes, -15 minutes, 0 minutes, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 8 minutes, 10 minutes, 19 minutes, 22 minutes, 25 minutes, 30 minutes, 40 minutes, 50 minutes, 70 minutes, 100 minutes, 140 minutes, and 180 minutes. SI and glucose utilization efficiency (SG) were calculated using Bergman's modified minimal model computer program before and after the study. The acute insulin response to glucose was determined over the first 19 minutes of the IVGTT, and the glucose disappearance rate (Kg) was determined from 8 minutes to 19 minutes of the IVGTT. Body composition was measured by bioelectrical impedance before and after the study. Resting energy expenditure (REE) was measured by indirect calorimetry after an overnight 12-hour fast with the subject supine for a period of 30 minutes. Urine was collected over the respective 24 hours before and after the study to measure total nitrogen and determine substrate use.

[0501] 3. Treatment of obesity in humans by co-administration of diazoxide and phentermine

[0502] Long-term co-administration of solid oral dosage forms of diazoxide or derivatives thereof and phentermine was evaluated in humans who were moderately to morbidly obese and had a body mass index (BMI) greater than or equal to 30 kg / m2. 2 Each subject received a complete physical examination at the initial evaluation, body weight was measured on a standard electronic scale, and body composition was measured by DEXA.

[0503] All subjects were placed on a low-calorie diet for a 1-week run-in period prior to the start of the study. This was designed to exclude individuals who were unlikely to comply and to ensure pre-treatment weight stabilization. Up to 100 patients were tested. The daily dose of diazoxide was set at 200 mg. The daily dose was administered in 2 doses. At each administration, the dose was administered as 100 mg capsules or 100 mg tablets. The individual patients were dosed once a day for up to 12 months. Phentermine was administered at a single daily dose of 15 mg. Patients were seen every two weeks, weighed, and questioned about any side effects or concurrent illnesses.

[0504] All patients continued to receive a low-calorie diet and were encouraged to participate in regular exercise. Laboratory tests as described in the above examples were obtained before and after the start of the study.

[0505] 4. Prevention of diabetes in pre-diabetic humans

[0506] The example describes the use of diazoxide in pre-diabetic individuals to prevent the development of diabetes. The individuals included in the study all have an elevated risk of developing diabetes, as measured by one of two methods. In the fasting glucose assay, they have a plasma glucose value of 100 to 125 mg / dl, which indicates impaired fasting glucose, or in the oral glucose tolerance test, they have a plasma glucose value of 140 to 199 mg / dl at 2 hours after glucose load, which indicates that they have impaired glucose tolerance. Treatment is initiated in any individual who meets either criterion. The individuals receiving treatment receive 200 mg of diazoxide per day, in the form of 100 mg capsules or tablets twice a day or two 100 mg capsules or tablets once a day. The individuals receiving placebo receive one placebo capsule or tablet twice a day or two placebo capsules or tablets once a day.

[0507] Treatment continues for one year, with measurement of OGTT or fasting glucose once a month.

[0508] 5. Sustained release co-formulation of diazoxide hydrochloride and metformin hydrochloride for the treatment of diabetic patients

[0509] A sustained release co-formulation of diazoxide hydrochloride and metformin hydrochloride is produced by forming a compressed tablet matrix that includes 750 mg of metformin hydrochloride and 100 mg of diazoxide hydrochloride. These active ingredients are blended with sodium carboxymethylcellulose (about 5% (w / w)), hydroxypropyl methylcellulose (about 25% (w / w)), and magnesium stearate (< 2% (w / w)). The compressed tablet is further coated with a combination of ethyl cellulose (80% (w / w)) and methyl cellulose (20% (w / w)) as a film to control the rate of hydration and drug release.

[0510] Type II diabetic patients are treated with the oral dosage form by administering two tablets once a day or one tablet every 12 hours. Patients are treated with the drug until one of two treatment endpoints is reached, or for as long as the patient derives therapeutic benefit from the administration. The two treatment endpoints that will be used as the basis for deciding to stop treatment include the patient reaching a body mass index (BMI (kg / m 2 )) of 18 to 25 or reestablishing normal glucose tolerance in the absence of treatment. Patients are monitored periodically for: (a) glucose tolerance using an oral glucose tolerance test; (b) glycemic control using standard blood sugar assays; (c) weight gain or loss; (d) progression of diabetic complications; and (e) adverse effects associated with the use of these active ingredients.

[0511] 6. Prevention or treatment of weight gain in patients receiving olanzapine therapy

[0512] Patients meeting DSM III-R criteria for schizophrenia are initiated on drug therapy for schizophrenia. The patients are administered 10 mg of olanzapine (Zyprexa, Lilly) once daily. Adjunctive therapy for the schizophrenic patients includes valproic acid as the 250 mg equivalent of divalproex sodium (Depakote, Abbott Labs). Weight gain, dyslipidemia, and impaired glucose tolerance, as well as metabolic syndrome, are adverse events that occur at a high rate in patients receiving this combination of therapies for schizophrenia. The weight gain, dyslipidemia, impaired glucose tolerance, or metabolic syndrome is treated by co-administration of a therapeutically effective dose of a channel opener. The patients are treated by administration of 200 mg / day of diazoxide in a once-a-day tablet formulation. The diazoxide administration is continued until the weight gain, dyslipidemia, impaired glucose tolerance, or metabolic syndrome is corrected or until the patient is discontinued on olanzapine therapy. Dyslipidemia is detected by measuring circulating concentrations of total cholesterol, HDL cholesterol, and LDL cholesterol, triglycerides, and non-esterified fatty acids. Impaired glucose tolerance is detected via use of oral or intravenous glucose tolerance tests. Metabolic syndrome is detected by measuring key risk factors for metabolic syndrome, including central obesity, dyslipidemia, impaired glucose tolerance, and circulating concentrations of key proinflammatory cytokines. ATP Patients meeting DSM III-R criteria for schizophrenia are initiated on drug therapy for schizophrenia. The patients are administered 10 mg of olanzapine (Zyprexa, Lilly) once daily. Adjunctive therapy for the schizophrenic patients includes valproic acid as the 250 mg equivalent of divalproex sodium (Depakote, Abbott Labs). Weight gain, dyslipidemia, and impaired glucose tolerance, as well as metabolic syndrome, are adverse events that occur at a high rate in patients receiving this combination of therapies for schizophrenia. The weight gain, dyslipidemia, impaired glucose tolerance, or metabolic syndrome is treated by co-administration of a therapeutically effective dose of a channel opener. The patients are treated by administration of 200 mg / day of diazoxide in a once-a-day tablet formulation. The diazoxide administration is continued until the weight gain, dyslipidemia, impaired glucose tolerance, or metabolic syndrome is corrected or until the patient is discontinued on olanzapine therapy. Dyslipidemia is detected by measuring circulating concentrations of total cholesterol, HDL cholesterol, and LDL cholesterol, triglycerides, and non-esterified fatty acids. Impaired glucose tolerance is detected via use of oral or intravenous glucose tolerance tests. Metabolic syndrome is detected by measuring key risk factors for metabolic syndrome, including central obesity, dyslipidemia, impaired glucose tolerance, and circulating concentrations of key proinflammatory cytokines.

[0513] * All screening procedures must be completed by Day -14

[0514] A single center, open-label, single arm clinical study (PC025) with double-blind, placebo-controlled, random withdrawal extension phase has been conducted. Patients started on a DCCR dose of about 1.5 mg / kg (maximum starting dose of 145 mg) and were titrated every 14 days to about 2.4 mg / kg, 3.3 mg / kg, and 4.2 mg / kg (maximum dose of 507.5 mg). These DCCR doses are equivalent to a diazoxide dose of 1.03 mg / kg, 1.66 mg / kg, 2.28 mg / kg, and 2.9 mg / kg, respectively. Up-titration of patients was at the discretion of the investigator at each visit. Any patient showing an increase in resting energy expenditure and / or reduction in hyperphagia relative to baseline by Day 27 or Day 55 was designated a responder and eligible to be randomized in the double-blind phase. Everyone who completed the open-label phase was a responder and randomized in the double-blind phase and completed the double-blind phase. During the double-blind, placebo-controlled, random withdrawal phase, responders were randomized in a 1 : 1 ratio to continue active treatment at the dose they were receiving at 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 they were receiving at Day 55 for an additional 29 days. A total of 12 patients were enrolled in the study.

[0515] schematic diagram

[0516]

[0517] Figures 1-4

[0518] Inclusion Criteria: Essential Requirements

[0519] • Able to follow oral and written instructions with or without the help of a caregiver;

[0520] • Signed informed consent by the subject or their legal guardian;

[0521] • Completion of screening procedures 2 to 4 weeks prior to the baseline visit.

[0522] General Demographic Characteristics

[0523] • Male and female patients 10 to 22 years of age, inclusive, at the time of dosing;

[0524] • Genetically confirmed Prader-Willi Syndrome;

[0525] • BMI above the 95th percentile of age-specific BMI values on the CDC BMI chart or > 35% percent body fat (body fat criteria will only be used if measured within 12 months of the screening visit and the patient has not lost weight from that measurement. In all other cases, the BMI criteria will apply.)

[0526] • General health as documented by medical history, physical examination, vital sign assessments, 12-lead electrocardiogram (ECG), and clinical laboratory assessments.

[0527] Specific laboratory test results

[0528] • Fasting glucose < 126 mg / dL

[0529] • HbAlc < 6.5%

[0530] Endpoints and statistical analysis

[0531] Each endpoint was measured over two timeframes: (1) change (or percent change) from baseline to Day 69 during the open-label treatment phase; and (2) change (or percent change) from Day 69 to Day 97 during the double-blind, placebo-controlled, randomized withdrawal phase.

[0532] Endpoints measured during the open-label treatment phase were analyzed by paired t-tests, while those measured during the double-blind, placebo-controlled treatment phase were analyzed by analysis of variance and paired t-tests.

[0533] Efficacy endpoints included: eating disorder (measured using parent / caregiver responses on the Modified Dykens Eating Disorder Questionnaire, converted to a numeric score ranging from 0 to 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 questionnaires. Table 2 and Table 3 summarize the visits at which each efficacy parameter was measured.

[0534] Table 2: Timepoints at which efficacy parameters were assessed during the open-label phase

[0535]

[0536] Table 3: Timepoints at which efficacy parameters were assessed during the double-blind treatment phase

[0537]

[0538] Patients in the study

[0539] The demographic information and relevant medical history of each patient is shown in Table 4. Eleven of the thirteen subjects enrolled in the clinical study PC025 completed the open-label phase. All were identified as responders and thus, were randomized in the double-blind phase of the study. All subjects randomized in the double-blind phase of the study completed the phase.

[0540] The baseline characteristics of the patients enrolled in the study are provided in Table 5.

[0541] Table 4: Demographic information and relevant medical history of patients enrolled in PC025

[0542]

[0543] Table 5: Baseline characteristics of subjects randomized in the double-blind phase of the clinical study PC025

[0544]

[0545]

[0546] Dosing

[0547] One subject (a treated type 2 diabetic patient) ended the open-label treatment period at a dose of 1.5 mg / kg. Of the remaining 10 subjects, 1 ended the open-label treatment period at a dose of 2.4 mg / kg, and 3 ended the open-label treatment period at a dose of 3.3 mg / kg. The last 6 subjects enrolled in the study ended the open-label treatment phase at a dose of 4.2 mg / kg.

[0548] Changes in body composition, waist circumference, and body weight

[0549] Body fat and lean mass were measured by DEXA at baseline and again at the end of the open-label treatment. Since DEXA was not performed at day 97, the only body composition measurements performed on subjects randomized in the double-blind phase occurred during the period from baseline to day 69. Changes in body composition are summarized in Table 6. Changes in body composition measured by DEXA were evaluated separately for subjects receiving growth hormone treatment and for subjects not receiving growth hormone treatment. These results are shown in Table 6.

[0550] Body weight measured by DEXA was calculated as the sum of body fat and lean mass. The ratio of lean mass to body fat was also calculated.

[0551] Table 6:

[0552] Changes in body composition measured by DEXA from baseline to day 69

[0553]

[0554] Treatment with DCCR for 10 weeks had very significant and clinically relevant effects on body composition, including reductions in body fat, increases in lean body mass, and very significant increases in the ratio of lean body mass to body fat. Since these patients had nearly equal lean and fat mass at baseline, the concurrent increases in lean body mass and decreases in body fat resulted in little net change in body weight. In general, the changes in body composition were of similar magnitude in subjects receiving growth hormone therapy and those not receiving growth hormone therapy.

[0555] The changes in body composition were dose dependent. Those subjects who completed the open label treatment phase at a dose of 4.2 mg / kg experienced a 6.3% reduction 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.

[0556] Three subjects in the study showed increases in lean body mass greater than 10%. Each of these subjects also showed an increase in the ratio of lean body mass to fat mass. Over half of the subjects in the study showed an increase in the ratio of lean body mass to fat mass >10%, and 1 showed an increase of over 20%.

[0557] Parameter The percent change in body fat, lean body mass, and the ratio of lean body mass to fat mass from baseline to day 69 is summarized.

[0558] Body weight and waist circumference were measured at each visit during the physical examination. This data can be used to evaluate the change from baseline to day 69 in all subjects randomized in the double-blind phase, the change in the phase from day 69 to day 97 by group, and the change from baseline to day 97 in those subjects who continued to receive DCCR in the double-blind phase. Results from the phase covering baseline to day 69 are summarized in Table 7. Results from the phase covering day 69 to day 97 are shown in Table 8. Results from baseline to day 97 in subjects who continued to receive DCCR in the double-blind phase are shown in Table 9.

[0559] Table 7: Change in body weight and waist circumference from baseline to day 69

[0560] Change / percent change n p-value Weight Waist circumference 11 0.53％ 0.317 -3.5 cm 11 Parameter 0.003

[0561] Table 8: Change in body weight and waist circumference from day 69 to day 97

[0562]

[0563] Table 9: Change in body weight and waist circumference from baseline to day 97 in those subjects who received DCCR treatment in the double-blind phase

[0564]

[0565] Interestingly, the change in weight from baseline to day 69 as measured by DEXA and by standard body weight measurements produced nearly identical results (0.67% increase as measured by DEXA and 0.53% increase as measured by the standard method). In contrast to no change in weight, all subjects randomized in the double-blind phase lost waist circumference by day 69; those continuing to receive DCCR lost waist circumference statistically significantly by day 97. Comparison of the change in waist circumference between groups between day 69 and day 97, patients receiving placebo during the period showed a gradual increase in waist circumference, while those continuing to receive DCCR showed a significant decrease. The decrease in waist circumference is consistent with the interpretation that subjects receiving DCCR treatment are reducing visceral fat.

[0566] Changes in eating disorders

[0567] The eating disorder questionnaire was administered at all visits. This data can be used to evaluate the change from baseline to day 69 in all subjects randomized in the double-blind phase, the change in phase from day 69 to day 97 by group, and the change from baseline to day 97 in those continuing to receive DCCR in the double-blind phase. Results from the phase covering baseline to day 69 are summarized in Table 10. Results from the phase covering day 69 to day 97 are shown in Table 11. Results from baseline to day 97 in subjects continuing to receive DCCR in the double-blind phase are shown in Table 12.

[0568] Table 10: Change in eating disorders from baseline to day 69

[0569] Percent change n p-value Binge eating Figure 1 11 -31.6％ 0.003

[0570] Table 11: Change in eating disorders from day 69 to day 97

[0571]

[0572] Table 12: Change in eating disorders from baseline to day 97 in those subjects receiving DCCR treatment in the double-blind phase

[0573]

[0574]

[0575] There was a statistically significant reduction in eating disorders from baseline to day 69 in all subjects randomized in the double-blind phase and from baseline to day 97 in those continuing to receive DCCR in the double-blind phase.

[0576] Patients receiving DCCR treatment through the end of the 97-day treatment showed a 29.2% improvement in eating disorder, while those receiving DCCR treatment for 69 days followed by 28 days of placebo showed only a 13.9% improvement in eating disorder at day 97. Thus, at the end of the double-blind phase, patients receiving DCCR treatment showed more than twice the improvement in eating disorder than those randomized to placebo in the double-blind phase. Once patients discontinue DCCR treatment, it takes approximately 7-10 days to clear DCCR completely from the circulation given its long half-life (28-32 hours). In the study, verbatim statements were obtained from the parents of the subjects indicating that they had seen their child's food-related behaviors worsen only in the last few weeks of the study, suggesting that a longer double-blind phase could have resulted in further separation of the groups. In general, the impact on the degree to which subjects became agitated when denied food, the ease with which they were able to distract themselves once denied food, and the magnitude of the impact on the occurrence of stealing food, digging through trash for food, and bargaining for food were of equal or greater magnitude than the overall impact on eating disorder scores. DCCR appeared to have a smaller impact on the degree to which subjects were sneaky or quick about food and the frequency with which they got up at night to find food.

[0577] Improvements in eating disorder were observed in subjects with baseline eating disorder ranging from 0 to 34 points on the 0 to 34 point scale of 29 points (-45%) to at least 5 points (-33%).

[0578] Approximately 25% of the subjects ended the open label phase with very low levels of eating disorder (2 or 3 points on the 0 to 34 point scale). These subjects tended to be able to reduce more body fat than the average. Two such subjects (both female, one receiving growth hormone treatment and one not) reduced their initial body fat mass by more than 10% in 10 weeks.

[0579] Parameter Changes in eating disorder from baseline to day 69 are shown.

[0580] Changes in lipids

[0581] The lipid panel was evaluated at baseline and again at day 69 and day 97. This data can be used to evaluate the change from baseline to day 69 in all subjects randomized in the double-blind phase, the change in the phase from day 69 to day 97 by group, and the change from baseline to day 97 in those subjects continuing DCCR in the double-blind phase. Results from the phase covering baseline to day 69 are summarized in Table 13. Results from baseline to day 97 for subjects continuing DCCR in the double-blind phase are shown in Table 14.

[0582] Table 13: Change in lipids from baseline to Day 69

[0583] Percent change n p-value Total cholesterol Triglycerides 8 -4.0％ 0.044 HDL-C 7 -21.0％ 0.084 LDL-C 8 10.8％ 0.244 Non-HDL-C 8 -7.0％ 0.030 Parameter 8 -6.5％ 0.019

[0584] Table 14: Median percent change in lipids from baseline to Day 97 in those subjects receiving DCCR in the double-blind phase

[0585] Median percent change from baseline to Day 97 Total cholesterol Triglycerides -11.0％ HDL-C -41.8％ LDL-C 25.2％ Non-HDL-C -7.9％ Example 4: Clinical study with Smith-Magenis syndrome patients -13.4％

[0586] Consistent with previous studies involving DCCR, treatment with DCCR resulted in a number of statistically significant changes in lipids from baseline to Day 69 in subjects randomized in the double-blind phase, including decreases in total cholesterol, LDL cholesterol, and non-HDL cholesterol. Even though the effect on triglycerides was of greater magnitude, it did not reach significance because n was smaller and variability in the population was greater. In general, greater reductions in triglycerides were seen in those patients who had a significant elevation in triglycerides at baseline. A similar pattern was observed in those subjects who received DCCR through the end of the double-blind treatment. Reductions in total cholesterol, triglycerides, LDL-C, and non-HDL-C were all greater in those patients who received DCCR for a longer period of time.

[0587] Changes in leptin and ghrelin

[0588] Leptin and ghrelin were measured at baseline and again at Day 69. Results for leptin and ghrelin from baseline to Day 69 are provided in Table 15.

[0589] Table 15: Change in leptin and ghrelin from baseline to Day 69

[0590]

[0591]

[0592] Further evidence for a reduction in body fat came from the analysis of leptin, the results of which were consistent with the DEXA data and the data on waist circumference. Although not quite reaching statistical significance, leptin decreased by more than 20% from baseline.

[0593] While ghrelin can or can not substantially contribute to hyperphagia in PWS, a reduction in ghrelin is beneficial in PWS patients.

[0594] Behavioral changes

[0595] A questionnaire adapted from a natural history study of PWS was used to document the presence or absence of 23 PWS-related behaviors at baseline and again at Day 69. These behaviors were generally grouped into 4 categories:

[0596] (1) aggressive, threatening, and destructive behaviors;

[0597] (2) self-injurious behaviors;

[0598] (3) compulsive behaviors; and

[0599] (4) other behaviors.

[0600] The questionnaire was administered at baseline and again at day 69. The discontinuation rates for aggressive, threatening, and destructive behaviors and all other behaviors are shown in Table 16.

[0601] Table 16: Discontinuation rates for various categories of behaviors in clinical study PC025

[0602]

[0603] The effect on aggressive, threatening, and destructive behaviors was not related to the effect on eating disorders.

[0604] Changes in resting energy expenditure and respiratory quotient

[0605] Measurements of resting energy expenditure and respiratory quotient were quite variable between visits. Despite the variability, resting energy expenditure and respiratory quotient did not appear to change from baseline to day 69.

[0606] Changes in insulin sensitivity

[0607] Treatment with DCCR in other clinical studies has been associated with improvements in insulin resistance, as measured by changes in the homeostatic model assessment of insulin resistance (HOMA-IR). Improvements in insulin sensitivity are well-documented in the literature on diazoxide. Subjects enrolled in the double-blind phase of this study were quite sensitive to insulin at baseline, which is typical of PWS patients in this age range. Consistent with previous DCCR clinical studies and historical diazoxide literature, treatment with DCCR for 10 weeks 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).

[0608] ​

[0609] 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 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 increasing the dose by about 0.5 mg / kg at each titration step and continuing treatment for 1 to 2 weeks at each step continues until the patient shows an adequate response to treatment or the maximum dose of 5 mg / kg is reached. Potential responses to treatment can include reduction in body fat, reduction in hypotonia, increase in lean mass / fat mass ratio, reduction in hyperphagia, reduction in waist circumference, weight loss, reduction in temper tantrums and aggressive behavior, and improvement in cardiovascular risk factors. Treatment with the drug is long term and can continue for the lifetime of the patient.

[0610] 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 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 2.1 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 increasing the dose by about 0.6 mg / kg at each titration step and continuing treatment for 1 to 2 weeks at each step continues until the patient shows an adequate response to treatment or the maximum dose of 5 mg / kg is reached. Potential responses to treatment can include reduction in body fat, reduction in hypotonia, increase in lean mass / fat mass ratio, reduction in hyperphagia, reduction in waist circumference, weight loss, reduction in temper tantrums and aggressive behavior, and improvement in cardiovascular risk factors. Treatment with the drug is long term and can continue for the lifetime of the patient.

[0611] In a third embodiment, a patient with Smith-Magenis syndrome is treated with a controlled release tablet formulation of dinitazoxime 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 2.2 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 increasing the dose by about 0.7 mg / kg at each titration step and continuing treatment for 1 to 2 weeks at each step continues until the patient shows an adequate response to treatment or the maximum dose of 5 mg / kg is reached. At the same time, the patient can also be treated with beloranib. Potential responses to treatment can include reduction in body fat, reduction in hypotonia, increase in lean mass / fat mass ratio, reduction in hyperphagia, reduction in waist circumference, weight loss, reduction in irritability and aggressive behavior, and improvement in cardiovascular risk factors. Treatment with the drug is long term and can continue for the lifetime of the patient.

[0612] In a fourth embodiment, a patient with Smith-Magenis syndrome is treated with a controlled release tablet formulation of dinitazoxime 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 increasing the dose by about 0.8 mg / kg at each titration step and continuing treatment for 1 to 2 weeks at each step continues until the patient shows an adequate response to treatment or the maximum dose of 5 mg / kg is reached. At the same time, the patient can also be treated with an unacylated ghrelin analog. Potential responses to treatment can include reduction in body fat, reduction in hypotonia, increase in lean mass / fat mass ratio, reduction in hyperphagia, reduction in waist circumference, weight loss, reduction in irritability and aggressive behavior, and improvement in cardiovascular risk factors. Treatment with the drug will be long term and can continue for the lifetime of the patient.

[0613] In a fifth embodiment, a patient with Prader-Willi Syndrome is treated with a controlled release tablet formulation of Dizocilpine. The initial dose is about 1.5 mg / kg administered once daily. After the patient has been treated stably 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 treated stably 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 increasing the dose by about 0.9 mg / kg at each titration step and continuing treatment for 1 to 2 weeks at each step continues until the patient shows an adequate response to treatment or the maximum dose of 5 mg / kg is reached. At the same time, the patient can also be treated with an MC4 agonist. Potential responses to treatment can include reduction in body fat, reduction in hypotonia, increase in lean mass / fat mass ratio, reduction in hyperphagia, reduction in waist circumference, weight loss, reduction in temper tantrums and aggressive behavior, and improvement in cardiovascular risk factors. Treatment with the drug will be long term and can continue for the life of the patient.

[0614] In a sixth embodiment, a patient with Prader-Willi Syndrome is treated with a controlled release tablet formulation of Dizocilpine. The initial dose is about 1.5 mg / kg administered once daily. After the patient has been treated stably 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 treated stably 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 increasing the dose by about 1.0 mg / kg at each titration step and continuing treatment for 1 to 2 weeks at each step continues until the patient shows an adequate response to treatment or the maximum dose of 5 mg / kg is reached. At the same time, the patient can also be treated with an MC4 agonist. Potential responses to treatment can include reduction in body fat, reduction in hypotonia, increase in lean mass / fat mass ratio, reduction in hyperphagia, reduction in waist circumference, weight loss, reduction in temper tantrums and aggressive behavior, and improvement in cardiovascular risk factors. Treatment with the drug will be long term and can continue for the life of the patient.

[0615] All patents and other references cited in this specification are indicative of the level of skill of those skilled in the art to which this application pertains and are incorporated by reference herein in their entirety, including any tables and figures, to the same extent as if each individual reference had been incorporated by reference in its entirety individually.

[0616] Those skilled in the art will readily understand that the application is well adapted to carry out the objects and advantages and those inherent therein. The methods, variations, and compositions described herein as presently representative of preferred embodiments are exemplary and not intended as limitations on the scope. Changes therein and other uses will occur to those skilled in the art, which are encompassed within the spirit of the application, as defined by the scope of the claims.

[0617] Unless defined otherwise, all terms provided herein are intended to have the meanings as commonly understood by one of ordinary skill in the art.

[0618] The application illustratively described herein suitably can be practiced in the absence of any element or elements, limitation or limitations that are not specifically disclosed herein. Thus, for example, the terms "comprising," "including," containing", etc. shall be read expansively and without limitation. Furthermore, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described herein, but it is recognized that modifications are possible within the scope of the application claimed. Thus, it should be understood that although the present application has been specifically disclosed by preferred embodiments and optional features, modification and variation of the specific embodiments and features disclosed can be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of the application.

[0619] The application has been described herein in considerable detail. However, other modifications and variations to those specifically set forth herein can be resorted to by those skilled in the art, and will be those apparent to those skilled in the art from consideration of the disclosure and the detailed description of the application given herein. All such modifications and variations are believed to be within the scope of the application, as defined by the claims. It is to be understood that the application is defined by the claims.

[0620] Other embodiments fall within the following claims. Moreover, where a dependent claim refers to a specific combination of claim elements, such combination is considered to be within the scope of the application, even if the claim does not explicitly recite such a combination.

[0621] In view of the foregoing, the present application includes at least the following:

[0622] 1. A method of treating a subject having Prader-Willi Syndrome (PWS) or Smith-Magenis Syndrome (SMS), the method comprising administering to the subject a pharmaceutical formulation comprising an effective amount of a K ATP channel opener for at least 10 weeks.

[0623] 2. The method of item 1, wherein the K ATP The channel opener is diazoxide or a pharmaceutically acceptable salt thereof.

[0624] 3. The method of item 2, wherein the pharmaceutically acceptable salt is diazoxide choline.

[0625] 4. The method of item 2, wherein the diazoxide or pharmaceutically acceptable salt thereof is administered orally.

[0626] 5. The method of item 2, wherein the pharmaceutical formulation includes at least one excipient that affects the release rate of the diazoxide or pharmaceutically acceptable salt thereof.

[0627] 6. The method of item 5, wherein the pharmaceutical formulation includes at least one excipient that delays release of diazoxide or a pharmaceutically acceptable salt thereof.

[0628] 7. The method of item 1, wherein the formulation further comprises at least one other active ingredient.

[0629] 8. The method of item 1, further comprising administering human growth hormone to the subject.

[0630] 9. The method of item 8, wherein the human growth hormone is administered by injection.

[0631] 10. The method of item 1, wherein the subject's lean body mass or lean body mass / fat mass ratio is increased by at least 1%.

[0632] 11. The method of item 1, wherein the subject's lean body mass or lean body mass / fat mass ratio is increased by at least 2%.

[0633] 12. The method of item 1, wherein the subject's lean body mass or lean body mass / fat mass ratio is increased by at least 3%.

[0634] 13. The method of item 1, wherein the subject's lean body mass or lean body mass / fat mass ratio is increased by at least 4%.

[0635] 14. The method of item 1, wherein the subject's lean body mass or lean body mass / fat mass ratio is increased by at least 5%.

[0636] 15. The method of item 1, wherein the administration is for 1 year or more.

[0637] 16. The method of item 1, wherein the subject's eating disorder is reduced by at least 10%.

[0638] 17. The method of item 1, wherein the subject's hyperphagia is reduced by at least 20%.

[0639] 18. The method of item 1, wherein the subject's hyperphagia is reduced by at least 30%.

[0640] 19. The method of item 1, wherein circulating concentrations of IGF-1 are not increased.

[0641] 20. A method of increasing lean body mass in a subject having Prader-Willi Syndrome, wherein the subject has been treated by administering to the subject a growth hormone, the method comprising co-administering to the subject an effective amount of a K ATP channel opener in addition to the growth hormone.

[0642] 21. A method of increasing lean body mass in a subject having Prader-Willi Syndrome, wherein the subject has been treated by administering to the subject an effective amount of a K ATP channel opener, the method comprising co-administering to the subject an effective amount of a growth hormone in addition to the K ATP channel opener.

[0643] 22. A method of increasing lower extremity muscle mass in a subject having Smith-Magenis Syndrome (SMS), the method comprising administering to the subject an effective amount of a K ATP channel opener.

[0644] 23. A kit comprising:

[0645] a unit dose of a K ATP channel opener, and

[0646] a unit dose of a growth hormone.

[0647] 24. A method of reducing one or more aggressive behaviors in a subject having Prader-Willi Syndrome (PWS) or Smith-Magenis Syndrome (SMS), the method comprising administering to the subject an effective amount of a K ATP channel opener for at least 10 weeks, wherein administration reduces one or more aggressive behaviors in the subject.

[0648] 25. The method of item 24, wherein a second therapeutic product is administered, wherein the second product is intended to further reduce the one or more aggressive behaviors.

[0649] 26. A method of reducing hyperphagisemia in a subject having Prader-Willi Syndrome (PWS) or Smith-Magenis Syndrome (SMS), the method comprising administering to the subject an effective amount of a KATP the subject for at least 10 weeks, wherein administration reduces one or more aggressive behaviors of the subject.

[0650] 27. The method of item 1, wherein the pharmaceutical preparation is administered twice a day.

[0651] 28. The method of item 1, wherein the pharmaceutical preparation is administered once a day.

Claims

1. Use of diazoxide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method of treating a Prader-Willi Syndrome in a subject for overeating, wherein the method comprises orally administering to the subject once a day a pharmaceutical composition comprising an effective amount of diazoxide or a pharmaceutically acceptable salt thereof, wherein administration reduces overeating and one or more aggressive behaviors in the subject.

2. The use of claim 1, wherein the diazoxide or pharmaceutically acceptable salt thereof is administered for at least 10 weeks.

3. The use of claim 1, wherein the diazoxide or pharmaceutically acceptable salt thereof is administered for one or more years.

4. The use of claim 1, wherein the amount of diazoxide or pharmaceutically acceptable salt thereof administered is about 3.3 mg / kg / day.

5. The use of claim 1, wherein the amount of diazoxide or pharmaceutically acceptable salt thereof administered is about 4.2 mg / kg / day.

6. The use of claim 1, wherein the amount of diazoxide or pharmaceutically acceptable salt thereof administered once a day is 25 mg to 100 mg.

7. The use of claim 1, wherein the amount of diazoxide or pharmaceutically acceptable salt thereof administered once a day is 50 mg to 180 mg.

8. The use of claim 1, wherein the amount of diazoxide or pharmaceutically acceptable salt thereof administered once a day is 50 mg to 275 mg.

9. The use of claim 1, wherein the amount of diazoxide or pharmaceutically acceptable salt thereof administered once a day is 300 mg to 500 mg.

10. The use of claim 1, wherein the amount of diazoxide or pharmaceutically acceptable salt thereof administered once a day is 500 mg to 2000 mg.

11. The use of claim 1, wherein the amount of diazoxide or pharmaceutically acceptable salt thereof administered once a day is 25 mg to 500 mg.

12. The use of claim 3, wherein the amount of diazoxide or pharmaceutically acceptable salt thereof administered once a day is 25 mg to 100 mg.

13. The use of claim 3, wherein the amount of diazoxide or pharmaceutically acceptable salt thereof administered once a day is 50 mg to 180 mg.

14. The use of claim 3, wherein the amount of diazoxide or pharmaceutically acceptable salt thereof administered once a day is 50 mg to 275 mg.

15. The use of claim 3, wherein the amount of diazoxide or pharmaceutically acceptable salt thereof administered once a day is 300 mg to 500 mg.

16. The use of claim 3, wherein the amount of diazoxide or pharmaceutically acceptable salt thereof administered once a day is 500 mg to 2000 mg.

17. The use of claim 3, wherein the amount of diazoxide or pharmaceutically acceptable salt thereof administered once a day is 25 mg to 500 mg.

18. The use of claim 1, wherein the administration of the diazoxide or a pharmaceutically acceptable salt thereof is initiated at an initial dose of diazoxide or a pharmaceutically acceptable salt thereof and then titrated every two weeks to achieve an administration dose of diazoxide or a pharmaceutically acceptable salt thereof.

19. The use of claim 18, wherein the administration dose of diazoxide or a pharmaceutically acceptable salt thereof is about 3.3 mg / kg / day of diazoxide or a pharmaceutically acceptable salt thereof.

20. The use of claim 18, wherein the administration dose of diazoxide or a pharmaceutically acceptable salt thereof is about 4.2 mg / kg / day of diazoxide or a pharmaceutically acceptable salt thereof.

21. The use of claim 18, wherein the administration dose of diazoxide or a pharmaceutically acceptable salt thereof is 25-100 mg of diazoxide or a pharmaceutically acceptable salt thereof.

22. The use of claim 18, wherein the administration dose of diazoxide or a pharmaceutically acceptable salt thereof is 50-180 mg of diazoxide or a pharmaceutically acceptable salt thereof.

23. The use of claim 21, wherein the administration dose of diazoxide or a pharmaceutically acceptable salt thereof is 100-200 mg of diazoxide or a pharmaceutically acceptable salt thereof.

24. The use of claim 22, wherein the administration dose of diazoxide or a pharmaceutically acceptable salt thereof is 200-300 mg of diazoxide or a pharmaceutically acceptable salt thereof.

25. The use of claim 22, wherein the administration dose of diazoxide or a pharmaceutically acceptable salt thereof is 300-500 mg of diazoxide or a pharmaceutically acceptable salt thereof.

26. The use of claim 22, wherein the administration dose of diazoxide or a pharmaceutically acceptable salt thereof is 500-2000 mg of diazoxide or a pharmaceutically acceptable salt thereof.

27. The use of claim 22, wherein the administration dose of diazoxide or a pharmaceutically acceptable salt thereof is 100-500 mg of diazoxide or a pharmaceutically acceptable salt thereof.

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