Methods for treating subjects with Prader-Willi syndrome or Smith-Mageli syndrome.

Abstract

This invention provides for the immediate or long-term administration of certain potassium-ATP (Kᴀᴛᴘ) 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 Kᴀᴛᴘ channels. Pharmaceutical formulations, administration methods, and delivery methods of Kᴀᴛᴘ channel openers for achieving these outcomes and reducing the incidence of adverse effects in treated individuals are also provided. Methods for co-administering Kᴀᴛᴘ channel openers with other drugs (e.g., in combination with growth hormone) are also provided for the treatment of diseases in humans and animals (e.g., Prader-Willi syndrome (PWS), Smith-Magilli syndrome (SMS), etc.).

Description

Technical Field

[0001] This invention relates to potassium ATP (K ATP Pharmaceutical formulations of channel openers and their use in treating various diseases and conditions such as Prader-Willi Syndrome (PWS) and Smith-Magenis Syndrome (SMS). Background Technology

[0002] The following description of the background of the present invention is provided merely as an aid to understanding the present invention and is not intended to describe or constitute prior art of the present invention.

[0003] ATP-sensitive potassium (K) ATP K channels play an important role in various tissues by coupling cellular metabolism with electrical activity. ATP The channel has been identified as an octamer complex of two unrelated proteins assembled in a 4:4 stoichiometric ratio. The first is the pore-forming subunit Kir6.x, which forms the inward rectifying K... + The second type is the ABC (ATP-binding cassette) transporter, also known as the sulfonylurea receptor (SURx) (Babenko et al., Annu. Rev. Physiol., 60:667-687 (1998)). The Kir6.x pore-forming subunit is involved in many types of K... ATP The channel is common 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.

[0004] Based on their organizational positioning, K ATP Channels exist as different isotypes or subtypes resulting from the assembly of the SUR and Kir subunits in various combinations. The combination of the SUR1 subunit and the Kir6.2 subunit (SUR1 / Kir6.2) typically forms K cells in adipocytes and pancreatic B cells. ATP The channels, and the combinations of SUR2A / Kir6.2 and SUR2B / Kir6.2 or Kir6.1 typically form cardiac and smooth muscle type K, respectively. ATP The channel (Babenko et al., Annu. Rev. Physiol., 60:667-687 (1998)). There is also evidence that the channel may include the Kir2.x subunit. These types of potassium channels are inhibited by intracellular ATP and activated by nucleosides diphosphates within the cell. Such K... ATPChannels link cellular metabolic state to plasma membrane potential and, in this way, play a crucial role in regulating cellular activity. In most excited cells, K... ATP The channels are closed under normal physiological conditions and open when tissues are metabolically impaired (e.g., when the (ATP:ADP) ratio decreases). This promotes K+ efflux and cellular hyperpolarization, thereby preventing the opening of voltage-operated Ca2+ channels (VOCs). (Prog Res Research, (2001) 31:77-80).

[0005] Potassium channel openers (PCO or KCO) (also known as channel activators or channel agonists) are a group of structurally distinct compounds that do not share a common pharmacophore to antagonize intracellular nucleotide pairs of potassium. ATP The ability to inhibit the channel is associated. Diazide is a stimulatory agent for K+ in pancreatic β-cells. ATP The PCO of the channel (see Trube et al., Pfluegers, Archk, Eur J Physiol, 407, 493-99 (1986)). Pinacidil and chromakalim are the PCOs that activate myofibril membrane potassium channels (see Escande et al., Biochem Biophys Res Commun, 154, 620-625 (1988); Babenko et al., J Biol Chem, 275(2), 717-720 (2000)). The reactivity to diazoxide has been confirmed to exist in the 6th to 11th predicted transmembrane domains (TMD6-11) of the SUR1 subunit and the first nucleotide-binding fold (NBF1).

[0006] Diazide is a nondiuretic benzothiadiazine derivative having the formula 7-chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide (empirical formula C8H7ClN2O2S). It is commercially available in three different formulations for the treatment of two distinct disease indications: 1) hypertensive emergencies and 2) hyperinsulinemic hypoglycemia. Hyperstat IV is used to treat hypertensive emergencies; this is an aqueous formulation of diazide for intravenous use, adjusted to pH 11.6 with sodium hydroxide. Hyperstat IV is administered as a bolus injection into a peripheral vein to treat malignant hypertension or sulfonylurea overdose. In this application, diazide is used to open potassium channels in vascular smooth muscle, thereby stabilizing the membrane potential at resting levels and preventing vascular smooth muscle contraction.

[0007] Proglycem is used to treat hyperinsulinemic hypoglycemia. Proglycem is an oral form of diazoxide that can be administered to infants, children, and adults. It is available as a chocolate mint-flavored oral suspension comprising 7.25% alcohol, sorbitol, chocolate cream flavoring, propylene glycol, magnesium aluminum silicate, sodium carboxymethyl cellulose, mint flavoring, sodium benzoate, methylparaben, pH-adjusting hydrochloric acid, poloxamer 188, propylparaben, and water. Diazoxide is also available as capsules containing 50 mg or 100 mg of diazoxide, including lactose and magnesium stearate.

[0008] Several experimental formulations of diazoxide have been tested in humans and animals. These include oral solutions tested in pharmacodynamic and pharmacokinetic studies, as well as tablet formulations that are under development 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); US Patent 6,361,795).

[0009] Current oral formulations of diazoxide are labeled for administration two or three times daily at 8- or 12-hour intervals. Most patients receiving diazoxide are administered three times daily. Commercial and investigational formulations of diazoxide are characterized by rapid drug release after ingestion, with release completed within approximately 2 hours.

[0010] 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.

[0011] 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)).

[0012] The effects of diazoxide in humans with obesity or diabetes have been reported. See, for example, 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 Sper53:1860-1866(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 patients with hyperinsulinemia). 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);"The effect of diazoxide on residual insulin secretion in adult type I diabetes patients"; and Qvigstad et al. (Diabetic Medicine 21:73-76 (2004)).

[0013] U.S. Patent No. 5,284,845 describes a method for normalizing the blood glucose and insulin levels of an individual who exhibits normal fasting blood glucose and insulin levels and elevated glucose levels in an oral glucose tolerance test, and who has at least one insulin level abnormality selected from the group consisting of: a delayed insulin peak, an amplified 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 kilogram of body weight before each meal in a dose effective in normalizing blood glucose and insulin levels.

[0014] U.S. Patent No. 6,197,765 describes the administration of diazoxide as a treatment for syndrome X and its associated complications, including hyperlipidemia, hypertension, central obesity, hyperinsulinemia, and impaired glucose tolerance. According to this reference, diazoxide interferes with pancreatic function by eliminating endogenous insulin secretion, thereby inducing an insulin deficiency and hyperglycemia comparable to that of diabetic patients who rely on exogenous insulin administration to maintain normal blood glucose levels.

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

[0016] U.S. Patent No. 5,629,045 describes diazoxide for topical ophthalmic application.

[0017] WO 98 / 10786 describes the use of diazoxide for the treatment of syndrome X, including obesity associated with it.

[0018] US Patent Publication No. 2003 / 0035106 describes a diazoxide-containing compound for use in reducing the intake of fatty foods.

[0019] US Patent Publication No. 2004 / 0204472 describes the use of a Cox-2 inhibitor plus diazoxide for the treatment of obesity.

[0020] US Patent Publication No. 2002 / 0035106 describes a K-type compound comprising diazonium and a metal salt. ATP Channel openers are used to reduce the consumption of fatty foods. Summary of the Invention

[0021] This article provides K ATP Pharmaceutical formulations of channel openers and their use in the treatment of various diseases and conditions (optionally in combination with growth hormone), including Prader-Willi syndrome (PWS), Smith-Magilli syndrome (SMS), etc. These formulations are characterized by their bioavailability. For example, K used herein... ATP Channel openers possess one or more of the following properties: (1) opening SUR1 / Kir6.2 potassium channels; (2) interacting with K ATP (2) Binding to the SUR1 subunit of the channel; and (3) Inhibiting glucose-induced insulin release after administration of the compound in vivo. Preferably, K ATP The channel opener is K with all three properties. ATP Channel opening agent. As defined above, K... ATP The channel opener preferably has the structure of compounds of formulas I-VII as shown below.

[0022] According to one aspect of the invention, one or more K methods have been discovered. ATP Channel openers (optionally in combination with growth hormone) are effective in treating subjects with Prader-Willi syndrome (PWS), Smith-Magilli syndrome (SMS), etc., and are particularly effective in increasing lean body mass in these subjects. Therefore, in one aspect of the invention, a method for increasing lean body mass in subjects with Prader-Willi syndrome (PWS), Smith-Magilli syndrome (SMS), etc., is provided, the method comprising administering an effective amount of K to the subject. ATP Channel openers (optionally in combination with growth hormone) for at least 4 weeks.

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

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

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

[0026] In another aspect, the present invention provides a method for increasing lean body mass in subjects suffering from Prader-Willi syndrome (PWS), Smith-Magilli syndrome (SMS), etc., wherein the subjects have been treated by administering growth hormone, the method comprising, in addition to the growth hormone, co-administering an effective amount of K to the subjects. ATP Channel opening agent.

[0027] In another aspect, the present invention provides a method for increasing lean body mass in subjects suffering from Prader-Willi syndrome (PWS), Smith-Magilli syndrome (SMS), etc., wherein the subjects have been administered an effective amount of K ATP The method includes, in addition to the K, receiving treatment with a channel opener. ATP In addition to the channel opener, an effective amount of growth hormone was also administered to the subjects.

[0028] K as defined by equation I ATP The following are channel opening agents:

[0029]

[0030] in:

[0031] R 1a and R 1b When present, it is independently selected from the group consisting of: hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, amino, and substituted amino;

[0032] R 2a and R 2b When present, it is independently selected from the group consisting of hydrogen and lower alkyl groups;

[0033] 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.

[0034] In this context, ring A and ring B are each independently saturated, monounsaturated, polyunsaturated, or aromatic.

[0035] And all its biological equivalents, including salts, prodrugs, and isomers.

[0036] 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.

[0037] K is defined by Equation II as a subclass of Equation I. ATP The following are channel opening agents:

[0038]

[0039] in:

[0040] R 1 Choose from the group consisting of: hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, amino, and substituted amino;

[0041] R 2a Select from the group consisting of hydrogen and lower alkyl groups;

[0042] 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.

[0043] Among them, ring B can be saturated, monounsaturated, polyunsaturated, or aromatic;

[0044] And all its biological equivalents, including salts, prodrugs, and isomers.

[0045] 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, sulfonylamino, aminosulfonyl, sulfonyl, etc. In another embodiment, R a and R b Independently selected from the group consisting of: hydroxyl, substituted oxygen, substituted thiol, alkylthio, substituted alkylthio, sulfinyl, sulfonyl, substituted sulfinyl, substituted sulfonylamino, substituted amino, substituted amine, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, etc. In a preferred embodiment, R 1 It is not an amino group. In another preferred embodiment, ring B does not contain any heteroatoms.

[0046] K is defined by Equation III as a subclass of Equation I. ATP The following are channel opening agents:

[0047]

[0048] in:

[0049] R 1 Choose from the group consisting of: hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, amino, and substituted amino;

[0050] R 2b Select from the group consisting of hydrogen and lower alkyl groups;

[0051] 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.

[0052] Among them, ring B can be saturated, monounsaturated, polyunsaturated, or aromatic;

[0053] And all its biological equivalents, including salts, prodrugs, and isomers.

[0054] In a specific implementation of Equation III, X is C(R) a )C(R b ), where R a and R b Independently selected from the group consisting of: hydrogen, halogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkoxy, substituted lower alkoxy, amino, sulfonylamino, aminosulfonyl, sulfonyl, etc. In another embodiment, R a and Rb Independently selected from the group consisting of: hydroxyl, substituted oxygen, substituted thiol, alkylthio, substituted alkylthio, sulfinyl, sulfonyl, substituted sulfinyl, substituted sulfonylamino, substituted amino, substituted amine, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, etc. In a preferred embodiment, R 1 It is not an amino group. In another preferred embodiment, ring B does not contain any heteroatoms.

[0055] K is defined by Equation IV, which is a subclass of Equation I. ATP The following are channel opening agents:

[0056]

[0057] in:

[0058] R 1 Choose from the group consisting of: hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, amino, and substituted lower amino;

[0059] R 2a Choose from the group consisting of: hydrogen, lower alkyl groups, and substituted lower alkyl groups;

[0060] R 3 Choose from the group consisting of: hydrogen, halogens, lower alkyl groups, substituted lower alkyl groups, amino groups, and substituted amino groups;

[0061] R 4 Choose from the group consisting of: hydrogen, halogens, lower alkyl groups, substituted lower alkyl groups, amino groups, and substituted amino groups;

[0062] And all its biological equivalents, including salts, prodrugs, and isomers.

[0063] In the specific implementation scheme of Formula IV, R 1 It is a lower alkyl group (preferably ethyl or methyl); R 2a It is hydrogen; and R 3 and R 4 Each is a halogen on its own.

[0064] In a preferred embodiment of formula IV, R 1 It is not amino.

[0065] In another implementation of Formula IV, R 1 It is methyl; R 2a 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 R4 It is chlorine.

[0066] K is defined by equation V, which is a subclass of equation I. ATP The following are channel opening agents:

[0067]

[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 biological equivalents, 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 R 6 They combine to form a 6-membered ring. In another implementation, R 5 and R 6 They combine to form a 6-membered ring, wherein at least one nitrogen atom is present. Preferably, it is formed from R. 5 and R 6 The formed ring does not contain any heteroatoms.

[0090] K as defined by equation VII ATP The following are channel opening agents:

[0091]

[0092] in:

[0093] 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;

[0094] R 2b Choose from the group consisting of: hydrogen, lower alkyl groups, and substituted lower alkyl groups;

[0095] 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;

[0096] 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;

[0097] 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.

[0098] Among them, R1 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.

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

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

[0101] In another embodiment of formula VI, R 5 and R 6 They combine to form a 6-membered ring. In another implementation, R 5 and R 6 They combine to form a 6-membered ring, wherein at least one nitrogen atom is present. Preferably, it is formed from R. 5 and R 6 The formed ring does not contain any heteroatoms.

[0102] Unless otherwise specified, K is mentioned in this application. ATP When referring to a channel opener, it should be understood as meaning one or more of the following properties, and preferably one or more of all three: K. ATP Channel openers: (1) open SUR1 / Kir6.2 potassium channels; (2) interact with K ATP (3) Binding to the SUR1 subunit of the channel; and (4) inhibiting glucose-induced insulin release after in vivo administration of the compound. Such K ATP The channel opener preferably has the structure of any one of the compounds of formulas I-VII; or more preferably, the structure of any one of the compounds of formulas I-VII, wherein R 1 Not amino and furthermore, wherein ring B or its equivalents do not contain 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 It is not an amino group, and furthermore, ring B or its equivalents do not contain any heteroatoms, or more preferably, the structure is diazine. Structural variations or bioequivalents of compounds of any one of formulas I-VII, such as derivatives, salts, prodrugs, or isomers, are also considered. Other K compounds considered for use herein ATP Channel openers include BPDZ62, BPDZ73, NN414, and BPDZ154.

[0103] For KATP In vitro analysis of glucose-induced insulin release in the presence of channel openers can be performed using rat islets, as provided by DeTullio et al., J. Med. Chem., 46:3342-3353 (2003), or as provided by... The method provided by Diabetes, 49:1840-1848 (2000) is determined by using human islets of Langerhans.

[0104] This article provides K ATP Formulations of channel openers and their bioequivalents, such as controlled-release drug 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 potassium in a single administration dose. ATP Channel opener. In some embodiments, the formulation contains K ATP The dosage of the channel opener can be determined based on the weight of the patient to whom it will be administered, meaning that the formulation may contain 0.1 mg to 20 mg of potassium per kilogram of patient body weight in a single dose. ATP Channel openers; or 0.1 mg to 0.5 mg K per kilogram of patient body weight. ATP Channel openers; or 0.5 mg to 1 mg of potassium per kilogram of patient body weight. ATP Channel opener; or 1 to 2 mg of potassium per kilogram of patient body weight. ATP Channel opener; or 2 to 5 mg of potassium per kilogram of patient body weight. ATP Channel openers; or 5 to 10 mg of potassium per kilogram of patient body weight. ATP Channel openers; or 10 to 15 mg of potassium per kilogram of patient body weight. ATP Channel openers; or 15 mg to 20 mg of potassium per kilogram of patient body weight. ATP Channel opening agent.

[0105] This article also provides information containing K. ATP A controlled-release drug formulation of a channel opener, said formulation being obtained by at least one of the following: (a) particle size reduction involving pulverization, spray drying, or other micronization techniques; (b) using K ATP (c) Pharmaceutical salts of channel openers; (d) Use of ion exchange resins; (e) Use of inclusion complexes, such as cyclodextrins; ATP The channel opener is pressed together with a solubilizer, said solubilizer comprising low-viscosity hydroxypropyl methylcellulose, low-viscosity methylcellulose, or excipients or combinations thereof that perform similar functions; (f) K is made prior to formulation. ATPChannel openers associate with salts; (g) using K ATP (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 ATPChannel openers exhibit sustained release over a period of 2 to 4 hours after administration, or over a period of 4 to 8 hours after administration, or over a period of more than 8 to 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 diffusion rate of the drug from the coated matrix; (d) a soluble matrix that controls the drug release rate; (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] As used herein, the soluble matrix is ​​the tablet core of a tablet formulation that initiates a disintegration process upon exposure to an aqueous environment, which promotes the release of the drug from the matrix. The rate of drug release from the tablet is controlled by both the drug's solubility and the matrix's disintegration rate.

[0110] The above-mentioned formulation may also contain one or more additional pharmaceutically active agents (excluding K) that can be used to treat conditions selected from the group consisting of the following groups. ATP (Apart from channel openers): Obesity, prediabetes, diabetes, hypertension, depression, high cholesterol, fluid retention, other obesity-related comorbidities, ischemia and reperfusion injury, epilepsy, schizophrenia, mania, or other mental illnesses.

[0111] It also provides K ATP A controlled-release drug formulation of a channel opener, wherein administration to an obese, overweight, or obesity-susceptible individual causes at least one of the following: (a) inhibition of fasting insulin secretion; (b) inhibition of stimulated insulin secretion; (c) increased energy expenditure; (d) increased β-oxidation of fat; (e) suppression of overeating over approximately 24 hours; or (f) increased lean body mass.

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

[0113] It also provided K ATPA controlled-release drug formulation of a channel opener, which, when administered to obese, overweight, or obesity-susceptible individuals, causes at least one of the following: (a) inhibition of fasting insulin secretion; (b) inhibition of glucose-stimulated insulin secretion; (c) increased energy expenditure; (d) increased β-oxidation of fat; (e) suppression of overeating over approximately 24 hours; or (f) increased lean body mass.

[0114] K is also provided. ATP A controlled-release drug formulation of a channel opener, which, when administered to obese, overweight, or obesity-susceptible individuals, causes at least one of the following: (a) inhibition of fasting insulin secretion; (b) inhibition of glucose-stimulated insulin secretion; (c) increased energy expenditure; (d) increased β-oxidation of fat; (e) suppression of overeating over approximately 18 hours; or (f) increased lean body mass.

[0115] This article provides a method for treating hypoglycemia, the method comprising oral administration of K ATP A controlled-release formulation of a channel opener, optionally combined with growth hormone.

[0116] This article also provides a method for treating obesity-related comorbidities in obese, overweight, or obesity-susceptible individuals, the method comprising administering a therapeutically effective dose of K. ATP Solid oral dosage forms of channel openers, 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.

[0117] This article further provides a method for achieving weight loss in obese, overweight, or obesity-prone individuals, the method comprising administering a therapeutically effective dose of K. ATP Solid oral dosage form of channel opener or K ATP A controlled-release formulation of a channel opener, optionally combined with growth hormone. In a preferred embodiment, administration is performed no more than twice every 24 hours, or once every 24 hours. The daily dose administered is preferably 50 mg to 180 mg. In some embodiments, the obese individual has a weight greater than 30 kg / m² at the start of the method. 2 or greater than 35kg / m 2 or greater than 40 kg / m 2 or greater than 50 kg / m 2 or greater than 60 kg / m 2 Body Mass Index (BMI).

[0118] A method for maintaining weight loss in obese, overweight, or obesity-prone individuals is also provided, the method comprising administering a therapeutically effective dose of K. ATP Solid oral dosage form of channel opener or K ATP A controlled-release formulation of a channel opener, optionally combined with growth hormone. Once a certain degree of weight loss has occurred, maintaining the weight of the obese individual is preferred when the alternative is to regain weight. In a preferred embodiment, administration is performed no more than twice every 24 hours, or once every 24 hours.

[0119] A method for increasing energy expenditure in overweight, obese, or obesity-prone individuals is also 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 drug formulation of a channel opener, optionally combined with growth hormone. In a preferred embodiment, administration is performed no more than twice every 24 hours, or once every 24 hours. In some embodiments, the individual has a growth rate greater than 20 kg / m² at the start of the method. 2 or greater than 25 kg / m 2 or greater than 30kg / m 2 or greater than 35kg / m 2 or greater than 40 kg / m 2 or greater than 50 kg / m 2 or greater than 60 kg / m 2 Body Mass Index (BMI).

[0120] Another method for increasing β-oxidation of fat in overweight, obese, or obesity-prone individuals is provided, the method comprising administering an effective amount of K ATP Solid oral dosage form of channel opener or K ATP A controlled-release drug formulation of a channel opener, optionally combined with growth hormone. In a preferred embodiment, administration is performed no more than twice every 24 hours, or once every 24 hours. In some embodiments, the individual has a growth rate greater than 20 kg / m² at the start of the method. 2 or greater than 25 kg / m 2 or greater than 30kg / m 2 or greater than 35kg / m 2 or greater than 40 kg / m 2 or greater than 50 kg / m 2 or greater than 60 kg / m 2 Body Mass Index (BMI).

[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 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] A method for increasing lean body mass in patients with Prader-Willi syndrome, Smith-Magilli syndrome, Froelich's syndrome, Cohen syndrome, Summit syndrome, Alstrom syndrome, Borjeson syndrome, or Bardet-Biedl syndrome is also provided, the method comprising administering an effective amount of K ATP Channel openers (optionally in combination with growth hormone) 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.

[0128] Furthermore, a method for treating obesity or elevated triglycerides in patients with type I, II, III, or IV hyperlipoproteinemia 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.

[0129] It also provides a way to reduce the incidence of disease in treated subjects caused by the administration of K. ATP A method for determining the incidence of adverse effects caused by channel openers, said method being achieved by any of the following: (a) using a product that, at the time of administration, reduces C compared to the current Proglycem oral suspension or capsule product. max (a) a dosage form that reduces the incidence of adverse side effects associated with peak drug levels; (b) a dosage form that uses delayed release until the stomach has passed through completely to reduce the incidence of adverse side effects associated with drug release in the stomach; (c) a dosage form that starts administration at a subtherapeutic level and gradually increases the dose daily until a therapeutic dose is reached, wherein the number of steps is 2 to 10 to reduce the incidence of transient adverse side effects at the start of treatment; (d) a dosage form that uses the lowest effective dose to achieve the desired therapeutic effect to reduce the incidence of dose-dependent adverse side effects; or (e) a dosage form that optimizes the timing of administration throughout the day and relative to meals.

[0130] A method for preventing weight gain, dyslipidemia, or impaired glucose tolerance in subjects receiving antipsychotic medication is also provided, the method comprising administering K ATPDrug formulations of channel openers, optionally combined with growth hormones.

[0131] Furthermore, a method is provided for treating weight gain, dyslipidemia, or impaired glucose tolerance in subjects receiving antipsychotic medication, the method comprising administering K... ATP Drug formulations of channel openers, optionally combined with growth hormones.

[0132] A method for treating diseases characterized by obesity, overeating, dyslipidemia, or reduced energy expenditure is also provided, said diseases including (a) Prader-Willi syndrome; (b) Flehrich syndrome; (c) Cohen syndrome; (d) peak syndrome; (e) Alstrélé syndrome; (f) Boyerson syndrome; (g) Barbie II syndrome; (h) type I, II, III, and IV hyperlipoproteinemia; or (i) Smith-Magilli syndrome (SMS), said method comprising administering K ATP Drug formulations of channel openers, optionally combined with growth hormones.

[0133] It also provides K ATP A pharmaceutical formulation of a channel opener, the formulation further comprising, in addition to the K ATP Other pharmaceutically active agents besides channel openers. In such formulations, the other pharmaceutically active agents are agents that can be used to treat conditions selected from the group consisting of: obesity, prediabetes, diabetes, hypertension, depression, high cholesterol, fluid retention, or other obesity-related comorbidities, ischemia and reperfusion injury, epilepsy, schizophrenia, mania, and other psychotic conditions.

[0134] The article contains K ATP Channel opener formulations offer improved compliance, efficacy, and safety, and provide co-formulation options with other medications. This includes K. ATP A co-formulation of a channel opener with one or more other pharmaceutically active agents having complementary or similar activities or targets. It can be combined with K. ATP Channel opener combinations for treating obesity or maintaining weight loss in individuals susceptible to obesity include, but are not limited to: sibutramine, orlistat, phentermine, rimonabant, diuretics, antiepileptic drugs, or other active pharmaceutical agents whose therapeutic effect includes weight loss. Once some weight loss has been achieved, maintaining the obese individual's weight is preferred when the alternative is to regain weight. This can be combined with K... ATPChannel opener combinations for the treatment of type 2 diabetes or prediabetes include other active pharmaceutical agents such as acarbose, miglitol, metformin, repaglinide, nateglinide, rosiglitazone, pioglitazone, ramipril, metataglidasen, or any other active pharmaceutical agent whose mode of action is not to enhance insulin secretion, improve insulin sensitivity, or improve glucose utilization or glycemic control. Can be combined with K. ATP The combination of channel openers to treat obesity-related comorbidities includes other pharmacologically active agents used to lower cholesterol, pharmacologically active agents used to lower blood pressure, anti-inflammatory drugs that are not Cox-2 inhibitors, drugs used as antidepressants, drugs used to treat urinary incontinence, or other drugs routinely used to treat disease conditions in which the incidence of the aforementioned disease conditions is increased in overweight or obese individuals compared to individuals of normal weight, including but not limited to drugs used to treat the following conditions: atherosclerosis, osteoarthritis, herniated discs, knee and hip joint degeneration, 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 hernia, menstrual disorders, infertility, etc.

[0135] In the context of this invention, the terms "therapeuticly effective" or "effective amount" mean that the material or amount of material effectively prevents, alleviates, or improves one or more symptoms of a disease or medical condition in a subject receiving treatment and / or prolongs the survival of said subject.

[0136] The term "pharmaceutically acceptable" means that the identified material does not possess characteristics that would cause a reasonably cautious practitioner to avoid administering the material to a patient, taking into account the disease or condition to be treated and the corresponding route of administration. For example, such materials are typically required to be substantially sterile, such as for injectable preparations.

[0137] As used herein, the term "composition" refers to a formulation suitable for administration to intended animal subjects to achieve a therapeutic purpose; exemplary formulations contain at least one pharmaceutically active compound and at least one pharmaceutically acceptable carrier or excipient. Other terms used herein are defined below.

[0138] Adipocytes: Connective tissue cells in animals that are specifically used for fat synthesis and storage.

[0139] Agonists: Compounds that have an affinity for cell receptors and stimulate physiological activity at the receptors, usually by naturally occurring substances, thereby triggering biochemical reactions. Receptor agonists can also be considered receptor activators.

[0140] Approximately: In this text, it is used to mean adding or subtracting 10% from the quantity.

[0141] Adipose tissue: tissue mainly containing fat cells.

[0142] Teenagers: People aged 10 to 19.

[0143] Adiponectin: A protein hormone produced and secreted solely by adipocytes that regulates lipid and glucose metabolism. Adiponectin affects the body's response to insulin. It also has anti-inflammatory effects on the cells lining blood vessel walls.

[0144] The improvement of symptoms of a specific condition by applying a specific pharmaceutical composition refers to any relief that can be attributed to or related to the application of the composition, whether permanent or temporary, continuous or transient.

[0145] Analogous compounds: compounds that are structurally similar to another compound, but differ by at least one atom.

[0146] Antagonists: Substances that, as drugs, bind to cell receptors without eliciting a biological response, tend to eliminate the effects of another substance.

[0147] Atherosclerotic plaques: The accumulation of cholesterol and fatty substances in blood vessels due to the effects of atherosclerosis.

[0148] Bariatric surgery: A variety of surgical procedures designed to help manage or treat obesity and related diseases.

[0149] β-cell resting: Temporarily placing β-cells in a state where metabolic stress is reduced due to the inhibition of insulin secretion.

[0150] Bilayer laminate: A component of a drug dosage form consisting of two laminates of two different materials.

[0151] Bioavailability refers to the amount or extent of a therapeutically active substance released from a drug product and made available at the intended site of action in the body. The amount or extent of drug released can be measured by pharmacokinetic parameters such as the area under the blood or plasma concentration-time curve (AUC) and peak blood or plasma concentration (C). max To determine.

[0152] Bioequivalence: Two formulations of the same active substance are bioequivalent when there is no significant difference in the rate and extent to which the active substance becomes available at the site of action when administered at the same molar dose under similar conditions. In this definition, "formulation" can include the free base of the active substance or different salts of the active substance. Bioequivalence can be demonstrated by several in vivo and in vitro methods. These methods, in descending order of priority, include pharmacokinetic studies, pharmacodynamic studies, clinical studies, and in vitro studies. Specifically, bioequivalence is a pharmacokinetic measure of the drug's metabolism, such as the area under the blood or plasma drug concentration-time curve (AUC) and peak blood or plasma concentration (C). max ), which was confirmed using statistical standards.

[0153] Cannabinoid receptors: Receptors in the endocannabinoid (EC) system, which are associated with food intake and tobacco dependence. Blocking cannabinoid receptors can reduce tobacco dependence and food cravings.

[0154] Combination: refers to any association between or between two or more items. A combination can be two or more individual items, such as two compositions or two collections. 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 tablets: Tablets formed by applying pressure to a certain volume of tablet matrix in a mold.

[0157] Compressed coated tablets: Tablets formed by adding a coating to a compressed tablet core containing a pharmaceutical active agent through compression.

[0158] Derivatives: Chemical substances derived from another substance through modification or substitution.

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

[0160] Diazine: 7-chloro-3-methyl-2-H-1,2,4-benzothiadiazine 1,1-dioxide, with the empirical formula C8H7ClN2O2S and a molecular weight of 230.7.

[0161] Encapsulation system: A structural feature that contains a drug within a capsule, such as a drug capsule. Gels containing drugs are also considered encapsulation systems.

[0162] Equivalent dose: The amount of a drug derivative that produces the same effect as a specified amount of the non-derivative drug in the assay or when administered to a subject.

[0163] Fatty acid synthase: The 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] Gliding agents: Inactive components in pharmaceutical formulations that prevent the matrix from clumping during processing steps.

[0166] Growth hormone (GH), also known as auxin or growth promoter, is a peptide hormone that stimulates growth, cell proliferation, and regeneration in humans and other animals. It is a type of mitogen specific to certain cell types. GH is a single-chain polypeptide of 191 amino acids synthesized, stored, and secreted by growth hormone cells in the lateral aspect of the anterior pituitary gland. GH is a stress hormone that increases glucose and free fatty acid concentrations. It also stimulates the production of IGF-1.

[0167] Hyperinsulinemia: Excessively high levels of insulin in the blood. This is distinct from hyperinsulinemia, which is caused by excessive insulin secretion from the pancreas. Hyperinsulinemia can result from a variety of conditions such as obesity and pregnancy.

[0168] Hyperinsulinism: Excessive secretion of insulin by the pancreas.

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

[0170] Overeating: Consuming more food than the optimal amount.

[0171] Components of a pharmaceutical composition: These refer to one or more materials used in the manufacture of the pharmaceutical composition. Components can refer to the active ingredient (pharmaceutical) or other materials in the composition. Components may include water and other solvents, salts, buffers, surfactants, water, non-aqueous solvents, and flavoring agents.

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

[0174] Ischemic injury: tissue damage caused by a hypoxic state, usually due to obstruction of arterial blood supply or insufficient blood flow, resulting in tissue hypoxia.

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

[0176] Reagent kit: refers to a package combination. The package combination may optionally include one or more labels, instructions and / or reagents for use with the combination.

[0177] Kir:K ATP The pore-forming subunit of the channel. Also known as K. ATP The inward rectifier subunit of the channel. It typically exists in the form of Kir6.x and occasionally in the form of the Kir2.x subspecies.

[0178] K ATP Channel: An ATP-sensitive potassium channel spanning the cell membrane, formed by the association of four copies of the sulfonylurea receptor and four copies of the pore-forming subunit Kir. Activation of this channel can induce membrane hyperpolarization.

[0179] Lean body mass: Lean body mass is a component of the body, calculated by subtracting body fat weight from total weight. Total weight is lean body mass 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 typically cited; it is usually 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 an index superior to total weight in prescribing appropriate medication levels and assessing metabolic disorders because body fat is less relevant to metabolism.

[0183] Leptin: a product of the ob (obesity) gene locus (16kD). It is present in the blood plasma of mammals and acts as a hormone that reduces food intake and increases energy expenditure.

[0184] Lipogenesis: the formation 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 through the synergistic action of multiple enzymes.

[0186] Lipoprotein lipase: A hydrolytic enzyme that catalyzes the reaction of triacylglycerol and water to produce diacylglycerol and fatty acid anions. The enzyme hydrolyzes triacylglycerol into chylomicrons, very low-density lipoproteins, low-density lipoproteins, and diacylglycerols.

[0187] Lubricant: An inactive component in pharmaceutical preparations that enables the material to flow through various processing steps, especially during tableting.

[0188] Microparticles: Small particles formed during the process of opening a pharmaceutical formulation, which may be coated before the final dosage form is produced.

[0189] Obesity: Weight gain exceeding the limits required by bones and the body, resulting from excessive accumulation of fat in the body. It is formally defined as having a body weight greater than 30 kg / m². 2 Body Mass Index (BMI).

[0190] Obesity susceptibility: Individuals who have a higher-than-average risk of becoming obese due to genetic predisposition or a previous history of obesity.

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

[0192] Osmotic controlled release: This type of drug formulation is mainly achieved through the hydration of the swelling components of the formulation.

[0193] Overweight: An individual's weight is higher than the ideal weight for their height, but does not meet the criteria for being classified as obese. This is defined using the Body Mass Index (kg / m²). 2 In humans, overweight individuals have a BMI of 25 to 30.

[0194] Fat oxidation: a series of reactions involving acyl-CoA compounds, which undergo β-oxidation and thiolytic cleavage, accompanied by the formation of acetyl-CoA; the main pathway of fatty acid catabolism in living tissues.

[0195] Pharmaceutical composition: refers to a composition containing a pharmaceutical agent and one or more other ingredients, formulated for administration to a subject. The pharmaceutical agent refers to the active ingredient in the 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 those used to treat obesity or diabetes. The pharmaceutical agent may be referred to as a "pharmaceutical active ingredient".

[0196] Drug action: refers to the effect observed when a drug is administered to treat a disease or condition or to improve its symptoms.

[0197] Pharmacodynamics: The effects mediated by drug action.

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

[0199] Polymorphs: Compounds that share the same chemical properties but have different crystal structures.

[0200] Prader-Willi syndrome (PWS): a complex neurobehavioral / metabolic disorder attributed to the absence of a normally active paternally expressed gene in the 15q11-q13 region. PWS is an imprinted condition in which 70%–75% of cases are attributed to a de novo deletion in the 11-q13 region of paternally inherited chromosome 15, 20%–30% to maternally inherited uniparental disodium 15 (UPD), and the remaining 2%–5% to microdeletions or epigenetic mutations in the imprinted center (i.e., imprinting defects) (Bittel and Butler, Expert Rev Mol Med 7(14):1–20 (2005); Cassidy and Driscoll, Eur JHum Genet 17(1):3–13 (2009)).

[0201] The clinical manifestations of this condition begin with decreased fetal activity in utero (Miller Am J Med Genet A155A(5):1-10(2011)). Lean body mass and decreased tone are common in PWS and persist throughout life (Brambilla Am J Clin Nutr 65(5):1369-1374(1997); Lloret-lineras Int J Obes 37:1198-1203(2013)). Intellectual disability occurs to varying degrees, with an average IQ of 70 (PWSUSA). Patients with PWS exhibit a variety of behavioral complications, including autism spectrum disorder-like behaviors, compulsive behaviors, self-harming behaviors, and aggressive, threatening, and destructive behaviors. Approximately 80% of patients with PWS have growth hormone deficiency (Goldstone, Trends Endocrinol Metab 15:12-120 (2004); Davies et al., Front Neuroendocrinol 29:413-427 (2008); Cassidy and Driscoll, 2009 (ibid.)). Almost all patients with PWS have hypogonadism and therefore require sex hormone supplementation (Goldstone, 2004 (ibid.); Davies et al., 2008 (ibid.); Cassidy and Driscoll, 2009 (ibid.)). These patients also have hypothalamic dysfunction (Goldstone Am J Clin Nutr 75(3):468-475 (2002)).

[0202] Excessive body fat accumulation may begin around age 2 and may continue into adulthood (Miller 2011, ibid.). The vast majority of body fat in PWS is subcutaneous (Brambilla 1997, ibid.; Sode-Carlson, Growthhormone and IGF research 20:179-184 (2010); Bedogni J Endocrinol Invest DOI10.1007 / s40618-015-0266-y (2015)). Obesity is not common in PWS, unlike the prevalence of lean body mass and decreased tone. For example, Sode-Carlson et al. (2010, ibid.) evaluated 46 adult PWS patients, 25 women and 21 men. The mean BMI of these adult PWS patients was 27.2 kg / m². 2Therefore, on average, these patients were overweight rather than obese, suggesting that, in fact, according to the optimal measure, more than half were not obese. Similarly, Brambilla et al., Nutr Metab Cardiovasc Dis 21(4):269-276 (2011) studied a group of 109 children with PWS. They found that 54% No The best measure of obesity is that it is not prevalent in both adults and children with PWS, but may actually occur in less than half of the population. Subcutaneous fat accounts for a greater percentage of total fat in PWS than it does in obese controls of all ages (Sode-Carlson 2010, ibid.)

[0203] Pejaculation with associated problematic food-related behaviors typically begins around age 8 (Miller 2011, ibid.). These individuals experience hunger even when they are not hungry. During a pyelonephric episode, PWS patients will consume any food within sight, eat at night, dig through the trash for food, steal food, eat frozen food, pet food, spoiled food, and even non-food items (Miller 2011, ibid.). If denied food, they will become angry or throw tantrums. During this stage and throughout their lives thereafter, access to food is strictly restricted, with cupboards and refrigerators locked. Meal times and dietary composition are strictly controlled to limit food-related anxiety.

[0204] The mortality rate for patients with PWS is three times that of the general population of all ages (Cassidy Genet Med 14(1):10-26(2012)), with a mean age at death of approximately 29 years (PWSUSA Mortality Database, n=488). Conversely, 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; eds. Crimmons, EM, Preston, SH, Cohen, B, National Academies Press).

[0205] Patients with Prader-Willi syndrome (PWS) expend 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 A143A(5):449-459 (2007) compared energy expenditure and total work in a group of 48 PWS patients with a group of 24 obese controls. Compared with controls, PWS patients had significantly lower total energy expenditure (-20%), resting energy expenditure (-16%), and mechanical work (-35%). 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), mean daily metabolic rate (ADMR), activity-induced energy expenditure (AEE), and ADMR / BMR (PAL) in a group of PWS patients and matched controls. Compared with the control group, the PWS group had significantly lower ADMR, AEE, and PAL (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 pulmonary vasculitis (PWS). They confirmed that 63% of infants with PWS and 73% of pre-pubescent children with PWS had at least one cardiovascular risk factor, defined as dyslipidemia or hypertension. Therefore, the cardiometabolic risk of PWS is elevated even in younger children.

[0208] Preadipocytes: Progenitor cells of adipocytes.

[0209] Prediabetes: The condition preceding a diagnosis of type 2 diabetes. Type 2 diabetes is a form of diabetes characterized by insulin insensitivity or insulin resistance.

[0210] Prodrugs are compounds that, upon metabolism, produce the desired active compound. Typically, prodrugs are inactive or have less activity than the active compound, but can provide advantageous processing, 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. Additionally, some prodrugs are enzymatically activated to produce the active compound or, upon further chemical reactions, produce 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-Magilie syndrome is characterized by clinically identifiable phenotypes, including physical, developmental, neurological, and behavioral features. Short stature (<5th percentile) is observed in approximately 67% of young patients. Short stature regresses over time, with most individuals reaching the 10th–25th percentile by adulthood (see, for example, Burns et al., ibid.). Most children with SMS also exhibit significant early-onset obesity (see, for example, European Journal of Human Genetics (2008) 16, 412–421). Obesity is common in adolescents and adults, often characterized by broad chest and trunk obesity. RAI1 haplo-insufficiency represents a monogenic model of obesity accompanied by overeating, abnormal fat distribution, and hypothalamic gene expression alterations related to satiety, food intake, behavior, and obesity.

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

[0220] A prenatal history of SMS is noteworthy for fetal movements that are significantly reduced in 50% of pregnancies. Early infancy can be complicated by feeding difficulties leading to developmental arrest, significant oral sensorimotor dysfunction with poor sucking reflexes, gastroesophageal reflux, and hypotonia.

[0221] Most individuals with Smarty Mind (SM) have mild to moderate intellectual disability. IQ decreases with age, eventually resulting in mild intellectual disability in adulthood. Language delay, with or without hearing loss, occurs in 96% of people with SM. In addition, fine motor / gross motor skill delays, sensory integration problems, and poor adaptive functioning are observed. Other neurological features include pes cavus or flat feet, an unusual 'flustered' gait, balance problems, and decreased sensitivity to pain, which is often observed to be associated with self-harm in this condition.

[0222] Sleep disorders have been reported in 75%–100% of SMS cases. Infants typically experience excessive sleepiness during the first year of life. Sleep disorders in older children include difficulty falling asleep, reduced REM sleep, reduced 24-hour and nighttime sleep, fragmented and shortened sleep cycles with frequent nighttime and early morning awakenings, and excessive daytime sleepiness.

[0223] Behavioral problems are one of the unique and characteristic features of SMS. Maladaptive behaviors are a primary concern and include frequent irritability / temper tantrums, attention-seeking, aggression, disobedience, distractibility, and self-harm. Self-harm behaviors include head-banging, skin-scratching, wrist-biting, onychotillomania, and polyembolokoilamania. SMS behavioral phenotypes progressively escalate with age, typically with the onset of puberty. Age, the degree of developmental delay, the severity of any associated systemic conditions, and the degree of sleep disturbance all strongly influence maladaptive behaviors. Individuals also exhibit a lack of respect for personal space and mood swings during conversations.

[0224] SMS patients share many characteristics with PWS patients. These include: (1) reduced fetal activity; (2) hypotonia; (3) feeding difficulties in early infancy; (4) short stature; (5) early-onset obesity, which may include overeating; (6) developmental delay; (7) intellectual disability; (8) irritability; (9) aggressive behavior; (10) self-harm; (11) excessive sleepiness in infancy and similar sleep disorders in older children and adults; (12) frequent ear infections; (13) scoliosis; and (14) strabismus. Although the underlying genetic basis of these conditions is very different, the presentation and natural history of the diseases are very similar.

[0225] Solid oral dosage forms: pharmaceutical preparations designed for oral administration, including capsules and tablets.

[0226] Subjects: refers to animals, including mammals such as humans.

[0227] Sulfonylurea receptor: K ATP The channel is responsible for sulfonylureas and other K+. ATP Channel antagonists, diazoxide, and other K+ ATP Components involved in channel agonist interactions.

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

[0229] Thermoproduction: The physiological process of generating heat in the body.

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

[0231] Treatment: refers to any means by which the symptoms of a condition, ailment, disease, or other indication are improved or otherwise beneficially changed.

[0232] Triglycerides: Storage fats in animal and human adipose tissue, mainly composed of glycerides of saturated fatty acids.

[0233] Type 1 diabetes: a chronic condition in which the pancreas produces little or no insulin due to the destruction of beta cells.

[0234] Uncoupling proteins: a family of proteins that allow oxidation to occur in mitochondria without the phosphorylation that usually accompanies ATP production.

[0235] Visceral fat: mainly found in subcutaneous fat and adipose tissue beneath the muscle layer in the human body. Attached Figure Description

[0236] Figure 1 The changes in overeating scores of all participants in the PC025 clinical trial were summarized.

[0237] Figure 2 The percentage change in lean body mass was summarized for all subjects who participated in the PC025 clinical study.

[0238] Figure 3 The percentage change in body fat mass was summarized for all subjects who participated in the PC025 clinical study.

[0239] Figure 4 The percentage change in lean body mass / fat mass ratio was summarized for all subjects participating in the PC025 clinical study. Detailed Implementation

[0240] This article provides specific K ATP A pharmaceutical formulation of a channel opener, wherein the pharmaceutical formulation, when administered to a subject, achieves novel pharmacodynamic, pharmacokinetic, therapeutic, physiological, and metabolic outcomes. Specific K-type drugs are also provided. ATP Drug formulations, administration methods, and delivery methods of channel openers (optionally combined with growth hormone) achieve therapeutic outcomes while reducing the incidence of adverse effects.

[0241] Specifically, pharmaceutical formulations prepared for oral administration exhibit advantageous properties, including: improved absorption among treated patients, consistent pharmacokinetic and pharmacodynamic responses, improved patient compliance, and enhanced product safety characteristics, such as by reducing the incidence of serious adverse effects. Methods for treating metabolic and other diseases in humans and animals are also provided, the methods being achieved by administering the formulation.

[0242] Compounds of formulas II and III, IV and V, and VI and VII, such as diazine (shown below), can be proton tautomers. Proton tautomers are isomers that differ from one another only in the positions of the hydrogen atoms and the double bond. The hydrogen atoms and the double bond change positions between the carbon atom and a heteroatom, such as N. Therefore, when the nitrogen substituent is hydrogen, the two isomeric chemical structures can be used interchangeably.

[0243]

[0244] Specific K that can be used in the formulations of this invention ATP Channel openers include any of those from Formulas I to VII. Exemplary such compounds include diazoxide, BPDZ62, BPDZ73, NN414, and BPDZ154 (see, for example, Schou et al., Bioorg. Med. Chem., 13, 141-155 (2005)). Compound BPDZ154 is also an effective K+ kinase inhibitor in patients with hyperinsulinemia and patients with pancreatic insulinoma. ATP Channel activators. The synthesis of BPDZ compounds is provided in Cosgrove et al., J. Clin. Endocrinol. Metab., 87, 4860-4868 (2002).

[0245] Analogs of diazine include 3-isopropylamino-7-methoxy-4H-1,2,4,-benzothiadiazine 1,1-dioxide, which is a selective Kir6.2 / SUR1 channel opener (see Dabrowski et al., Diabetes, 51, 1896-1906 (2002)). This includes 2-alkyl-substituted diazines (see, for example, Ouedraogo et al., Biol. Chem., 383, 1759-1768 (2002)); these channel openers exhibit reduced insulin-releasing activity and increased activity in vascular smooth muscle tissue. Furthermore, 2-alkyl-substituted diazines are generally not used as conventional potassium channel activators, but instead show activity as Ca2+ channel activators. 2+ The potential of blockers.

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

[0247]

[0248] At position 3 of the molecule (labeled as R below) 3Diazine analogs with different alkyl substituents are described in Bertolino et al., Receptors and Channels, 1, 267-278 (1993).

[0249]

[0250] 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).

[0251] 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).

[0252] 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).

[0253] K can be determined by combining experiments. ATP The ability of channel openers to bind SUR1, SUR2A, and SUR2B. See, for example, Schwanstecher et al., EMBO J., 17, 5529-5535 (1998).

[0254] The preparation of SUR1 and SUR2A chimeras, as described by Babenko et al., allows for comparison of the pharmacological characteristics (i.e., sulfonyl sensitivity and responsiveness to diazonium or other potassium channel openers) of SUR1 / Kir6.2 and SUR2A / Kir6.2 potassium channels. See Babenko et al., J. Biol. Chem., 275(2), 717-720 (2000). Sulfonylurea receptors and inward rectifier K +The cloning of the channel is described by Isomoto et al., J. Biol. Chem., 271(40), 24321-24324 (1996); D'hahan et al., PNAS, 96(21), 12162-12167 (1999).

[0255] The differences between the human SUR1 gene and the human SUR2 gene are described and illustrated in Aguilar-Bryan et al., Physiological Review, 78(1), 227-245 (1998).

[0256] "Halogen" and "halogen" refer to all halogens, namely chlorine (Cl), fluorine (F), bromine (Br), or iodine (I).

[0257] "Hydroxyl" and "hydroxyl" refer to the -OH group.

[0258] "Substituted oxygen group" refers to the -OR group. f , where R f It is an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, an aralkyl group, a substituted aralkyl group, a cycloalkyl group, a substituted cycloalkyl group, a heterocyclic group, or a substituted heterocyclic group.

[0259] "Substituted thiols" 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, heterocyclic, or substituted heterocyclic.

[0260] "Alkyl" refers to an alkane-derived group containing 1 to 10, preferably 1 to 6, carbon atoms. Alkyl groups include straight-chain alkyl groups, branched alkyl groups, and cycloalkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc. Straight-chain or branched alkyl groups contain 1 to 10, preferably 1 to 6, more preferably 1 to 4, and even more preferably 1 to 2 carbon atoms. Alkyl groups are attached at any available point to produce stable compounds.

[0261] "Substituted alkyl" refers to an alkyl group independently substituted by one or more, such as one, two, or three groups or substituents, such as halogenated, hydroxyl, optionally substituted alkoxy, optionally substituted alkylthio, alkylsulfinyl, alkylsulfonyl, optionally substituted amino, optionally substituted amide, amidine, optionally alkyl-substituted urea, optionally alkyl-substituted aminosulfonyl, alkylsulfonylamino, carboxyl, heterocyclic, substituted heterocyclic, nitro, cyano, thiol, sulfonylamino, etc., wherein the alkyl group is connected at any available point to produce a stable compound. Specifically, "fluorine-substituted" refers to substitution by one or more, such as one, two, or three fluorine atoms. "Optional fluorine-substituted" means that the substitution, if present, is fluorine.

[0262] "Lower alkyl" refers to alkyl groups having 1 to 6 carbon atoms.

[0263] "Substituted lower alkyl" is a lower alkyl group that is replaced by one or more, such as one, two or three groups or substituents as defined above, said alkyl group being connected at any available point to produce a stable compound.

[0264] "Cycloalkyl" refers to a saturated or unsaturated, non-aromatic monocyclic, bicyclic, or tricyclic carbocyclic system with 3 to 8, more preferably 3 to 6, ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, etc. "Cycloalkylene" is a divalent cycloalkyl group.

[0265] "Alkoxy" indicates the -OR group. f , where R f It is a lower alkyl group.

[0266] "Substituted alkoxy" indicates the group -OR f ', where R f ' is a substituted lower alkyl group.

[0267] "Alkylthio" or "thioalkoxy" refers to the group -SR, where R is a lower alkyl group.

[0268] "Substituted alkylthio" or "Substituted thioalkoxy" refers to the group -SR, where R is a substituted lower alkyl group.

[0269] “Sulinate” represents the group -S(O)-.

[0270] “Sulfoyl” represents the group -S(O)2-.

[0271] "Substituted sulfinyl" represents the group -S(O)-R, where R is a lower alkyl group, a substituted lower alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a cycloalkyl group, a substituted cycloalkyl group, a heterocyclic group, a substituted heterocyclic group, a heterocyclic alkyl group, a substituted heterocyclic alkyl group, an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, a heteroaryl alkyl group, a substituted heteroaryl alkyl group, an aralkyl group, or a substituted aralkyl group.

[0272] "Substituted sulfonyl" represents the group -S(O)2-R, where R is a lower alkyl group, a substituted lower alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a cycloalkyl group, a substituted cycloalkyl group, a heterocyclic group, a substituted heterocyclic group, a heterocyclic alkyl group, a substituted heterocyclic alkyl group, an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, a heteroaryl alkyl group, a substituted heteroaryl alkyl group, an aryl group, or a substituted aryl alkyl group.

[0273] “Sulfoamide” represents the group -NRS(O)2-, where R is hydrogen or a lower alkyl group.

[0274] "Substituted sulfonylamino" indicates the group -NR a S(O)2-R b , where R a It is hydrogen or a lower alkyl group and R b It is a lower alkyl group, a substituted lower alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a heterocyclic group, a substituted heterocyclic group, an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, a heteroaryl group, a substituted heteroaryl group, a aryl group, a substituted heteroaryl group, an aryl group, or a substituted aryl group.

[0275] "Amino" or "amine" indicates the group -NH2. "Divalent amine" indicates the group -NH-. "Substituted divalent amine" indicates the group -NR-, where R is a lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl, substituted acyl, sulfonyl, or substituted sulfonyl.

[0276] "Substituted amino" or "substituted amine" indicates the group -NR i R j , where R i and R j Independently, it is hydrogen, a lower alkyl group, a substituted lower alkyl group, an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, an acyl group, a substituted acyl group, a sulfonyl group, a substituted sulfonyl group, or a cycloalkyl group; however, the prerequisite is that R... i and R j At least one of them is not hydrogen. R i R j Combining with nitrogen can form optionally substituted heterocyclic or heteroaromatic rings.

[0277] "alkylsulfinyl" indicates the group -S(O)R p, where R p It is an alkyl group that is optionally substituted.

[0278] "alkylsulfonyl" indicates the group -S(O)2R p , where R p It is an alkyl group that is optionally substituted.

[0279] "alkylsulfonylamino" indicates the group -NR q S(O)2R p , where R p It is an optionally substituted alkyl group, and R q It is hydrogen or a lower alkyl group.

[0280] Contains K ATP The pharmaceutical formulation of the channel opener comprises a free base of the drug or a salt of the drug. Such a salt may have one or more of the following characteristics: (1) stability in solution during synthesis and formulation; (2) stability in the solid state; (3) compatibility with excipients used in the manufacture of tablet formulations; (4) quantitative production of K+ upon exposure to simulated or actual gastric and duodenal conditions. ATP (5) Channel opener; (6) Releases K from sufficiently small particles that are easily soluble and absorbed. ATP (6) Channel openers; (7) when incorporated into a pharmaceutical formulation, providing greater than 80% absorption of the administered dose; ATP Compared to free bases, channel openers do not pose an increased toxicological risk; (8) they can be formulated into acceptable pharmaceutical preparations for the treatment of obesity and other diseases in humans; (9) they can be used as a base for pharmaceutical products and are FDA-approved; (10) they can be recrystallized to improve purity; (11) they can be used to form K ATP The channel opener is a eutectic of two or more salts; (12) has limited hygroscopicity to improve stability; or (13) the conditions for the synthesis and crystallization of the salt can be altered so that different crystal structures (polymorphs) can be controlled in the synthesis of the salt.

[0281] K ATP Channel openers can be formulated as pharmaceutically acceptable salts. Pharmaceutically acceptable salts are those that are non-toxic at their dosage and concentration. Preparing such salts can facilitate pharmacological use by altering the physical properties of the compound without impairing its physiological effects. Useful modifications to physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate administration of lower effective doses of the drug.

[0282] Pharmaceutically acceptable salts include acid addition salts, such as those containing sulfate, chloride, hydrochloride, fumarate, maleic acid, phosphate, aminosulfonate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylaminosulfonate, and quinic acid. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, aminosulfonic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylaminosulfonic acid, fumarate, and quinic acid.

[0283] Pharmaceutically acceptable salts, when containing acidic functional groups such as carboxylic acids or phenols, 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, for example... Remington Pharmacy Remington's Pharmaceutical Sciences) , 19th edition, Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995. Such salts can be prepared using appropriate corresponding bases.

[0284] Pharmaceutically acceptable salts can be prepared, for example, by dissolving the free base form of a compound in a suitable solvent, such as an aqueous solution containing a suitable acid or an aqueous alcoholic solution, and then separating the solution by evaporation. In another embodiment, the salt is prepared by reacting the free base and the acid in an organic solvent.

[0285] Pharmaceutically acceptable salts of different compounds can exist as complexes. Examples of complexes include 8-chlorotheophylline complexes (similar to, for example, dimenhydrinate: diphenhydramine 8-chlorotheophylline (1:1) complex; dramamine)) and various cyclodextrin inclusion complexes.

[0286] K ATPThe specific salts of channel openers and diazoxides may include, but are not limited to, acetates, acetone compounds, acetyl groups, adipates, aspartate, benzenesulfonates, diacetates, hydrogen tartrate, bromides, butanol salts, butyrates, calcium salts, camphor sulfonates, hexanoates, carbonates, citrates, cyclopentylpropionate, decanoates, diacetates, diglucamine salts, dinitrates, dipotassium salts, dipropionates, disodium salts, disulfides, ethanedisulfonates, heptanoates, etolates, etocarbonates, ethylsuccinate, trans-butenedioic acid, furoate, gluconate, gluconate, hexacetonide, hippurate, hexanoate, hydrobromide, hydrochloride, hydroxyethylsulfonate, and emulsions. Uromates, malates, maleate, meglumine salts, methyl bromide, methyl sulfates, methyl diatrizoate, sodium formyl ester (nafate), naphthalene sulfonate, nitrates, oleates, palmitates, dihydroxynaphthalate, phenylpropionate, phosphates, tervapotranolate, sulfonated divinylbenzene-vinylbenzene copolymer (polistirex), polygalacturonic acid urate, propionate, propionate, glycosides, sodium glycinate, sodium phosphate, sodium succinate, stearates, succinate, sulfates, sulfonates, sulfosalicylate, tartrates, terbuate, p-phthalates, terephthalate, toluene sulfonate, trifluoroacetate, trihydrate, trisilicate, tromethamine, valerate, sine, etc.

[0287] The formulations presented herein exhibit some or all of the following characteristics: (1) they remain stable at ambient temperature for at least one year; (2) they offer the convenience of oral administration; (3) they promote patient adherence to administration; (4) at the time of administration, they consistently promote high levels of absorption of the active pharmaceutical ingredient; and (5) when administered orally once or twice daily, they allow K... ATP The channel opener is released over a sustained period of time to allow K to... ATP The circulating concentration of the channel opener or its metabolically active metabolite does not decrease below the therapeutically effective concentration; (6) they achieve these results independently of the pH of the gastrointestinal tract of the individual receiving the treatment; and (7) they delay release until the stomach has passed through or is nearly passed through.

[0288] Formulations designed for oral administration can be provided, for example, as capsules or tablets. Capsule or tablet formulations include many distinguishing components. One such component is an ingredient that enhances K... ATP The absorption components of a channel opener. Another type maintains drug release for more than 2 hours. A third type delays significant drug release until gastric passage is complete.

[0289] The formulations disclosed in this article exhibit improved K compared to previous formulations of these drugs. 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.

[0290] 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.

[0291] Delay K ATPThe release of the channel opener from the formulation until gastric passage is complete is achieved in the formulations provided herein through any of several mechanisms. A pH-sensitive polymer or copolymer is used, which acts as an effective barrier to the release of the active agent at pH 3.0 or lower when applied around the drug matrix and is unstable at pH 5.5 and above. This provides control over the release of the active compound in the stomach, but allows rapid release once the formulation has been passed into the small intestine. Alternatives to pH-sensitive polymers or copolymers are non-water-soluble polymers or copolymers. The degree of resistance to release in the gastric environment can be controlled by coating with a blend of a non-water-soluble polymer and a water-soluble polymer. In this approach, neither of the blended polymers or copolymers is pH-sensitive. An example of a pH-sensitive copolymer is Eudragit methacrylic acid copolymer, including Eudragit L100, S100, or L100-55 solids, L30D-55 or FS 30D dispersions, or L12,5 or S12,5 organic solutions.

[0292] Delayed-release polymers can be applied to tablets via spray coating (as a film) or compression coating. If capsules are used, one or more polymers can be applied to the surface of the capsule or to particles of the drug, which can then be encapsulated in a capsule or gel. If the capsule is coated, it will resist disintegration until after gastric passage. If the particles are coated, the capsule can disintegrate in the stomach, but little or no drug will be released until the free particles have completed gastric passage. Ultimately, osmotic pump systems using, for example, swollen hydrogels can be used to delay drug release in the stomach. The swollen hydrogel absorbs water after administration. The swelling of the gel causes the drug to be displaced from the system for absorption. The timing and rate of drug release depend on the gel used and the rate at which water reaches the gel, which can be controlled by the size of the opening in the system for allowing fluid entry. See the online article on drug delivery technologies, Dong et al., “For Controlled Release of Non-Aqueous Liquid Formulations”. SOFTCAP TM ( SOFTCAP TM for Controlled Release of Non-Aqueous Liquid Formulations)”.

[0293] Therefore, delay K ATPThe release of the channel opener from the formulation of the present invention until gastric passage is complete is achieved in the formulation provided herein by any of several mechanisms, including but not limited to: (a) a pH-sensitive polymer or copolymer applied as a compression coating on a tablet; (b) a pH-sensitive polymer or copolymer applied as a 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; or (j) using a system controlled by an ion exchange resin; or (k) a combination of these methods, wherein the pH-sensitive polymer or copolymer is resistant to degradation under acidic conditions.

[0294] Formulations designed for once-daily (every 24 hours) administration are available. These may contain 25 mg to 500 mg of potassium. ATP Channel openers. Formulations intended for twice-daily (every 24 hours) administration are also provided. These may contain 25 mg to 250 mg of potassium. ATP Channel opening agent.

[0295] The formulations described herein exhibit improved safety of the administered pharmaceutical products. This improvement in safety occurs through at least two mechanisms. First, delaying the release of the active drug until the stomach has completely passed reduces the incidence of various gastrointestinal adverse side effects, including nausea, vomiting, indigestion, abdominal pain, diarrhea, and intestinal obstruction. Second, by maintaining the release of the active drug for 2 hours or longer, up to 24 hours, peak drug levels are lower than those observed at the same administered dose when using any oral formulation without sustained or controlled release. This reduction in peak drug levels can contribute to a reduction in adverse effects that are partly or entirely determined by peak drug levels. These adverse effects include: fluid retention with associated decreases in sodium, chloride, and uric acid excretion; edema; hyperglycemia and progression to ketoacidosis; cataracts and the possibility of nonketotic hyperosmolar coma; headache; tachycardia; and palpitations.

[0296] This article also provides K ATP A controlled-release formulation of a channel opener, the formulation having one characteristic from each of the ADs shown in Table 1.

[0297] Table 1: Characteristics and Properties of Controlled-Release Formulations

[0298] A. Unit format: tablets or capsules

[0299] B. Dosage / unit: 10mg-100mg

[0300] 100mg-200mg

[0301] 200mg-300mg

[0302] 300mg-500mg

[0303] 500mg-2000mg

[0304] C. Administer once daily (24 hours).

[0305] Twice a day (24 hours)

[0306] D. Release time: 2-4 hours

[0307] 4 hours - 8 hours

[0308] 8 hours - 24 hours

[0309] For example, a controlled-release composition may contain 25 mg to 100 mg of potassium. ATP Tablets of channel openers, administered once daily to achieve a controlled release time of 2-4 hours. All of these formulations may further include features that substantially delay the release of the active pharmaceutical ingredient until after gastric passage is complete.

[0310] In addition, any of the formulations from Table 1 may include increasing K ATP At least one characteristic of the solubility or absorption of the channel opener.

[0311] The controlled-release formulations described herein contain active compounds (e.g., K). ATP A channel opener (optionally in combination with growth hormone) and a matrix comprising a gelling agent that swells upon contact with an aqueous fluid. One or more active compounds encapsulated within the gel are slowly released into the body upon gel dissolution. The one or more active compounds may be uniformly dispersed within the matrix or may be present in the matrix as drug pouches. For example, the drug may be formulated as small particles dispersed within the matrix. Furthermore, the drug particles may also include the matrix, thus providing a primary matrix and a secondary matrix, as described in Rhodes' U.S. Patent No. 4,880,830.

[0312] The gelling agent is preferably a polymeric material, which may include, for example, any pharmaceutically acceptable water-soluble or water-insoluble slow-release polymer, such as xanthan gum, gelatin, cellulose ether, gum arabic, locust bean gum, guar gum, carboxyvinyl polymer, agar, gum arabic, tragacanth gum, magnesium aluminum silicate, sodium alginate or alginic acid, polyvinylpyrrolidone, polyvinyl alcohol, or film-forming polymers such as methylcellulose (MC), carboxymethylcellulose (CMC), hydroxypropyl methylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), ethyl cellulose (EC), acrylic resin, or mixtures thereof (see, for example, U.S. Patent No. 5,415,871).

[0313] The gelling agent of the matrix can also be a heterogeneous dispersion containing heteropolysaccharide and homopolysaccharide components, producing a rapidly forming and rigid gel, as described in U.S. Patent No. 5,399,359. The matrix may also include crosslinking agents, such as monovalent or polyvalent metal cations, to further increase rigidity and reduce matrix solubility, thereby further slowing drug release. The amount of crosslinking agent added can be determined using methods conventional to those skilled in the art.

[0314] The matrix of the controlled-release composition may also include one or more pharmaceutically acceptable excipients recognized by those skilled in the art, i.e., formulation excipients. Such excipients include, for example, binders: polyvinylpyrrolidone, gelatin, starch paste, microcrystalline cellulose; diluents (or fillers): starch, sucrose, dextrose, lactose, fructose, xylitol, sorbitol, sodium chloride, dextrin, calcium phosphate, calcium sulfate; and lubricants: stearic acid, magnesium stearate, calcium stearate, Precirol TM ; and flow aids: such as talc or colloidal silica.

[0315] The matrix of the controlled-release composition may also include a hydrophobic material that slows down the hydration of the gelling agent without compromising the hydrophilicity of the matrix, as described in U.S. Patent No. 5,399,359. The hydrophobic polymer may include, for example, alkyl cellulose, such as ethyl cellulose, other hydrophobic cellulose materials, polymers or copolymers derived from acrylates or methacrylates, copolymers of acrylates and methacrylates, zein, waxes, shellac, hydrogenated vegetable oils, waxes and waxy substances such as carnauba wax, cetearyl wax, candelilla wax, cocoa butter, cetearyl alcohol, beeswax, ceresin, paraffin wax, myristyl alcohol, stearyl alcohol, cetyl alcohol and stearic acid, and any other pharmaceutically acceptable hydrophobic material known to those skilled in the art.

[0316] The amount of hydrophobic material incorporated into the controlled-release composition is the amount that effectively slows down the hydration of the gelling agent without disrupting the hydrophilic matrix formed upon exposure to ambient fluids. In some preferred embodiments, the hydrophobic material is included in the matrix in an amount of about 1% to about 20% by weight, replacing a corresponding amount of formulation excipients. The solvent used for the hydrophobic material can be an aqueous solvent or an organic solvent, or a mixture thereof.

[0317] Examples of commercially available alkyl cellulose are (Aqueous dispersion of ethyl cellulose available from FMC) and (Aqueous dispersions of ethyl cellulose available from Colorcon). Examples of commercially available acrylic polymers suitable for use as hydrophobic materials include... RS and RL (polymers of acrylates and methacrylates with low content (e.g., 1:20 or 1:40) of quaternary ammonium compounds).

[0318] Controlled-release compositions can also be coated to delay liquid access to the active compound and / or delay the release of the active compound via membrane coating. The membrane coating provides resistance to gastric acid and enteric coagulation by resisting rapid dissolution of the composition in the digestive tract. The membrane coating typically comprises about 5% to 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 membrane coatings, as are known in the art, and include gels, waxes, fats, emulsifiers, combinations of fats and emulsifiers, polymers, starches, etc.

[0319] Polymers and copolymers can be used as film coatings. Solution coating and dispersion coating can be used to coat individual active compounds or combinations of active compounds with a matrix. Coating is preferably applied to a drug or a combination of drug and matrix as a solid core material, as is known in the art.

[0320] The coating solution may include polymers in both organic and aqueous solvent systems, and typically also includes one or more compounds as plasticizers. Polymers that can be used in coating compositions include, for example, methylcellulose (…). A; Dow Chemical Co., Ltd., hydroxypropyl methylcellulose with a molecular weight of 1,000 to 4,000,000 ( E; Dow Chemical Company or Shin Etsu Corporation offers hydroxypropyl cellulose, ethyl cellulose, cellulose acetate, cellulose triacetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitic acid (Eastman Kodak), and carboxymethyl ethyl cellulose with molecular weights ranging from 2,000 to 2,000,000. Hydroxypropyl methylcellulose phthalate, ethylcellulose, methylcellulose and 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; 30% solids aqueous dispersion, Eudragit L30D), poly(meth)acrylate: poly(ethyl acrylate-methyl methacrylate) (2:1), 30% solids aqueous dispersion of Eudragit NE30D, polyaminomethacrylate Eudragit E100, poly(trimethylamine ethyl methacrylate chloride) quaternary ammonium methacrylate copolymer, Eudragit RL30D and Eudragit RS30D, carboxyvinyl polymers, polyvinyl alcohol, dextran, stearin, mannan, and xanthan gum.

[0321] Aqueous polymer dispersions include Eudragit L30D and RS / RL30D, as well as NE30D, Aquacoat ethyl cellulose, Surelease ethyl cellulose, EC N-10F ethyl cellulose, Aquateric cellulose acetate, Coateric poly(vinyl acetate phthalate), and Aqacoat hydroxypropyl methyl cellulose acetate succinate. Most of these dispersions are latex, pseudo-latex powders, or micronized powder media.

[0322] Plasticizers can be included in the coating to improve the elasticity and stability of the polymer film and to prevent changes in polymer permeability during long-term storage. Such changes may affect the drug release rate. Suitable conventional plasticizers include, for example, diethyl phthalate, triacetin, monoacetylated glycerol, tributyl acetylated citrate, triethyl acetylated citrate, castor oil, citrate, dibutyl phthalate, dibutyl sebacate, diethyl oxalate, diethyl malate, diethyl fumarate, diethyl phthalate, diethyl succinate, diethyl malonate, diethyl tartrate, dimethyl phthalate, glycerol, glycerol, triacetin, glyceryl triacetate, mineral oil and lanolin alcohol, petrolatum and lanolin alcohol, phthalates, polyethylene glycol, propylene glycol, rapeseed oil, sesame oil, triacetin, tributyl citrate, triethyl citrate, and triethyl acetylated citrate, or any two or more mixtures of the above substances. Plasticizers that can be used for water-based coatings include, for example, propylene glycol, polyethylene glycol (PEG 400), glyceryl triacetate, polysorbate 80, triethyl citrate, and diethyl d-tartrate.

[0323] A coating solution comprising a mixture of hydroxypropyl methylcellulose as a polymer and aqueous ethyl cellulose (e.g., Aquacoat) and dibutyl sebacate as a plasticizer can be used to coat microparticles. (Aquacoat is an aqueous polymer dispersion of ethyl cellulose and contains sodium dodecyl sulfate and cetyl alcohol). Preferably, the plasticizer comprises about 1%-2% of the composition.

[0324] In addition to polymers, the coating layer may also include excipients to facilitate the formulation of the coating solution. Such excipients may include lubricants or wetting agents. Suitable lubricants used as excipients for film coating include, for example, talc, calcium stearate, colloidal silica, glycerin, magnesium stearate, mineral oil, polyethylene glycol, and zinc stearate, aluminum stearate, or mixtures of any two or more of the above substances. Suitable wetting agents include, for example, sodium lauryl sulfate, gum arabic, benzalkonium chloride, polysitropyl emulsifying wax, cetearyl alcohol, cetyl alcohol, cholesterol, diethanolamine, sodium docusate, sodium stearate, emulsifying wax, glyceryl monostearate, hydroxypropyl cellulose, lanolin alcohol, lecithin, mineral oil, monoethanolamine, poloxamer, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearate, propylene glycol alginate, sorbitan esters, stearyl alcohol, and triethanolamine, or any two or more mixtures of the above substances.

[0325] The specified tablet or capsule formulations in Table 1 may include those used with obesity treatment drugs (except K). ATPCommon formulations other than channel openers. Medications that can be used to treat obesity include, but are not limited to, sibutramine hydrochloride (5 mg / unit to 30 mg / unit), orlistat (50 mg / unit to 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), rimonaban (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 daily. For twice-daily dosing, K ATP The amount of a channel opener is half the amount included in the once-daily formulation, and co-formulated obesity treatments refer to half the quantification. Alternative obesity treatments may include: selective serotonin 2c receptor agonists, dopamine antagonists, cannabinoid-1 receptor antagonists, leptin analogs, leptin transporter and / or leptin receptor promoters, neuropeptide Y and guinea pig-related peptide antagonists, pro-melanocortin and cocaine and amphetamine transcription promoters, melanocyte-stimulating hormone analogs, melanocortin-4 receptor agonists, and agents affecting insulin metabolism / activity, including protein tyrosine phosphatase-1B inhibitors, peroxisome proliferator-activated receptor-receptor antagonists, short-acting bromocriptine (ergoset), somatostatin agonists (octreotide), and adiponectin; gastrointestinal neural pathway agents, including those that increase cholecystokinin activity. Sexual activity, those that increase glucagon-like peptide-1 activity (exenatide 4, liraglutide, dipeptidyl peptidase IV inhibitors), and those that increase protein YY3-36 activity and decrease ghrelin activity; as well as amylin analogs, agents that can increase resting metabolic rate ("selective" β-3 stimulators / agonists, uncoupling protein homologs, and thyroid receptor agonists), melanin-concentrating hormone antagonists, phytosterol analogs, amylase inhibitors, growth hormone fragments, synthetic analogs of dehydroepiandrosterone sulfate, adipocyte type 1 11B hydroxysteroid dehydrogenase activity antagonists, corticotropin-releasing hormone agonists, fatty acid synthesis inhibitors, carboxypeptidase inhibitors, indanone / indanol, aminosterols, and other gastrointestinal lipase inhibitors.

[0326] 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.

[0327] 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.

[0328] The tablet or capsule formulations specified in Table 1 may include co-preparations with medications for treating depression. Medications for treating depression that may 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), and amitriptyline hydrochloride (10 mg / unit). These preparations are preferably used once daily. For twice-daily dosing, K... ATP The amount of the channel opener is preferably half the amount included in the once-daily formulation, and for co-formulated antidepressant medications, it refers to half the quantification.

[0329] The specified tablet or capsule formulations in Table 1 may include co-formulations with antihypertensive medications. Suitable antihypertensive medications include, but are not limited to, enalapril (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 tert-butylamine (4 mg / unit to 8 mg / unit), and ramipril (1...).25 mg / unit to 20 mg / unit, trandolapril (1 mg / unit to 8 mg / unit), fosinopril sodium (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 cilexetil 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), betasolol hydrochloride (10 mg / unit to 40 mg / unit), acebutolol hydrochloride (200 mg / unit to 800 mg / unit). The following are listed: pindolol (5 mg / unit to 20 mg / unit), bisoprolol (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), and prazosin hydrochloride (2 mg / unit to 100 mg / unit).5 mg / unit to 10 mg / unit), or alfuzosin hydrochloride (10 mg / unit to 20 mg / unit). These formulations are preferably used once daily. For twice-daily administration, K... ATP The amount of the channel opener is preferably half the amount included in the once-daily formulation, and for co-formulated hypertension treatment drugs, it refers to half the quantitative amount.

[0330] The specified tablet or capsule formulations in Table 1 may include co-preparations with diuretics for the treatment of edema. Diuretics that may 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), and ethacrynic acid. Sodium ethacrylate (all in doses of 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 preparations are preferably used once daily. For twice-daily administration, K ATP The amount of the channel opener is preferably half the amount included in the once-daily formulation, and the co-formulated diuretic refers to half the quantitative amount.

[0331] The tablet or capsule formulations specified in Table 1 may include co-preparations with medications for treating inflammation or pain. Medications that may be used for treating 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), acetaminophen (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), and flurbiprofen sodium. Sodium or flurbiprofen (both in doses of 50 mg / unit to 200 mg / unit), or any of these in combination with a steroid or aspirin. These preparations are preferably used once daily. For twice-daily dosing, K ATP The amount of the channel opener is preferably half the amount included in the once-daily formulation, and the co-formulated diuretic refers to half the quantitative amount.

[0332] The specified tablet or capsule formulations in Table 1 may include co-preparations with the following medications: medications for treating obesity-related comorbidities, including those specified above for treating diabetes, cholesterol, depression, hypertension, and edema; or medications for treating atherosclerosis, osteoarthritis, herniated discs, knee and hip joint degeneration, breast cancer, endometrial cancer, cervical cancer, colon cancer, leukemia, prostate cancer, hyperlipidemia, asthma / reactive airway disease, gallstones, GERD, obstructive sleep apnea, obesity hypoventilation syndrome, recurrent abdominal hernia, menstrual disorders, and infertility.

[0333] The specified tablet or capsule formulations in Table 1 may include co-preparations with antipsychotic drugs, said combinations being used to treat psychotic conditions and to treat or prevent weight gain, dyslipidemia, or impaired glucose tolerance in the treated individual. Drugs that may be used to treat various psychotic conditions include, but are not limited to, lithium or its salts (250 mg / unit to 2500 mg / unit), carbamazepine or its salts (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 co-preparations are preferably intended for once-daily administration. For twice-daily administration, K ATP The amount of the channel opener is preferably half the amount included in the once-daily formulation, and for co-formulated antipsychotics, it refers to half the quantification.

[0334] The specified tablet or capsule formulations in Table 1 may include co-formulations with drugs for the treatment or prevention of ischemia or reperfusion injury. Drugs that may be used for the treatment or prevention of ischemia 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, ACEA1021, GV150526, Eliprodil, Ifenprodil, Lubeluzole, Naloxone, Nalfemene, Citicoline, Acetyl-L-carnitine, Nifedipine, Resveratrol, Nitroketone derivatives, Clopidogrel, Dabigatram, Prasugrel, Troxoprodil, AGY-94806, or KAI-9803.

[0335] The drug was administered to obese or overweight subjects once or twice daily to produce sufficient levels of K to induce weight loss. ATP A formulation of a channel opener at circulating concentrations. Weight loss occurs by preferentially reducing body fat. Additional weight loss may occur when the formulation is administered in combination with a low-calorie diet.

[0336] Provided K ATP A formulation of a channel opener, which is administered as a single dose to obese, overweight, or obesity-susceptible subjects, thereby inhibiting fasting insulin secretion or glucose-stimulated insulin secretion for approximately 24 hours or approximately 18 hours.

[0337] Provided K ATPA formulation of a channel opener, which is administered as a single dose to obese, overweight, or obesity-susceptible subjects, resulting in an increase in energy expenditure for approximately 24 hours or approximately 18 hours.

[0338] Provided K ATP A formulation of a channel opener, administered as a single dose to obese, overweight, or obesity-susceptible subjects, resulting in an increase in lipid β-oxidation for approximately 24 hours or approximately 18 hours.

[0339] Provided K ATP A formulation of a channel opener, which is administered as a single dose to obese, overweight, or obesity-susceptible overeating subjects, thereby suppressing overeating for approximately 24 hours or approximately 18 hours.

[0340] A formulation is provided that is administered to a subject once or twice daily (every 24 hours) to produce sufficient K+ to induce resting or improved insulin sensitivity in β-cells, or both. ATP The circulating concentration of the channel opener. Such improvements in β-cell resting and insulin sensitivity can contribute to the effective treatment of type 1 diabetes, type 2 diabetes, and prediabetes. Such improvements in β-cell resting and insulin sensitivity can contribute to the effective restoration of normal glucose tolerance in subjects with type 2 diabetes and prediabetes.

[0341] Various drugs 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 prone to obesity; (3) treatment of hyperinsulinemia or hyperinsulinemia; (4) treatment of hypoglycemia; (5) treatment of hyperlipidemia; (6) treatment of type II diabetes; (7) protection of pancreatic function in patients with type I diabetes; (8) treatment of metabolic syndrome (or syndrome X); (9) prevention of prediabetes from developing into diabetes; (10) correction of defects in insulin secretion and insulin sensitivity leading to prediabetes and type II diabetes; (11) treatment of polycystic ovary syndrome; (12) prevention of ischemia or reperfusion injury; (13) treatment of patients receiving antipsychotics. (14) To prevent weight gain, dyslipidemia, or impaired glucose tolerance in subjects receiving antipsychotic medication; and (15) To treat any disease in which hyperlipidemia, hyperinsulinemia, hyperinsulinemia, hyperlipidemia, overeating, or obesity are contributing factors to the severity or progression of the disease, including but not limited to Prader-Willi syndrome, Smith-Magilli syndrome, Flehrich syndrome, Cohen syndrome, peak syndrome, Alstrlem syndrome, Boyerson syndrome, Barbie II syndrome, type I, II, III, and IV hyperlipoproteinemia.

[0342] In one implementation, K ATP The channel opener is administered as a solid oral dose once every 24 hours to overweight or obese individuals, optionally in combination with growth hormone, to induce weight loss. In another embodiment, the individual (a) is not a patient with type 1 diabetes; (b) is not a patient with type 2 diabetes; (c) is not experiencing chronic, recurrent, or drug-induced hypoglycemia; (d) does not have metabolic syndrome; or (e) is not experiencing malignant hypertension.

[0343] In one implementation, K ATP The channel opener is administered twice daily (every 24 hours) as a solid oral dose to overweight or obese individuals, optionally in combination with growth hormone, to induce weight loss. This treatment may be the sole treatment for inducing weight loss. In another embodiment, the overweight or obese individual (a) does not have an insulin-secreting tumor; (b) does not have polycystic ovary syndrome; (c) is not a patient with type 1 diabetes; (d) is not a patient with type 2 diabetes; (e) does not have metabolic syndrome; (f) is not experiencing chronic, relapsing, or drug-induced hypoglycemia; (g) is not receiving haloperidol treatment for schizophrenia; or (h) is not experiencing malignant hypertension. In another embodiment, the overweight or obese adolescent (a) has not been diagnosed with type 1 or type 2 diabetes; (b) is not experiencing chronic, relapsing, or drug-induced hypoglycemia; or (c) has not been diagnosed with metabolic syndrome.

[0344] In another implementation scheme, K ATP The channel opener is administered three times every 24 hours to overweight or obese individuals as a solid oral dosage form, optionally in combination with growth hormone, to induce weight loss. This treatment may be the sole treatment for inducing weight loss. In another embodiment, the overweight or obese individual (a) does not have an insulin-secreting tumor; (b) does not have polycystic ovary syndrome; (c) is not a patient with type 1 diabetes; (d) is not a patient with type 2 diabetes; (e) does not have metabolic syndrome; or (f) is not experiencing chronic, recurrent, or drug-induced hypoglycemia.

[0345] In another implementation scheme, K ATP The channel opener is administered three times every 24 hours to overweight or obese adolescents as a solid oral dosage form, optionally in combination with growth hormone, to induce weight loss. This treatment may be the sole treatment for inducing weight loss. In another embodiment, the overweight or obese adolescent (a) is a patient with type I or type II diabetes; (b) is not experiencing chronic, relapsing, or drug-induced hypoglycemia; or (c) does not have metabolic syndrome.

[0346] In another implementation scheme, KATP The channel opener is administered three times every 24 hours to overweight or obese adults as a solid oral dosage form, optionally in combination with growth hormone to induce weight loss, provided that the adults (a) are not concurrently receiving glucagon injections, triiodothyronine, or furosemide; (b) are not receiving haloperidol treatment for schizophrenia; or (c) are not experiencing malignant hypertension.

[0347] In another implementation scheme, K ATP Channel openers are administered as solid oral dosage forms to overweight or obese individuals four times every 24 hours, optionally in combination with growth hormone, to induce weight loss.

[0348] In another implementation scheme, K ATP The channel opener is administered as a solid oral dosage form, given once, twice, three or four times every 24 hours, at a daily dose of 50 mg to 275 mg to overweight or obese individuals, optionally in combination with growth hormone, to induce weight loss. In another embodiment, the overweight or obese individual (a) is not a patient with type 1 diabetes; (b) is not a patient with type 2 diabetes; (c) does not have chronic, relapsing or drug-induced hypoglycemia; or (d) does not have metabolic syndrome.

[0349] In another implementation scheme, K ATP The channel opener is administered as a solid oral dosage form, given once, twice, three or four times every 24 hours, at a daily dose of 130 mg to 275 mg to overweight or obese individuals, optionally in combination with growth hormone, to induce weight loss. In another embodiment, the overweight or obese individual (a) is not a patient with type 1 diabetes; (b) is not a patient with type 2 diabetes; (c) does not have chronic, relapsing or drug-induced hypoglycemia; or (d) does not have metabolic syndrome.

[0350] In another implementation scheme, K ATP The channel opener, administered as a solid oral dosage form, is given once, twice, three times, or four times every 24 hours to overweight or obesity-prone individuals, optionally in combination with growth hormone, to maintain weight loss. This is because once a certain amount of weight loss has been achieved, maintaining the weight of the obese individual is preferred when the alternative is to regain weight. In another embodiment, the administered K... ATP The daily dose of the channel opener is 50 mg to 275 mg.

[0351] In other implementation schemes, K ATP Channel openers are administered as solid oral dosage forms to overweight, obese, or obesity-susceptible individuals, optionally in combination with growth hormone, to (a) increase energy expenditure; (b) increase β-oxidation of lipids; or (c) decrease circulating triglyceride concentrations.

[0352] In other embodiments, K is a solid oral dose. ATP Channel openers are administered to individuals in need on a long-term basis to induce a 25%, 50%, or 75% reduction in initial body fat.

[0353] In another implementation, the K of the solid oral dose ATP Channel openers are administered to individuals in need on a long-term basis, optionally in combination with growth hormone, to induce (a) preferential reduction of body fat; or (b) preferential reduction of visceral body fat.

[0354] In another embodiment, the K of the solid oral dose ATP Channel openers are administered to individuals once, twice, or three times every 24 hours at a daily dose of 50 mg to 275 mg on a long-term basis, optionally in combination with growth hormone, to (a) induce a 25%, 50%, or 75% reduction in initial body fat; (b) induce a preferential reduction in body fat; or (c) induce a preferential reduction in visceral fat.

[0355] In another implementation, the K of the solid oral dose ATP Channel openers are administered to individuals, optionally in combination with growth hormone, to induce preferential reduction of body fat and decrease of circulating triglycerides.

[0356] In another implementation, the K of the solid oral dose ATP Channel openers are used in combination with growth hormones.

[0357] In yet another embodiment, the solid oral dose of K ATP Channel openers are administered concurrently with growth hormone and one or more of the following optionally: sibutramine, orlistat, rimonaban, appetite suppressants, antidepressants, antiepileptic drugs, diuretics other than furosemide, and drugs that pass through a pathway different from K. ATP Channel openers cause weight loss through mechanisms different from those of K-channel drugs. ATP The mechanism of action of the channel opener is to induce weight loss, but it is not a drug such as metformin, furosemide, or triiodothyronine, or a blood pressure lowering agent, to induce weight loss and / or treat obesity-related comorbidities in overweight, obese, or obesity-susceptible individuals. In another embodiment, the overweight, obese, or obesity-susceptible individual (a) has type 1 diabetes; (b) does not have type 2 diabetes; (c) does not have chronic, relapsing, or drug-induced hypoglycemia; or (d) does not have metabolic syndrome.

[0358] In another implementation, the K of the solid oral dose ATPChannel openers are co-administered with growth hormone and optionally one or more of the following to overweight, obese, or obesity-predisposed individuals: antidepressants, blood pressure-lowering drugs, cholesterol-lowering drugs, HDL-enhancing drugs, anti-inflammatory agents that are not Cox-2 inhibitors, and drugs that lower circulating triglycerides, to induce weight loss and / or treat obesity-related comorbidities. In another embodiment, the overweight, obese, or obesity-predisposed individual (a) is not a patient with type 1 diabetes; (b) is not a patient with type 2 diabetes; (c) does not have chronic, relapsing, or drug-induced hypoglycemia; or (d) does not have metabolic syndrome.

[0359] In another implementation, the K of the solid oral dose ATP The channel opener is administered in combination with growth hormone and optionally one or more of the following: a blood pressure lowering agent, a cholesterol lowering agent, a HDL-enhancing agent, an anti-inflammatory agent that is not a Cox-2 inhibitor, or a circulating triglyceride lowering agent, to maintain weight and / or treat obesity-related comorbidities in overweight, obese, or obesity-susceptible individuals, since maintaining the weight of an obese individual is preferred once a certain amount of weight loss has been achieved, when the alternative is to regain weight. In another embodiment, the overweight, obese, or obesity-susceptible individual (a) is not a patient with type 1 diabetes; (b) is not a patient with type 2 diabetes; (c) does not have chronic, relapsing, or drug-induced hypoglycemia; or (d) does not have metabolic syndrome.

[0360] In another implementation scheme, K ATP The tablet formulation of the channel opener is intended for administration of a therapeutically effective dose of K to obese, overweight, or obesity-susceptible individuals who require its use to treat obesity. ATP Channel openers, to (a) provide β-cell rest; (b) treat type I or type II diabetes; or (c) prevent the development of diabetes.

[0361] In another implementation scheme, K ATP A solid oral dosage form or tablet formulation of a channel opener may be co-administered with growth hormone and optionally phentermine or its derivatives to obese adults or adolescents to induce weight loss and / or treat obesity and obesity-related comorbidities. In an additional embodiment, K ATP Solid oral dosage forms or tablet formulations of channel openers are co-administered with phentermine or its derivatives to obese adults or adolescents, optionally in combination with growth hormone, to treat metabolic syndrome in patients in need.

[0362] In another implementation, a dose of K ranging from 50 mg / day to 275 mg / day ATPPharmaceutically acceptable formulations of channel openers are co-administered with growth hormone and optionally one or more of phentermine or its derivatives at daily doses of 15 mg to 37.5 mg to overweight or obese individuals to induce weight loss, treat metabolic syndrome, or induce weight loss and treat obesity-related comorbidities. In another embodiment, a tablet formulation is co-administered with growth hormone and optionally one or more of phentermine or its derivatives to treat a patient with metabolic syndrome.

[0363] In another implementation scheme, K ATP A rapidly dissolving formulation of a channel opener, optionally combined with growth hormone, is used to deliver a therapeutically effective dose to patients in need.

[0364] In another implementation scheme, K ATP The channel opener is administered once every 24 hours to overweight or obese individuals at a dose of 125 mg to 275 mg, optionally in combination with growth hormone, who are not patients with type 2 diabetes and are not receiving treatment for nocturnal hypoglycemia.

[0365] In another implementation scheme, K ATP The channel opener is formulated into tablets or capsules for oral administration. The tablets or capsules may be co-formulated with metformin. In another embodiment, K... ATP The channel opener is formulated into an oral suspension, and in another embodiment, the oral suspension may be further encapsulated.

[0366] In another implementation scheme, K ATP Pharmaceutical salts of channel openers are formulated into tablets or capsules for oral administration, or as oral suspensions or oral solutions, or as encapsulated oral solutions. If the opener is diazoxide, then the salt is preferably not a sodium salt.

[0367] In another implementation scheme, K ATP Channel openers are formulated with hydrochlorothiazide, chlorothiazide, cyclothiazide, benzthiazide, methachlorthiazide, benzfluthiazide, hydrofluthiazide, trichlormethiazide, or porithiazide to form a pharmaceutical preparation suitable for oral administration.

[0368] When administered the formulations described herein to humans or animals, some or all of the following effects were observed: (1) decreased production of lipoprotein lipases in adipocytes; (2) enhanced lipolysis in adipocytes; (3) decreased expression of fatty acid synthases in adipocytes; (4) decreased activity of glyceraldehyde-3-phosphate dehydrogenase in adipocytes; (5) little or no new triglycerides were synthesized and stored in adipocytes; (6) increased expression of β3-adrenergic receptors (β3AR) and improved adrenergic function in adipocytes; (7) decreased insulin secretion from pancreatic β-cells stimulated by glucose; (8) decreased insulinemia; (9) increased blood glucose levels; (10) increased expression of uncoupling protein 1 in adipocytes; (11) white (12) Increased thermogenesis in brown adipose tissue; (13) Decreased plasma triglyceride concentration; (14) Decreased circulating leptin concentration; (15) Upregulation of insulin receptors; (16) Increased glucose uptake; (17) Decreased adipocyte proliferation; (18) Decreased adipocyte hypertrophy; (19) Decreased rate of preadipocyte to adipocyte conversion; (20) Decreased rate of overeating; (21) Increased protective effect against ischemia or reperfusion injury on the CNS, heart and other tissues; (22) Improved insulin sensitivity; (23) Increased CSF insulin concentration; (24) Increased circulating adiponectin concentration; (25) Decreased circulating triglyceride concentration; (26) Increased β-cell resting function; and / or (27) Increased leptin mass.

[0369] The threshold concentration of the present invention includes K produced by administration of a drug to an overweight or obese individual as an intravenous formulation, an immediately released oral formulation, a controlled-release formulation, a transdermal formulation, or an intranasal formulation. ATP Those circulating concentrations of channel openers (optionally in combination with growth hormone) that cause (1) measurable inhibition of fasting insulin levels; (2) relative to the level of K+ in use ATP Baseline measurements of the same individual prior to treatment with a channel opener showed that fasting insulin levels were suppressed by at least 20%; (3) relative to the level of K+ used in the treatment. ATP Baseline measurements of the same individual prior to treatment with a channel opener showed that fasting insulin levels were suppressed by at least 30%; (4) relative to the level of K+ used in the treatment. ATP Baseline measurements of the same individual prior to treatment with a channel opener showed that fasting insulin levels were suppressed by at least 40%; (5) 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 50%; (6) relative to those on K+. ATP Baseline measurements of the same individual prior to treatment with a channel opener showed that fasting insulin levels were suppressed by at least 60%; (7) relative to those on K-line therapy. 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.

[0370] 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.

[0371] The threshold effect of the present invention includes K produced 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.

[0372] 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.

[0373] 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.

[0374] Long-term administration of K to overweight or obese humans or animals ATPDrug formulations of channel openers (optionally in combination with growth hormone) cause significant and sustained weight loss, including some or all of the following effects: (1) preferential reduction of body fat; (2) reduction of more than 25% of initial body fat mass; (3) reduction of more than 50% of initial body fat mass; (4) reduction of more than 75% of initial body fat mass; (5) significant increase in resting energy expenditure; (6) increased oxidation of fat and fatty acids; (7) decreased blood pressure; (8) decreased production of lipoprotein lipases in adipocytes; (9) enhanced lipolysis in adipocytes; (10) decreased expression of fatty acid synthases in adipocytes; (11) decreased activity of glyceraldehyde-3-phosphate dehydrogenase in adipocytes; (12) little or no new triglyceride synthesis and storage by adipocytes; (13) enhanced expression of β3-adrenergic receptors (β3AR) and improved adrenergic function in adipocytes; (14) increased production of β-glucose in pancreatic β-cells. (15) Decreased insulin secretion stimulated by glucose; (16) Decreased insulinemia; (17) Increased blood glucose levels; (18) Increased expression of uncoupling protein 1 in adipocytes; (19) Increased thermogenesis in white and brown adipose tissue; (20) Decreased plasma triglyceride concentration; (21) Decreased circulating leptin concentration; (22) Upregulation of insulin receptors; (23) Increased glucose uptake; (24) Decreased adipocyte proliferation; (25) Decreased rate of preadipocyte to adipocyte transformation; (26) Decreased rate of overeating; (27) First, the most metabolically active adipose tissue (visceral tissue) was continuously reduced, followed by the less metabolically active adipose tissue; (28) Increased circulating adiponectin concentration; (29) Increased cerebrospinal fluid insulin levels; (30) Increased insulin mRNA and insulin content in pancreatic islets; (31) Increased insulin metabolic efficiency; or (32) Increased leptin mass.

[0375] Long-term administration of K to obese susceptible humans or animals, including individuals who have undergone various types of bariatric surgery. ATPPreparations of channel openers (optionally in combination with growth hormone) result in sustained weight maintenance, including some or all of the following effects: (1) increased resting energy expenditure; (2) increased oxidation of fats and fatty acids; (3) decreased blood pressure; (4) decreased production of lipoprotein lipases in adipocytes; (5) enhanced lipolysis in adipocytes; (6) decreased expression of fatty acid synthases in adipocytes; (7) decreased activity of glyceraldehyde-3-phosphate dehydrogenase in adipocytes; (8) little or no new triglyceride synthesis and storage by adipocytes; (9) enhanced expression of β3-adrenergic receptors (β3AR) and improved adrenergic function in adipocytes; (10) decreased insulin secretion from pancreatic β-cells stimulated by glucose; 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 proliferation; (20) Decreased adipocyte hypertrophy; (21) Decreased rate of preadipocyte to adipocyte conversion; and (22) Decreased rate of overeating; (23) Increased circulating adiponectin concentration; (24) Increased cerebrospinal fluid insulin levels; (25) Increased insulin mRNA and insulin content in pancreatic islets; or (26) Increased insulin metabolic efficiency.

[0376] Immediate or long-term administration of K to prediabetic or type 1 diabetic humans or animals ATPFormulations of channel openers (optionally in combination with growth hormone) can induce prevention of β-cell exhaustion, improvement of glycemic control, and prevention of prediabetes into diabetes, including some or all of the following effects: (1) increased resting energy expenditure; (2) increased oxidation of fats and fatty acids; (3) decreased blood pressure; (4) decreased production of lipoprotein lipases in adipocytes; (5) enhanced lipolysis in adipocytes; (6) decreased expression of fatty acid synthases in adipocytes; (7) decreased activity of glyceraldehyde-3-phosphate dehydrogenase in adipocytes; (8) little or no new triglyceride synthesis and storage by adipocytes; (9) enhanced expression of β3-adrenergic receptors (β3AR) and improved adrenergic function in adipocytes; (10) increased activity of pancreatic β-cells. (11) Decreased insulinemia stimulated by glucose; (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 proliferation; (20) Decreased adipocyte hypertrophy; (21) Decreased rate of preadipocyte to adipocyte transformation; (22) Decreased rate of overeating; (23) Increased circulating adiponectin concentration; (24) Increased cerebrospinal fluid insulin levels; (25) Increased insulin mRNA and insulin content in pancreatic islets; or (26) Increased insulin metabolic efficiency.

[0377] Immediate or prolonged administration of K to humans or animals at risk of myocardial infarction or stroke, or undergoing surgical procedures to restore blood flow to the heart or brain. ATP Formulations of channel openers (optionally combined with growth hormone) can lead to improved treatment outcomes after surgery or myocardial infarction or stroke by improving tissue survival after blood flow is restored, reducing tissue stifling, and altering the nature of the inflammatory response.

[0378] As the pharmaceutical formulations described herein are designed for the treatment of obesity, hyperlipidemia, hypertension, weight maintenance, type 1 diabetes, prediabetes, type 2 diabetes, or any condition in which weight loss, reduction of circulating triglycerides, or β-cell rest contributes to therapeutic outcomes, K is provided for the dose administered. ATPSeveral key changes to the pharmacodynamic and pharmacokinetic responses of channel openers (optionally in combination with growth hormone), including one or more of the following: (1) prolonging the pharmacodynamic effect of the administered dose to more 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 current oral suspensions or capsule products of the same administered dose of the active pharmaceutical ingredient; (5) providing circulating concentrations of the unbound active pharmaceutical ingredient above a threshold concentration over 24 hours or longer from a single administered dose; and (6) resulting in more consistent drug absorption in treated individuals compared to existing capsule formulations.

[0379] The pharmaceutical co-formulations of the present invention are designed to treat a variety of conditions in humans and animals, including K. ATP Channel openers are combined with growth hormone and one or more of the following: (1) diuretics; (2) drugs that lower blood pressure; (3) drugs that suppress appetite; (4) cannabinoid receptor antagonists; (5) drugs that inhibit the action of gastric lipase; (6) any drugs used to induce weight loss; (7) drugs that lower cholesterol; (8) drugs that lower LDL-bound cholesterol; (9) drugs that improve insulin sensitivity; (10) drugs that improve glucose utilization or absorption; (11) drugs that reduce the incidence of atherosclerotic plaques; (12) drugs that reduce inflammation; (13) drugs used as antidepressants; (14) drugs used as antiepileptics; or (15) drugs used as antipsychotics.

[0380] This invention uses K ATP Drug formulations of channel openers (optionally in combination with growth hormone) for treatment in humans or animals reduce the incidence of adverse side effects, including but not limited to edema, fluid retention, decreased excretion of sodium, chloride, and uric acid, hyperglycemia, ketoacidosis, nausea, vomiting, indigestion, intestinal obstruction, and headache. This reduction in the incidence of these adverse side effects is achieved by: (1) starting administration to the individual at a subtherapeutic dose and gradually increasing the dose daily until a therapeutic dose is reached, wherein the gradual dose increase is achieved over a period of 2 to 10 days; (2) using the lowest effective dose to achieve the desired therapeutic effect; (3) using drug formulations that delay the release of the active agent until gastric passage is complete; (4) using drug formulations that delay the release of the active agent until gastric passage is complete; (5) using drug formulations that produce a lower peak circulating drug level compared to an immediately released oral suspension or capsule formulation of the same dose; and (6) optimizing the timing of administration within the day and relative to meals.

[0381] Using K in this invention ATP Drug formulations of channel openers (optionally in combination with growth hormone) for the treatment of patients with Prader-Willi syndrome, Smith-Magilli syndrome, Flehrich syndrome, Cohen syndrome, peak syndrome, Alstréd syndrome, Boyson syndrome, Barbie II syndrome, and type I, II, III, and IV hyperlipoproteinemia may produce some or all of the following therapeutic outcomes: (1) weight loss; (2) reduced rate of weight gain; (3) suppression of overeating; (4) reduced incidence of impaired glucose tolerance, prediabetes, or diabetes; (5) reduced incidence of congestive heart failure; (6) reduced hypertension; and (7) reduced all-cause mortality.

[0382] Using K in this invention ATP Drug formulations of channel openers (optionally in combination with growth hormone) in prediabetic subjects may produce some or all of the following outcomes: (1) weight loss; (2) restoration of normal glucose tolerance; (3) delayed rate of progression to diabetes; (4) reduced hypertension; and (5) reduced all-cause mortality.

[0383] Using K in this invention ATP Drug formulations of channel openers (optionally in combination with growth hormone) used to treat diabetic subjects may produce some or all of the following outcomes: (1) weight loss; (2) restoration of normal glucose tolerance; (3) delay in the rate of diabetes progression; (4) improved glucose tolerance; (5) reduced hypertension; and (6) reduced all-cause mortality.

[0384] Co-administration of drugs and K ATP Formulations of channel openers for the treatment of diseases in overweight, obese, or obesity-susceptible human and animal subjects involve co-administration of K. ATP Pharmaceutically acceptable formulations of channel openers and acceptable formulations of growth hormones and optionally one or more of the following: (1) sibutramine; (2) orlistat; (3) rimonaban; (4) drugs as appetite suppressants; (5) any drugs used to induce weight loss in obese or overweight individuals; (6) nonthiazide diuretics; (7) drugs that lower cholesterol; (8) drugs that increase HDL cholesterol; (9) drugs that lower LDL cholesterol; (10) drugs that lower blood pressure; (11) drugs as antidepressants; (12) drugs that improve insulin sensitivity; (13) drugs that improve glucose utilization and absorption; (14) drugs as antiepileptic agents; (15) drugs as anti-inflammatory agents; or (16) drugs that lower circulating triglycerides.

[0385] Co-administration of drugs and K ATPThe formulation of channel openers for the treatment or prevention of weight gain, dyslipidemia, or impaired glucose tolerance in subjects receiving antipsychotic medication involves co-administration of potassium. ATP Pharmaceutically acceptable formulations of channel openers include growth hormones and one or more of the following optional formulations: lithium, carbamazepine, valproic acid and sodium divalproate, and lamotrigine; antidepressants generally classified as monoamine oxidase inhibitors, including isocarboxazid, phenelzine sulfate and tranylcypromine sulfate; tricyclic antidepressants, including doxepin, clomipramine, amitriptyline, maproline, desipromine, nortriptyline, desipramine, doxepin, trimipramine, imipramine and protryptyline; tetracyclic antidepressants, including mianserin... The list includes ianserin, mirtazapine, maprotiline, oxaprotline, delequamine, levoprotline, triflucarbine, setiptiline, lortalaline, azipramine, aptazapine, and pirlindole; as well as major sedatives and atypical antipsychotics, including paroproxidol, perphenazine, thioridazine, risperidone, clozapine, olanzapine, and chlorpromazine.

[0386] In one implementation, K ATP Channel openers (optionally in combination with growth hormone) are administered orally as an oral suspension, or as an immediate-release capsule or tablet, or as a controlled-release formulation, or as a transdermal or intranasal formulation to overweight or obese individuals to achieve and maintain the threshold concentration required for a measurable reduction in fasting insulin levels over a prolonged period. Preferably, K... ATPChannel-opening formulations reduce 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 overnight fasting, the patient ingests a known amount of glucose. Initial glucose levels are determined by measuring pre-test glucose levels in blood and urine. Blood insulin levels are measured by drawing blood hourly for up to three hours after glucose ingestion. In a fasting glucose test, an individual with a plasma glucose value greater than 200 mg / dL at 2 hours post-glucose loading indicates impaired glucose tolerance.

[0387] In another implementation scheme, K ATP Channel openers (optionally in combination with growth hormone) are administered to overweight or obese individuals as oral suspensions, or immediate-release capsules or tablets, or controlled-release formulations, or transdermal or intranasal formulations, to achieve and maintain the threshold concentration required to induce weight loss over a prolonged period of time.

[0388] In another implementation scheme, K ATP Channel openers (optionally in combination with growth hormone) are administered to overweight or obese individuals as oral suspensions, or immediate-release capsules or tablets, or controlled-release formulations, or transdermal or intranasal formulations, to achieve and maintain the threshold concentration required to increase resting energy expenditure for an extended period of time.

[0389] In another implementation scheme, K ATP Channel openers (optionally in combination with growth hormone) are administered to overweight or obese individuals as oral suspensions, or immediate-release capsules or tablets, or controlled-release formulations, or transdermal or intranasal formulations, to achieve and maintain the threshold concentrations required to increase fat and fatty acid oxidation over a prolonged period of time.

[0390] In another implementation scheme, K ATP Channel openers (optionally in combination with growth hormone) are administered to obese susceptible individuals as oral suspensions, or immediate-release capsules or tablets, or controlled-release formulations, or transdermal or intranasal formulations, to achieve and maintain the threshold concentration required to induce weight loss over a prolonged period of time.

[0391] In another implementation scheme, K ATP Channel openers (optionally in combination with growth hormone) are administered to obese susceptible individuals as oral suspensions, or immediate-release capsules or tablets, or controlled-release formulations, or transdermal or intranasal formulations, to achieve and maintain the threshold concentration required for maintaining body weight over a prolonged period of time.

[0392] In another implementation scheme, K ATP Channel openers (optionally in combination with growth hormone) are administered to overweight or obese individuals as oral suspensions, or immediate-release capsules or tablets, or controlled-release formulations, or transdermal or intranasal formulations, to achieve and maintain drug concentrations above the threshold concentration required to induce weight loss for an extended period of time.

[0393] In another implementation scheme, K ATP Channel openers (optionally in combination with growth hormone) are administered to overweight or obese individuals over a prolonged period of time as oral suspensions, or immediate-release capsules or tablets or controlled-release formulations or transdermal or intranasal formulations to reduce body fat by more than 25%, more preferably at least 50%, and even more preferably at least 75%.

[0394] In another implementation scheme, K ATP Channel openers (optionally combined with growth hormone) are administered to overweight or obese individuals over a prolonged period of time as oral suspensions, or immediate-release capsules or tablets, or controlled-release formulations, or transdermal or intranasal formulations to preferentially reduce visceral fat deposition.

[0395] In another implementation scheme, K ATP Channel openers (optionally combined with growth hormone) are administered to overweight or obese individuals over a prolonged period of time as oral suspensions, or immediate-release capsules or tablets, or controlled-release formulations, or transdermal or intranasal formulations, to reduce visceral fat accumulation and other fat deposits.

[0396] In another implementation scheme, K ATP Channel openers (optionally in combination with growth hormone) are administered as oral suspensions, or immediate-release capsules or tablets, or controlled-release formulations, or transdermal or intranasal formulations to overweight or obese individuals with normal blood insulin levels to achieve and maintain drug concentrations above the threshold concentration required to induce weight loss for an extended period of time.

[0397] In another implementation scheme, K ATP Channel openers (optionally in combination with growth hormone) are administered to individuals with prediabetes as oral suspensions, or immediate-release capsules or tablets, or controlled-release formulations, or transdermal or intranasal formulations, to achieve and maintain drug concentrations above the threshold concentrations required to prevent the transition to diabetes for an extended period of time.

[0398] In another implementation scheme, K ATPChannel openers (optionally in combination with growth hormone) are administered to individuals with type 1 diabetes as oral suspensions, or immediate-release capsules or tablets, or controlled-release formulations, or transdermal or intranasal formulations, to achieve and maintain drug concentrations above the threshold concentration required to induce β-cell quiescence for an extended period of time.

[0399] In another implementation, a single dose of K is administered to the individual in need. ATP Pharmaceutically acceptable formulations of channel openers (optionally combined with growth hormone) that produce circulating concentrations of the active drug sufficient to reduce insulin secretion over 24 hours or longer.

[0400] In another implementation scheme, K is administered to individuals in need on a long-term basis no more than once every 24 hours. ATP Pharmaceutically acceptable formulations of channel openers (optionally combined with growth hormone) that produce circulating concentrations of the active drug sufficient to reduce insulin secretion on a sustained basis.

[0401] In another implementation, a single dose of K is administered to the individual in need. ATP Pharmaceutically acceptable formulations of channel openers (optionally combined with growth hormone) that produce circulating concentrations of the active drug sufficient to increase the levels of non-esterified fatty acids in circulation over 24 hours or longer.

[0402] In another implementation scheme, K is administered to individuals in need on a long-term basis no more than once every 24 hours. ATP Pharmaceutically acceptable formulations of channel openers (optionally combined with growth hormone) that produce circulating concentrations of the active drug sufficient to increase the levels of non-esterified fatty acids in circulation on a sustained basis.

[0403] In another implementation, a single dose of K is administered to the individual in need. ATP A pharmaceutically acceptable formulation of a channel opener (optionally combined with growth hormone) that produces a circulating concentration of active drug sufficient to treat circulating hypoglycemia over 24 hours or longer.

[0404] In another implementation scheme, K is administered to individuals in need on a long-term basis no more than once every 24 hours. ATP Pharmaceutically acceptable formulations of channel openers (optionally combined with growth hormone) that produce circulating concentrations of active drug sufficient to treat hypoglycemia on a sustained basis.

[0405] In another implementation scheme, K is administered to individuals in need on a long-term basis no more than once every 24 hours. ATPPharmaceutically acceptable formulations of channel openers (optionally combined with growth hormone) that produce circulating concentrations of the active drug sufficient to induce weight loss on a sustained basis.

[0406] In another implementation scheme, K is administered to individuals in need on a long-term basis no more than once every 24 hours. ATP Pharmaceutically acceptable formulations of channel openers (optionally combined with growth hormone) produce circulating concentrations of the active drug sufficient to maintain weight on a sustained basis, since maintaining the weight of an obese individual is preferred once a certain amount of weight loss has occurred, when the alternative is to regain weight.

[0407] In another implementation scheme, K is administered to individuals in need on a long-term basis no more than once every 24 hours. ATP Pharmaceutically acceptable formulations of channel openers (optionally combined with growth hormone) that produce circulating concentrations of the active drug sufficient to reduce circulating triglyceride levels on a sustained basis.

[0408] In another implementation, a single dose of K is administered to the individual in need. ATP Pharmaceutically acceptable formulations of channel openers (optionally in combination with growth hormone) that produce circulating concentrations of an active drug sufficient to reduce or prevent ischemia or reperfusion injury in circulation for 24 hours or longer.

[0409] In another implementation scheme, K is administered to individuals in need on a long-term basis no more than once every 24 hours. ATP Pharmaceutically acceptable formulations of channel openers (optionally combined with growth hormone) that produce circulating concentrations of active drug sufficient to reduce or prevent ischemia or reperfusion injury on a sustained basis.

[0410] In another implementation, K is used ATP The adverse effects of frequent treatment with channel openers (optionally in combination with growth hormone) are reduced by using pharmaceutically acceptable formulations of diazoxide or its derivatives administered to individuals in need on a daily basis, wherein the initial dose is known to be a subtherapeutic dose and the daily dose is subsequently gradually increased until a therapeutic dose is reached.

[0411] In another implementation, K is used ATP The adverse effects of frequent treatment with channel openers (optionally in combination with growth hormone) include the use of K on a daily basis to individuals in need. ATP A pharmaceutically acceptable formulation of a channel opener is used to reduce the release of the active ingredient from the formulation until the passage through the stomach is complete.

[0412] In another implementation, K is usedATP The adverse effects of frequent treatment with channel openers (optionally in combination with growth hormone) include the use of K on a daily basis to individuals in need. ATP A pharmaceutically acceptable formulation of a channel opener is used to reduce the release of the active ingredient from the formulation until the passage through the stomach is complete.

[0413] In another implementation, K is used ATP The adverse effects of frequent treatment with channel openers (optionally in combination with growth hormone) include the use of K on a daily basis to individuals in need. ATP The channel opener is reduced to a pharmaceutically acceptable formulation (optionally in combination with growth hormone) in which the maximum circulating concentration of the active ingredient is lower than that which would be achieved by administering the same dose using an oral suspension or capsule formulation.

[0414] In another implementation, K is used ATP The adverse effects of frequent treatment with channel openers (optionally in combination with growth hormone) include the use of K on a daily basis to individuals in need. ATP The channel opener is a pharmaceutically acceptable formulation (optionally combined with growth hormone) for reduction, wherein the initial dose is known to be a subtherapeutic dose and the daily dose is subsequently gradually increased until a therapeutic dose is reached, the active ingredient is not released from the formulation until gastric passage is complete, and wherein the maximum circulating concentration of the active ingredient is lower than the concentration that would be achieved by administering the same dose using an oral suspension or capsule formulation.

[0415] In another implementation, K is used ATP The adverse effects of frequent treatment with channel openers (optionally in combination with growth hormone) include the use of K+ on a daily basis to overweight or obese individuals in need. ATP The channel opener is a pharmaceutically acceptable formulation (optionally in combination with growth hormone) for reduction, wherein the initial dose is known to be a subtherapeutic dose, and the daily dose is subsequently gradually increased until a therapeutic dose is reached, wherein the active ingredient is not released from the formulation until gastric passage is complete, wherein the maximum circulating concentration of the active ingredient is lower than that which would be achieved by administering the same dose using an oral suspension or capsule formulation, and wherein the maximum dose is lower than 2.5 mg / kg / day.

[0416] In another implementation, K is used ATP The adverse effects of frequent treatment with channel openers (optionally in combination with growth hormone) include the use of K+ on a daily basis to overweight or obese individuals in need. ATPThe channel opener is a pharmaceutically acceptable formulation (optionally combined with growth hormone) for reduction, wherein the initial dose is known to be a subtherapeutic dose, and the daily dose is subsequently gradually increased until a therapeutic dose is reached, wherein the active ingredient is not released from the formulation until gastric passage is complete, wherein the maximum circulating concentration of the active ingredient is lower than the concentration that would be achieved by administering the same dose using an oral suspension or capsule formulation, and wherein the maximum dose is lower than 1.75 mg / kg / day.

[0417] In another implementation, treatment for overweight or obese individuals is achieved by administering K every 24 hours. ATP Pharmaceutically acceptable formulations of channel openers (optionally in combination with growth hormone) optimized for weight loss, wherein the release of the active ingredient from the formulation has been improved to provide near-zero-order release over at least 12 hours.

[0418] In another implementation, treatment for overweight or obese individuals is achieved by administering K every 24 hours. ATP Pharmaceutically acceptable formulations of channel openers (optionally in combination with growth hormone) optimized for weight loss, wherein the release of the active ingredient from the formulation has been improved to provide near-zero-order release over at least 18 hours.

[0419] In another implementation, treatment for overweight or obese individuals is achieved by administering K every 24 hours. ATP Pharmaceutically acceptable formulations of channel openers (optionally in combination with growth hormone) optimized for weight loss, wherein the release of the active ingredient from the formulation has been improved to provide an increased drug concentration in circulation over at least 12 hours.

[0420] In another implementation, treatment for overweight or obese individuals is achieved by administering K every 24 hours. ATP Pharmaceutically acceptable formulations of channel openers (optionally in combination with growth hormone) optimized for weight loss, wherein the release of the active ingredient from the formulation has been improved to provide an increased drug concentration in circulation over at least 18 hours.

[0421] In another implementation, treatment for overweight or obese individuals is achieved by administering K every 24 hours. ATP Pharmaceutically acceptable formulations of channel openers (optionally in combination with growth hormone) optimized for weight loss, wherein the release of the active ingredient from the formulation has been modified to match the basal insulin secretion pattern.

[0422] In another implementation, using K ATPThe incidence of adverse effects during channel opener therapy is based on the daily administration of K to obese-susceptible individuals in need. ATP The channel opener is a pharmaceutically acceptable formulation (optionally in combination with growth hormone) for reduction, wherein the initial dose is known to be a subtherapeutic dose, and the daily dose is subsequently gradually increased until a therapeutic dose is reached, wherein the active ingredient is not released from the formulation until gastric passage is complete, wherein the maximum circulating concentration of the active ingredient is lower than that which would be achieved by administering the same dose using an oral suspension or capsule formulation, and wherein the maximum dose is lower than 2.5 mg / kg / day.

[0423] In another implementation, using K ATP The incidence of adverse effects during treatment with channel openers (optionally in combination with growth hormone) is compared to the rate of adverse reactions when administered daily to obese susceptible individuals in need. ATP The channel opener is a pharmaceutically acceptable formulation (optionally in combination with growth hormone) for reduction, wherein the initial dose is known to be a subtherapeutic dose, and the daily dose is subsequently gradually increased until a therapeutic dose is reached, wherein the active ingredient is not released from the formulation until gastric passage is complete, wherein the maximum circulating concentration of the active ingredient is lower than the concentration that would be achieved by administering the same dose using an oral suspension or capsule formulation, and wherein the maximum dose is lower than 1.75 mg / kg / day.

[0424] In another implementation, treatment for individuals susceptible to obesity involves administering K every 24 hours. ATP Pharmaceutically acceptable formulations of channel openers (optionally in combination with growth hormone) optimized for weight maintenance, wherein the release of the active ingredient from the formulation has been improved to provide near-zero-order release over at least 12 hours.

[0425] In another implementation, treatment for individuals susceptible to obesity involves administering K every 24 hours. ATP Pharmaceutically acceptable formulations of channel openers (optionally in combination with growth hormone) optimized for weight maintenance, wherein the release of the active ingredient from the formulation has been improved to provide near-zero-order release over at least 18 hours.

[0426] In another implementation, treatment for individuals susceptible to obesity involves administering K every 24 hours. ATP Pharmaceutically acceptable formulations of channel openers (optionally in combination with growth hormone) optimized for weight maintenance, wherein the release of the active ingredient from the formulation has been improved to provide an increased drug concentration in circulation over at least 12 hours.

[0427] In another implementation, treatment for individuals susceptible to obesity involves administering K every 24 hours. ATP Pharmaceutically acceptable formulations of channel openers (optionally in combination with growth hormone) optimized for weight maintenance, wherein the release of the active ingredient from the formulation has been improved to provide an increased drug concentration in circulation over at least 18 hours.

[0428] In another implementation, treatment for individuals susceptible to obesity involves administering K every 24 hours. ATP Pharmaceutically acceptable formulations of channel openers (optionally in combination with growth hormone) are optimized for weight maintenance, wherein the release of the active ingredient from the formulation has been modified to match the basal insulin secretion pattern.

[0429] In another implementation scheme, K ATP Pharmaceutically acceptable formulations of channel openers (optionally in combination with growth hormone) are co-administered with sibutramine to overweight or obese individuals to induce weight loss.

[0430] In another implementation scheme, K ATP Pharmaceutically acceptable formulations of channel openers (optionally combined with growth hormone) are co-administered with orlistat to overweight or obese individuals to induce weight loss.

[0431] In another implementation scheme, K ATP Pharmaceutically acceptable formulations of channel openers (optionally combined with growth hormone) are co-administered with rimonaban to overweight or obese individuals to induce weight loss.

[0432] In another implementation scheme, K ATP Pharmaceutically acceptable formulations of channel openers (optionally combined with growth hormone) are co-administered with appetite suppressants to overweight or obese individuals to induce weight loss.

[0433] In another implementation scheme, K ATP Pharmaceutically acceptable formulations of channel openers (optionally combined with growth hormone) are co-administered with antidepressants to overweight or obese individuals to induce weight loss.

[0434] In another implementation scheme, K ATP Pharmaceutically acceptable formulations of channel openers (optionally combined with growth hormone) are co-administered with antiepileptic drugs to overweight or obese individuals to induce weight loss.

[0435] In another implementation scheme, K ATP Pharmaceutically acceptable formulations of channel openers (optionally combined with growth hormone) are co-administered with nonthiazide diuretics to overweight or obese individuals to induce weight loss.

[0436] In another implementation scheme, K ATP Pharmaceutically acceptable formulations of channel openers (optionally combined with growth hormone) are co-administered with drugs that induce weight loss through mechanisms different from diazoxide to overweight or obese individuals to induce weight loss.

[0437] In another implementation scheme, K ATP Pharmaceutically acceptable formulations of channel openers (optionally combined with growth hormone) are co-administered with blood pressure-lowering drugs to overweight, obesity-susceptible, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0438] In another implementation scheme, K ATP Pharmaceutically acceptable formulations of channel openers (optionally combined with growth hormone) are co-administered with cholesterol-lowering drugs to overweight, obesity-susceptible, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0439] In another implementation scheme, K ATP Pharmaceutically acceptable formulations of channel openers (optionally combined with growth hormone) are co-administered with drugs that increase HDL-related cholesterol to overweight, obesity-susceptible, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0440] In another implementation scheme, K ATP Pharmaceutically acceptable formulations of channel openers (optionally combined with growth hormone) are co-administered with drugs that improve insulin sensitivity to overweight, obesity-predisposed, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0441] In another implementation scheme, K ATP Pharmaceutically acceptable formulations of channel openers (optionally combined with growth hormone) are co-administered with anti-inflammatory agents to overweight, obesity-susceptible, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0442] In another implementation scheme, K ATP Pharmaceutically acceptable formulations of channel openers (optionally in combination with growth hormone) are co-administered with drugs that lower circulating triglycerides to overweight, obesity-susceptible, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0443] In another implementation scheme, K ATP The channel opener (optionally in combination with growth hormone) is formulated with sibutramine into a pharmaceutically acceptable formulation for administration to overweight, obesity-susceptible, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0444] In another implementation scheme, K ATP Channel openers (optionally in combination with growth hormone) are formulated with orlistat or other active agents that inhibit the action of gastric lipases into pharmaceutically acceptable formulations for administration to overweight, obesity-susceptible, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0445] In another implementation scheme, K ATP Channel openers (optionally in combination with growth hormone) are formulated with nonthiazide diuretics into pharmaceutically acceptable formulations for administration to overweight, obesity-susceptible, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0446] In another implementation scheme, K ATP Channel openers (optionally in combination with growth hormone) are formulated with appetite suppressants into pharmaceutically acceptable formulations for administration to overweight, obesity-susceptible, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0447] In another implementation scheme, K ATP Channel openers (optionally in combination with growth hormones) are formulated together with cannabinoid receptor antagonists into pharmaceutically acceptable formulations for administration to overweight, obesity-susceptible, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0448] In another implementation scheme, K ATP Channel openers (optionally in combination with growth hormone) are formulated together with anticholesterol activators to produce pharmaceutically acceptable formulations for administration to overweight, obesity-susceptible, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0449] In another implementation scheme, K ATP Channel openers (optionally combined with growth hormone) are formulated with antihypertensive active agents to produce pharmaceutically acceptable formulations for administration to overweight, obesity-susceptible, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0450] In another implementation scheme, K ATP Channel openers (optionally in combination with growth hormone) are formulated with insulin sensitizing agents to produce pharmaceutically acceptable formulations for administration to overweight, obesity-susceptible, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0451] In another implementation scheme, K ATPChannel openers (optionally in combination with growth hormone) are formulated with anti-inflammatory agents to produce pharmaceutically acceptable formulations for administration to overweight, obesity-susceptible, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0452] In another implementation scheme, K ATP Channel openers (optionally in combination with growth hormone) are formulated with antidepressant active agents to produce pharmaceutically acceptable formulations for administration to overweight, obesity-susceptible, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0453] In another implementation scheme, K ATP Channel openers (optionally in combination with growth hormone) are formulated with antiepileptic agents into pharmaceutically acceptable formulations for administration to overweight, obesity-susceptible, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0454] In another implementation scheme, K ATP Channel openers (optionally in combination with growth hormone) are formulated together with active agents that reduce the incidence of atherosclerotic plaques into pharmaceutically acceptable formulations for administration to overweight, obesity-susceptible, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0455] In another implementation scheme, K ATP Channel openers (optionally in combination with growth hormone) are formulated with active agents that reduce circulating triglyceride concentrations into pharmaceutically acceptable formulations for administration to overweight, obesity-susceptible, or obese individuals to induce weight loss and treat obesity-related comorbidities.

[0456] The reduction of circulating triglycerides in overweight, obese, or obesity-prone individuals is achieved through the administration of an effective dose of potassium. ATP This is achieved through solid oral dosage forms of channel openers (optionally combined with growth hormone).

[0457] K ATP Solid oral dosage forms of channel openers can be used to administer therapeutically effective doses of potassium to overweight or obesity-susceptible individuals in need. ATP Channel openers are used to maintain weight because once a certain amount of weight loss has occurred, maintaining the weight of an obese individual is preferred when the alternative is to regain weight.

[0458] Methods that can reduce initial body fat by more than 25% in overweight or obese individuals can be achieved through long-term administration of K. ATP This is achieved through solid oral dosage forms of channel openers (optionally combined with growth hormone).

[0459] Methods that can reduce initial body fat by more than 50% in overweight or obese individuals can be achieved through long-term administration of K. ATP This is achieved through solid oral dosage forms of channel openers (optionally combined with growth hormone).

[0460] Methods that can reduce initial body fat by more than 75% in overweight or obese individuals can be achieved through long-term administration of K. ATP This is achieved through solid oral dosage forms of channel openers (optionally combined with growth hormone).

[0461] For overweight or obese individuals, a preferred method to reduce visceral fat is long-term administration of potassium (K). ATP This is achieved through solid oral dosage forms of channel openers (optionally combined with growth hormone).

[0462] Methods to reduce body fat and lower circulating triglycerides in overweight or obese individuals may include long-term administration of potassium. ATP This is achieved through solid oral dosage forms of channel openers (optionally combined with growth hormone).

[0463] The invention will now be described with reference to the following non-limiting embodiments.

[0464] Example

[0465] Example 1: Formulation containing potassium ATP channel activator

[0466] 1. Compressed tablet formulations

[0467] About 15%-30% by weight of diazine or its derivatives are mixed with about 55%-80% by weight of hydroxypropyl methylcellulose, about 3%-10% by weight of ethylcellulose, and less than 3% by weight of magnesium stearate (as a lubricant) and talc (as a flow aid), respectively. 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 coated with a film, as described below for microparticles.

[0468] Tablets containing 100 mg of diazine or a derivative thereof will also contain approximately 400 mg of hydroxypropyl cellulose and 10 mg of ethyl cellulose. Tablets containing 50 mg of diazine or a derivative thereof will also contain approximately 200 mg of hydroxypropyl cellulose and 5 mg of ethyl cellulose. Tablets containing 25 mg of diazine or a derivative thereof will also contain approximately 100 mg of hydroxypropyl cellulose and 2.5 mg of ethyl cellulose.

[0469] 2. Encapsulation and coating of diazine microparticles

[0470] Diazine or its derivatives are encapsulated into microparticles according to known methods (see, for example, U.S. Patent No. 6,022,562). Microparticles with a diameter of 100 to 500 micrometers are formed using a granulator, containing either diazine or its derivatives alone or in combination with one or more suitable excipients, and then sieved to separate microparticles of appropriate size. The microparticles are coated with a film by spray drying using commercial equipment (e.g., a Uniglat spray coating machine). The film comprises ethyl cellulose, cellulose acetate, polyvinylpyrrolidone, and / or polyacrylamide. The coating solution for the film may include a plasticizer, such as castor oil, diethyl phthalate, triethyl citrate, and salicylic acid. The coating solution may also include a lubricant, such as magnesium stearate, sodium oleate, or polyoxyethylene sorbitan laurate. The coating solution may also include excipients such as talc, colloidal silica, or a mixture thereof, added at 1.5% to 3% by weight to prevent agglomeration of membrane coating particles.

[0471] 3. Tablet formulations for controlled-release diazine or its derivatives

[0472] Before mixing, both the active ingredient and hydroxypropyl methylcellulose (Dow Methocel K4MP) are passed through an ASTM 80-mesh sieve. A mixture is formed from 1 part diazonium or a derivative thereof / 4 parts hydroxypropyl methylcellulose. After thorough mixing, a sufficient volume of ethanol solution of ethylcellulose is slowly added as a granulating agent. The amount of ethylcellulose in each tablet in the final formulation is approximately 1 / 10 part. The material obtained by mixing the granulating agent is sieved through a 22 / 44 mesh. 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 that passed through the 44 mesh). 2% by weight of talc and magnesium stearate are added as flow aids and lubricants, respectively. A colorant is also added. Tablets are compressed using a single-punch tablet press.

[0473] 4. A formulation providing controlled-release diazine or its derivatives in compressed tablet form.

[0474] 20-40 wt% of diazine or its derivatives were mixed with 30 wt% of hydroxypropyl methylcellulose (DowMethocel K100LV P) and 20-40 wt% of fine lactose. The mixture was granulated by adding water. The granulated mixture was wet-milled and then dried at 110°C for 12 hours. The dried mixture was dry-milled. After milling, 25 wt% of ethyl cellulose resin (Dow Ethocel 10FP or Ethocel 100FP) was added, followed by 0.5 wt% of magnesium stearate. A colorant was also added. Tablets were compressed using a single-punch tablet press (Dasbach et al., poster for the AAPS Annual Meeting, November 10-14 (2002)).

[0475] 5. Formulations providing controlled-release diazine or its derivatives in compressed coated tablet form.

[0476] Tablet cores were formulated by mixing 100 mg of diazine or its derivatives with 10 mg of ethyl cellulose (Dow Ethocel 10FP), or by mixing 75 mg of diazine or its derivatives with 25 mg of lactose and 10 mg of ethyl cellulose (Dow Ethocel 10FP), or by mixing 50 mg of diazine or its derivatives with 50 mg of lactose and 10 mg of ethyl cellulose (Dow Ethocel 10FP). The tablet cores were formed using a concave tool on an automated press. A compression coating consisting of 400 mg of ethylene oxide (Union Carbide POLYOX WSR Coagulant) was applied and the tablets were compressed to 3000 psi (Dasbach et al., AAPS Annual Meeting Poster, October 26-30 (2003)).

[0477] 6. Controlled-release formulations of diazine or its derivatives using a osmotic controlled-release system.

[0478] Diazine or its derivatives are formulated into osmotically regulated release systems. Generally, two components—a expandable hydrogel that drives the release of the active drug and a diazine or its derivative—are assembled into a semi-permeable bilayer laminated shell. During assembly, pores are drilled into the shell to facilitate the release of the active agent upon hydration of the hydrogel.

[0479] The dosage form, adjusted, designed, and shaped into a permeation delivery system, is prepared as follows: First, a composition of diazoxide or its derivatives is provided by blending polyethylene oxide, diazoxide or its derivatives, and hydroxypropyl methylcellulose together to form a homogeneous blend. Then, a predetermined volume of denatured anhydrous ethanol, 70% by weight of its dry mass, is slowly added over 5 minutes under continuous mixing. The freshly prepared wet granules are sieved through a 20-mesh sieve, dried at room temperature for 16 hours, and sieved again through a 20-mesh sieve. Finally, the sieved granules are mixed with 0.5% by weight of magnesium stearate for 5 minutes.

[0480] The hydrogel composition was prepared as follows: First, 69 wt% polyethylene oxide, 25 wt% sodium chloride, and 1 wt% iron oxide were each sieved through a 40-mesh sieve. Then, all sieved components were mixed with 5 wt% hydroxypropyl methylcellulose to produce a homogeneous blend. Subsequently, a predetermined volume of denatured anhydrous ethanol equal to 50% of its dry weight was slowly added to the blend over 5 minutes with continuous mixing. The freshly prepared wet particles were passed through a 20-mesh sieve, dried at room temperature for 16 hours, and then passed through a 20-mesh sieve again. The sieved particles were then mixed with 0.5 wt% magnesium stearate for 5 minutes (see U.S. Patent No. 6,361,795 to Kuczynski et al.).

[0481] A diazine or derivative composition and a hydrogel composition are compressed into a bilayer laminated tablet. First, a diazine or derivative composition is added and compacted. Then, the hydrogel composition is added and the thin layer is pressed into a contact laminate arrangement under a 2-ton pressure head.

[0482] The bilayer laminate is coated with a semi-permeable wall (i.e., a film). The wall-forming composition comprises 93% cellulose acetate with a 39.8% acetyl content and 7% polyethylene glycol. The wall-forming composition is sprayed onto and around the bilayer laminate.

[0483] Finally, an outlet channel is drilled through a semi-permeable wall to connect the thin film of diazoxide or its derivatives to the outside of the drug delivery system. Residual solvent is removed by drying at 50°C and 50% humidity. Subsequently, the permeation system is dried at 50°C to remove excess moisture (see U.S. Patent No. 6,361,795 to Kuczynski et al.).

[0484] 7. Preparation of diazine salts

[0485] Diazine hydrochloride was prepared by dissolving 1 mole of diazine (230.7 g) in 500 ml of Et₂O. Dry HCl was passed through the solution until the weight of the container increased by 36 g. During the addition of HCl, the diazine hydrochloride precipitated as a powder. The salt was filtered off and washed with anhydrous Et₂O.

[0486] Example 2: In vivo obesity test

[0487] 1. Animal models of obesity

[0488] The efficacy of formulations of diazoxide or its derivatives prepared as described herein can be tested in animal models of obesity, as described by Surwit et al. (Endocrinology 141:3630-3637 (2000)). In short, 4-week-old male B6 mice (5 mice / cage) were housed in a temperature-controlled (22°C) chamber with a 12-hour light, 12-hour dark cycle. High-fat (HF) and low-fat (LF) experimental diets contained 58% and 11% of their calories from fat, respectively. One group of mice was fed the HF diet for the first 4 weeks of the study; the remaining 15 mice were fed the LF diet. Mice assigned to the LF diet maintained this diet throughout the study as a control group for lean mice. At week 4, all HF-fed mice were reassigned to two groups. The first group maintained the HF diet throughout the study as an obese control group. The remaining three groups of mice were fed a high-frequency (HF) diet and administered a controlled-release formulation of diazoxide or its derivatives via oral gavage at a single dose of approximately 150 mg of active agent per kilogram of body weight per day. Animals were weighed weekly, and food consumption per cage was measured twice weekly until dietary changes were implemented in week 4, at which point daily body weight and food intake were determined. Feed efficiency (weight in grams per unit of energy expenditure) was calculated on a cage-by-cage basis. Samples for insulin, glucose, and leptin analysis were collected on day 24 (4 days before dietary change), day 32 (4 days after change), and every two weeks thereafter. In all cases, food was removed 8 hours prior to sample collection. Glucose was analyzed using a glucose oxidase method. Insulin and leptin concentrations were determined using a dual-antibody RIA. Insulin measurements were based on rat standards, and leptin measurements used mouse standards. At the end of the study, postprandial plasma samples were collected, and triglyceride and non-esterified fatty acid concentrations were analyzed. After 4 weeks of drug treatment, a subset of 10 animals from each group were euthanized. White epididymal adipose tissue (EWAT), retroperitoneal (RP) fat, interscapular brown adipose tissue (IBAT) fat pad, and gastrocnemius muscle were removed, trimmed, and weighed. Body fat percentage was estimated from the weight of the epididymal fat pad. A subset of five animals from each group were intraperitoneally injected with 0.5 g / kg glucose. Plasma samples were collected 30 minutes after injection, and glucose content was analyzed by glucose oxidase method.

[0489] 2. Treatment of obesity in humans

[0490] The efficacy of diazine or its derivatives prepared as described herein can be tested in obese humans. This study was conducted as described by Alemzadeh (Alemzadeh et al., J Clin Endocr Metab 83:1911-1915 (1998)). Subjects were individuals with a body weight of 30 kg / m² or greater. 2 The composition of the body mass index (BMI) for moderate to morbidly obese adults. Each subject underwent a full physical examination at the initial assessment, with weight measured on a standard electronic scale and body composition measured via DEXA.

[0491] Prior to the start of the study, all subjects were placed on a low-calorie diet during a one-week introductory period. This was designed to exclude individuals who were unlikely to adhere and to ensure pre-treatment weight stability. Up to 50 patients were tested with each dose of the drug. Daily doses were set at 100 mg / day, 200 mg / day, and 300 mg / day. The daily dose was administered in two divided doses. At each administration, the dose was given as one, two, or three 50 mg capsules or tablets. Individual patients were given the medication once daily for up to 12 months. Patients were checked weekly, weighed, and asked about any side effects or complications.

[0492] A 24-hour dietary review was obtained from each patient. The dietary reviews were analyzed using standard computer software programs. All patients were placed on a low-calorie diet and encouraged to engage in regular exercise.

[0493] Before and after the study, the following laboratory tests were obtained: blood pressure, fasting plasma glucose, insulin, cholesterol, triglycerides, free fatty acids (FFA), and glycated hemoglobin, as well as measurements of the presence and oxidation rate of plasma-derived fatty acids. In addition, routine chemical characterization and fasting plasma glucose were obtained weekly to identify subjects showing signs of glucose intolerance and / or electrolyte abnormalities. Glucose in plasma was analyzed using a glucose oxidase method.

[0494] Insulin concentration was determined by intravenous glucose tolerance test (RIA) using a dual-antibody kit. Cholesterol and triglyceride concentrations were measured enzymatically. Plasma free fatty acid (FFA) was determined by enzymatic colorimetry. Insulin efficiency (SI) was assessed by intravenous glucose tolerance test (IVGTT) using a modified miniature model. After overnight fasting, an intravenous glucose bolus (300 mg / kg) was administered, followed by an insulin bolus (after 20 minutes). Blood samples were obtained from the 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 to determine glucose and insulin levels. SI and glucose utilization efficiency (SG) were calculated using Bergman's modified miniature model computer program before and after the study. Acute insulin response to glucose was determined within the first 19 minutes of the IVGTT, and glucose disappearance (kg) was determined between 8 and 19 minutes of the IVGTT. Body composition was measured by bioelectrical impedance analysis before and at the end of the study. Resting energy expenditure (REE) was measured by indirect calorimetry during a 30-minute supine period following an overnight 12-hour fast. Urine was collected within the corresponding 24-hour periods before and after the study to measure total nitrogen and determine substrate use.

[0495] 3. Treatment of human obesity by co-administration of diazoxide and phentermine

[0496] Moderate to morbidly obese individuals with a body weight of 30 kg / m² or greater. 2 The body mass index (BMI) of diazoxide or its derivatives in solid oral dosage forms and long-term co-administration with phentermine were evaluated in humans. Each subject underwent a full physical examination at initial evaluation, with weight measured on a standard electronic scale and body composition measured by DEXA.

[0497] Prior to the start of the study, all subjects were placed on a low-calorie diet during a one-week introductory period. This was designed to exclude individuals who were unlikely to adhere and to ensure pre-treatment weight stability. Up to 100 patients were tested. The daily dose of diazoxide was set at 200 mg. The daily dose was administered in two divided doses. Each dose was given as a 100 mg capsule or 100 mg tablet. Individual patients were given once daily for up to 12 months. Phentermine was administered as a single daily dose of 15 mg. Patients were checked every two weeks, weighed, and asked about any side effects or complications.

[0498] All patients continued to receive a low-calorie diet and were encouraged to engage in regular exercise. Laboratory tests as described in the examples above were obtained before and after the study began.

[0499] 4. Prevention of diabetes in prediabetic humans

[0500] The embodiments described above describe the use of diazoxide in individuals with prediabetes to prevent the development of diabetes. Individuals included in the study had an elevated risk of developing diabetes, as measured by one of two methods. In a fasting glucose test, they had plasma glucose levels of 100 mg / dL to 125 mg / dL, indicating impaired fasting glucose, or in an oral glucose tolerance test, they had plasma glucose levels of 140 mg / dL to 199 mg / dL 2 hours after a glucose load, indicating impaired glucose tolerance. Treatment was initiated in any individual meeting either criterion. Individuals receiving treatment received 200 mg of diazoxide daily, either twice daily in 100 mg capsules or tablets or once daily in two 100 mg capsules or tablets. Individuals receiving placebo received one placebo capsule or tablet twice daily or once daily in two placebo capsules or tablets.

[0501] Treatment lasted for one year, during which OGTT or fasting glucose was measured monthly.

[0502] 5. A sustained-release formulation of diazoxide hydrochloride and metformin hydrochloride for the treatment of diabetic patients.

[0503] A sustained-release co-formulation of diazoxide and metformin hydrochloride is produced by forming a compressed tablet matrix comprising 750 mg of metformin hydrochloride and 100 mg of diazoxide hydrochloride. These active ingredients are blended with sodium carboxymethyl cellulose (approximately 5% (w / w)), hydroxypropyl methylcellulose (approximately 25% (w / w)), and magnesium stearate (<2% (w / w)). The compressed tablets are 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.

[0504] Type 2 diabetes is treated with an oral dosage form by administering two tablets once daily or one tablet every 12 hours. Treatment continues until one of two treatment endpoints is achieved, or until the patient continues to receive a therapeutic benefit from the medication. The two treatment endpoints that will be used as the basis for deciding to discontinue treatment include a body mass index (BMI) of 18 to 25 (kg / m²). 2 Or, in the absence of treatment, to re-establish normal glucose tolerance. Monitor patients regularly for the following: (a) glucose tolerance using an oral glucose tolerance test; (b) glycemic control using a standard blood glucose test; (c) weight gain or loss; (d) progression of diabetic complications; and (e) adverse effects associated with the use of these active ingredients.

[0505] 6. To prevent or treat weight gain in patients receiving olanzapine treatment.

[0506] Pharmacological treatment for schizophrenia was initiated in patients meeting the DSM III-R criteria. Olanzapine (Zyprexa, Lilly) was administered once daily at a dose of 10 mg. Adjunctive therapy for schizophrenia included valproic acid as a 250 mg equivalent of sodium valproate (Depakote, Abbott Labs). Weight gain, dyslipidemia, impaired glucose tolerance, and metabolic syndrome were common adverse events in patients receiving this combination therapy with antipsychotics. This was achieved through co-administration of a therapeutically effective dose of K. ATP Channel openers are used to treat weight gain, dyslipidemia, impaired glucose tolerance, or metabolic syndrome. Patients are treated with diazoxide in a once-daily tablet formulation of 200 mg / day. Diazoxide administration continues until weight gain, dyslipidemia, impaired glucose tolerance, or metabolic syndrome is corrected, or until olanzapine treatment is discontinued. Dyslipidemia is detected by measuring circulating concentrations of total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and non-esterified fatty acids. Impaired glucose tolerance is detected by using an oral or intravenous glucose tolerance test. Metabolic syndrome is detected by measuring key risk factors, including central obesity, dyslipidemia, impaired glucose tolerance, and circulating concentrations of key pro-inflammatory cytokines.

[0507] Example 3: Clinical studies conducted in obese pediatric and adult PWS patients

[0508] A double-blind, placebo-controlled, randomized withdrawal extension single-center, open-label, single-arm clinical study (PC025) has been conducted. Patients started with a DCCR dose of approximately 1.5 mg / kg (maximum starting dose of 145 mg) and titrated every 14 days to approximately 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 1.03 mg / kg, 1.66 mg / kg, 2.28 mg / kg, and 2.9 mg / kg of diazoxide, respectively. Titration was performed on patients at the discretion of the investigators at each visit. Any patient who showed an increase in resting energy expenditure and / or a reduction in overeating symptoms relative to baseline by day 27 or day 55 was designated a responder and eligible for randomization in the double-blind phase. Everyone who completed the open-label phase was a responder and was randomized in the double-blind phase and completed the double-blind phase. During the double-blind, placebo-controlled, randomized withdrawal phase, responders were randomized in a 1:1 ratio to continue active treatment at the dose they received on day 55 or a placebo equivalent for an additional 4 weeks (29 days). Non-responders continued open-label DCCR treatment at the dose they received on day 55 for an additional 29 days. A total of 12 patients were enrolled in the study.

[0509]

[0510]

[0511] *All screening procedures must be completed by day -14.

[0512] Inclusion criteria: Basic requirements

[0513] • Able to follow verbal and written instructions, either with the assistance of a caregiver or without the assistance of a caregiver;

[0514] • Informed consent form signed by the participants or their legal guardians;

[0515] • The screening process should be completed 2 to 4 weeks prior to the baseline visit.

[0516] General demographic characteristics

[0517] • At the time of administration, male and female patients were aged 10 to 22 years, including the extreme values;

[0518] Prader-Willi syndrome has been genetically confirmed.

[0519] • BMI exceeding the 95th percentile of the age-specific BMI value on the CDC BMI chart or ≥35% of body fat percentage (Body fat criteria will only be used if the patient has not lost weight since the screening visit. In all other cases, BMI criteria will apply.)

[0520] • General health status as recorded through medical history, physical examination, vital sign assessment, 12-lead electrocardiogram (ECG), and clinical laboratory assessment.

[0521] Specific laboratory test results

[0522] Fasting glucose ≤126mg / dL

[0523] HbA1c ≤ 6.5%

[0524] Endpoint and Statistical Analysis

[0525] Each endpoint was measured in two timeframes: (1) during the open-label treatment phase, the change (or percentage change) from baseline to day 69; and (2) during the double-blind, placebo-controlled, randomized withdrawal phase, the change (or percentage change) from day 69 to day 97.

[0526] The endpoints measured during the open-label treatment phase were analyzed using paired t-tests, while those measured during the double-blind, placebo-controlled treatment phase were analyzed using ANOVA and paired t-tests.

[0527] Efficacy endpoints included: overeating (measured using parent / caregiver responses on a modified Dykens Overeating Questionnaire, converted to a numerical score of 0 to 34); 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 from behavioral questionnaires. Tables 2 and 3 summarize the visits used to measure each efficacy parameter.

[0528] Table 2: Time points for evaluating efficacy parameters during the open-label phase

[0529]

[0530] Table 3: Time points for assessing efficacy parameters during double-blind treatment

[0531]

[0532] Patients in the study

[0533] Demographic information and relevant medical history for each patient are shown in Table 4. Of the thirteen participants enrolled in the PC025 clinical study, eleven completed the open-label phase. All were identified as responders and therefore randomized in the double-blind phase of the study. All participants randomized in the double-blind phase of the study completed the phase.

[0534] The baseline characteristics of the patients recruited in the study are provided in Table 5.

[0535] Table 4: Demographic information and relevant medical history of patients recruited in PC025

[0536]

[0537] Table 5: Baseline characteristics of randomized subjects in the double-blind phase of the PC025 clinical trial

[0538]

[0539]

[0540] Dosage

[0541] One subject (a type 2 diabetes patient receiving treatment) completed the open-label treatment period at a dose of 1.5 mg / kg. Of the remaining 10 subjects, one completed the open-label treatment period at a dose of 2.4 mg / kg, and three completed it at a dose of 3.3 mg / kg. The last six subjects enrolled in the study completed the open-label treatment phase at a dose of 4.2 mg / kg.

[0542] Changes in body composition, waist circumference, and weight

[0543] Body fat and lean body mass were measured by DEXA at ​​baseline and again at the end of open-label treatment. Since no DEXA was performed on day 97, the only body composition measurements performed on randomized subjects in the double-blind phase occurred during the phase 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 those not receiving growth hormone treatment. These results are shown in Table 6.

[0544] Weight measured by DEXA was calculated as the sum of body fat and lean body mass. The ratio of lean body mass to body fat was also calculated.

[0545] Table 6:

[0546] Changes in body composition measured by DEXA from baseline to day 69

[0547]

[0548]

[0549] Ten weeks of DCCR treatment had highly significant and clinically relevant effects on body composition, including a reduction in body fat, an increase in lean body mass, and a highly significant increase in the lean body mass to body fat ratio. Because these patients had nearly equal lean body mass and body fat mass at baseline, the concurrent increase in lean body mass and reduction in body fat resulted in almost no net change in weight. Generally, changes in body composition were similar in magnitude between subjects receiving growth hormone treatment and those not receiving growth hormone treatment.

[0550] Changes in body composition were dose-dependent. Those who completed the open-label treatment phase at a dose of 4.2 mg / kg experienced a 6.3% decrease in fat mass, a 9.2% increase in lean body mass, and a 16.6% increase in the lean body mass to fat mass ratio.

[0551] In this study, three subjects showed an increase in lean body mass greater than 10%. Each subject showed an increase in lean body mass / fat mass ratio. More than half of the subjects in this study showed an increase in lean body mass / fat mass ratio >10%, and one showed an increase of more than 20%.

[0552] Figures 1-4 We summarized the percentage changes in body fat, lean body mass, and lean body mass / fat mass ratio from baseline to day 69.

[0553] Weight and waist circumference were measured during the physical examination at each visit. This data was used to evaluate changes from baseline to day 69 in all randomized subjects in the double-blind phase, changes by group from day 69 to day 97, and changes from baseline to day 97 in those who continued DCCR in the double-blind phase. Results from the phase covering 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 those who continued DCCR in the double-blind phase are shown in Table 9.

[0554] Table 7: Changes in weight and waist circumference from baseline to day 69

[0555]

[0556]

[0557] Table 8: Changes in weight and waist circumference from day 69 to day 97

[0558]

[0559] Table 9: Changes in weight and waist circumference from baseline to day 97 in subjects who received DCCR treatment during the double-blind phase.

[0560]

[0561] Interestingly, changes in weight from baseline to day 69, measured by DEXA and by standard weight measurement, yielded almost identical results (a 0.67% increase by DEXA and a 0.53% increase by standard methods). Contrary to the lack of change in weight, all randomized subjects in the double-blind phase showed statistically significant reductions in waist circumference by day 69; those continuing DCCR showed a significant reduction by day 97. Comparison of waist circumference changes between groups between day 69 and day 97 showed a gradual increase in waist circumference in patients receiving placebo, while those continuing DCCR showed a significant reduction. This reduction in waist circumference is consistent with the interpretation that subjects receiving DCCR are experiencing a reduction in visceral fat.

[0562] Changes in overeating

[0563] The overeating questionnaire was administered at all visits. This data can be used to evaluate changes from baseline to day 69 in all randomized subjects during the double-blind phase, changes by group from day 69 to day 97, and changes from baseline to day 97 in those who continued DCCR during the double-blind phase. Results from the phase covering 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 those who continued DCCR during the double-blind phase are shown in Table 12.

[0564] Table 10: Changes in overeating symptoms from baseline to day 69

[0565] parameter n Percentage of change p-value overeating 11 -31.6％ 0.003

[0566] Table 11: Changes in overeating symptoms from day 69 to day 97

[0567]

[0568] Table 12: Changes in overeating symptoms from baseline to day 97 in subjects receiving DCCR treatment during the double-blind phase.

[0569]

[0570] In the double-blind phase, all randomized subjects experienced a statistically significant reduction in overeating symptoms from baseline to day 69, and those who continued DCCR during the double-blind phase experienced a statistically significant reduction from baseline to day 97.

[0571] At the end of the 97-day treatment period, patients receiving DCCR showed a 29.2% improvement in overeating symptoms, compared to only a 13.9% improvement at day 97 for those receiving DCCR for 69 days followed by 28 days of placebo. Therefore, at the end of the double-blind phase, the improvement in overeating symptoms shown by patients receiving DCCR was more than twice that of those randomized to placebo in the double-blind phase. Once patients discontinued DCCR, given its long half-life (28-32 hours), it takes approximately 7-10 days for complete clearance from circulation. Verbal statements obtained from the parents of the participants in the study indicated that they had observed their children's food-related behaviors worsen only in the final weeks of the study, suggesting that a longer double-blind phase could lead to further group segregation. Generally, the effects on the degree to which subjects become agitated when denied food, the ease with which they are distracted by other things once denied food, and the frequency of food theft, rummaging through trash for food, and bargaining for food are equal to or greater than the overall effects on overeating scores. DCCR appears to have a smaller effect on the degree to which subjects steal or rush for food and the frequency of them getting up at night to look for food.

[0572] Improvement in overeating was observed in subjects with baseline overeating who had a score of at least 5 (-33%) on a 0 to 34-point scale, with a score of 29 (-45%).

[0573] Approximately 25% of participants ended the open-label phase with very low levels of overeating (2 or 3 on a scale of 0 to 34). These participants tended to be able to reduce more body fat than average. Two such participants (both women, one receiving growth hormone treatment and the other not) reduced their initial body fat mass by more than 10% within 10 weeks.

[0574] Figure 1 The changes in overeating from baseline to day 69 are shown.

[0575] Changes in lipids

[0576] The lipidome was evaluated at baseline and again at days 69 and 97. This data can be used to evaluate changes from baseline to day 69 in all randomized subjects in the double-blind phase, changes by group from day 69 to day 97, and changes from baseline to day 97 in those who continued 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 in subjects who continued DCCR in the double-blind phase are shown in Table 14.

[0577] Table 13: Changes in lipids from baseline to day 69

[0578] parameter n Percentage of change p-value Total cholesterol 8 -4.0％ 0.044 Triglycerides 7 -21.0％ 0.084 HDL-C 8 10.8％ 0.244 LDL-C 8 -7.0％ 0.030 Non-HDL-C 8 -6.5％ 0.019

[0579] Table 14: Median percentage change in lipids from baseline to day 97 in subjects receiving DCCR treatment during the double-blind phase.

[0580] parameter Percentage change from baseline to median day 97 Total cholesterol -11.0％ Triglycerides -41.8％ HDL-C 25.2％ LDL-C -7.9％ Non-HDL-C -13.4％

[0581] Consistent with previous studies involving DCCR, treatment with DCCR in randomized subjects in a double-blind phase resulted in numerous statistically significant changes in lipids from baseline to day 69, including reductions in total cholesterol, LDL cholesterol, and non-HDL cholesterol. Even though the effect on triglycerides was more pronounced, it did not reach statistical significance due to the smaller n and greater variability within the population. Generally, greater reductions in triglycerides were seen in patients with significantly elevated triglycerides at baseline. A similar pattern was observed in subjects receiving DCCR treatment until the end of the double-blind treatment. Patients receiving DCCR treatment for a longer period all experienced greater reductions in total cholesterol, triglycerides, LDL-C, and non-HDL-C.

[0582] Changes in leptin and ghrelin

[0583] Leptin and ghrelin were measured at baseline and again on day 69. The results of leptin and ghrelin from baseline to day 69 are provided in Table 15.

[0584] Table 15: Changes in leptin and ghrelin from baseline to day 69

[0585] parameter n Percentage of change p-value Leptin 6 -22.0％ 0.061 ghrelin 6 -15.0％ 0.052

[0586] Further evidence of body fat reduction came from leptin analysis, with results consistent with DEXA data and data on waist circumference. Although not fully statistically significant, leptin levels decreased by more than 20% from baseline.

[0587] Although ghrelin may or may not substantially contribute to overeating in PWS, a reduction in ghrelin is beneficial in PWS patients.

[0588] behavioral changes

[0589] A questionnaire adapted from the PWS Natural History Study was used to record the presence or absence of 23 PWS-related behaviors at baseline and again on day 69. These behaviors were generally categorized into four groups:

[0590] (1) Aggressive, threatening, and destructive behavior;

[0591] (2) Self-harm behavior;

[0592] (3) Compulsive behavior; and

[0593] (4) Other behaviors.

[0594] The questionnaire was administered at baseline and again on day 69. Discontinuation rates for aggressive, threatening, destructive, and all other behaviors are shown in Table 16.

[0595] Table 16: Discontinuation rates for various behavioral categories in the PC025 clinical study.

[0596]

[0597] The effects on aggressive, threatening, and destructive behaviors are not related to the effects on overeating.

[0598] Changes in resting energy expenditure and respiratory quotient

[0599] Measurements of resting energy expenditure and respiratory quotient were highly variable between visits. Despite this variability, resting energy expenditure and respiratory quotient appeared to remain unchanged from baseline to day 69.

[0600] Changes in insulin sensitivity

[0601] In other clinical studies, DCCR treatment has been associated with improved insulin resistance, as measured by changes in the Homeostasis Model of Insulin Resistance (HOMA-IR). Improved insulin sensitivity is well-documented in the literature on diazoxide. Subjects enrolled in this double-blind study were quite insulin-sensitive at baseline, a typical characteristic of PWS patients in this age range. Consistent with previous DCCR clinical studies and historical diazoxide literature, 10 weeks of DCCR treatment improved the HOMA-IR from 2.61 ± 1.85 at baseline to 1.46 ± 1.36 on day 69. This difference did not reach statistical significance (p = 0.095).

[0602] Example 4: A clinical study using patients with Smith-Mageli syndrome

[0603] In the first embodiment, patients with Smith-Magilli syndrome were treated with an oral suspension of diazoxide. The initial dose was approximately 1 mg / kg administered in divided doses. After the patient had been stably treated with 1 mg / kg for 1 to 2 weeks, the dose was titrated to approximately 1.5 mg / kg. After the patient had been stably treated with 1.5 mg / kg for 1 to 2 weeks, the dose was titrated to approximately 2.0 mg / kg. This process of increasing the dose by approximately 0.5 mg / kg at each titration step and continuing treatment for 1 to 2 weeks at each step continued until the patient showed an adequate response to treatment or the maximum dose of 5 mg / kg was reached. Potential responses to treatment may include reduction in body fat, lessening of hypotonia, increased lean body mass / fat mass ratio, lessening of overeating, reduction in waist circumference, weight loss, reduced irritability and aggressive behavior, and improvement in cardiovascular risk factors. Treatment with the drug is long-term and may continue for life.

[0604] In a second embodiment, patients with Smith-Magilli syndrome were treated with a controlled-release tablet formulation of diazoxidecholine. The initial dose was approximately 1.5 mg / kg once daily. After the patient had been stably treated with 1.5 mg / kg for 1 to 2 weeks, the dose was titrated to approximately 2.1 mg / kg. After the patient had been stably treated with 2.1 mg / kg for 1 to 2 weeks, the dose was titrated to approximately 2.7 mg / kg. This process of increasing the dose by approximately 0.6 mg / kg at each titration step and continuing treatment for 1 to 2 weeks at each step continued until the patient showed an adequate response to treatment or reached the maximum dose of 5 mg / kg. Potential responses to treatment may include reduction in body fat, lessening of hypotonia, increased lean body mass / fat mass ratio, lessening of overeating, reduction in waist circumference, weight loss, reduced irritability and aggressive behavior, and improvement in cardiovascular risk factors. Treatment with this drug is long-term and may continue for life.

[0605] In a third embodiment, patients with Smith-Magilli syndrome were treated with a controlled-release tablet formulation of diazoxidecholine. The initial dose was approximately 1.5 mg / kg once daily. After the patient had been stably treated with 1.5 mg / kg for 1 to 2 weeks, the dose was titrated to approximately 2.2 mg / kg. After the patient had been stably treated with 2.2 mg / kg for 1 to 2 weeks, the dose was titrated to approximately 2.9 mg / kg. This process of increasing the dose by approximately 0.7 mg / kg at each titration step and continuing treatment for 1 to 2 weeks at each step continued until the patient showed a sufficient response to treatment or reached the maximum dose of 5 mg / kg. Patients may also be treated with belaranib concurrently. Potential responses to treatment may include reduction in body fat, lessening of hypotonia, increased lean body mass / fat mass ratio, lessening of overeating, reduction in waist circumference, weight loss, reduced irritability and aggressive behavior, and improvement in cardiovascular risk factors. Treatment with the medication is long-term and may continue for life.

[0606] In a fourth embodiment, patients with Smith-Magilli syndrome were treated with a controlled-release tablet formulation of diazoxidecholine. The initial dose was approximately 1.5 mg / kg once daily. After the patient had been stably treated with 1.5 mg / kg for 1 to 2 weeks, the dose was titrated to approximately 2.3 mg / kg. After the patient had been stably treated with 2.3 mg / kg for 1 to 2 weeks, the dose was titrated to approximately 3.0 mg / kg. This process of increasing the dose by approximately 0.8 mg / kg at each titration step and continuing treatment for 1 to 2 weeks at each step continued until the patient showed a sufficient response to treatment or reached the maximum dose of 5 mg / kg. Patients may also be treated with an unacylated ghrelin analogue. Potential responses to treatment may include reduction in body fat, lessening of hypotonia, increased lean body mass / fat mass ratio, lessening of overeating, reduction in waist circumference, weight loss, reduced irritability and aggressive behavior, and improvement in cardiovascular risk factors. Treatment with the drug will be long-term and may continue for life.

[0607] In a fifth embodiment, patients with Smith-Magilli syndrome were treated with a controlled-release tablet formulation of diazoxidecholine. The initial dose was approximately 1.5 mg / kg once daily. After the patient had been stably treated with 1.5 mg / kg for 1 to 2 weeks, the dose was titrated to approximately 2.4 mg / kg. After the patient had been stably treated with 2.4 mg / kg for 1 to 2 weeks, the dose was titrated to approximately 3.3 mg / kg. This process of increasing the dose by approximately 0.9 mg / kg at each titration step and continuing treatment for 1 to 2 weeks at each step continued until the patient showed a sufficient response to treatment or reached the maximum dose of 5 mg / kg. Patients may also be treated with an MC4 agonist concurrently. Potential responses to treatment may include reduction in body fat, lessening of hypotonia, increased lean body mass / fat mass ratio, lessening of overeating, reduction in waist circumference, weight loss, reduced irritability and aggressive behavior, and improvement in cardiovascular risk factors. Treatment with the drug will be long-term and may continue for life.

[0608] In a sixth embodiment, patients with Smith-Magilli syndrome were treated with a controlled-release tablet formulation of diazoxidecholine. The initial dose was approximately 1.5 mg / kg once daily. After the patient had been stably treated with 1.5 mg / kg for 1 to 2 weeks, the dose was titrated to approximately 2.5 mg / kg. After the patient had been stably treated with 2.5 mg / kg for 1 to 2 weeks, the dose was titrated to approximately 3.5 mg / kg. This process of increasing the dose by approximately 1.0 mg / kg at each titration step and continuing treatment for 1 to 2 weeks at each step continued until the patient showed a sufficient response to treatment or reached the maximum dose of 5 mg / kg. Patients may also be treated with an MC4 agonist concurrently. Potential responses to treatment may include reduction in body fat, lessening of hypotonia, increased lean body mass / fat mass ratio, lessening of overeating, reduction in waist circumference, weight loss, reduced irritability and aggressive behavior, and improvement in cardiovascular risk factors. Treatment with the drug will be long-term and may continue for life.

[0609] All patents and other references cited in this specification demonstrate the skill of those skilled in the art to which this invention pertains, and are incorporated herein by reference in their entirety, including any tables and figures, as if each reference were individually incorporated herein by reference.

[0610] It will be readily apparent to those skilled in the art that the invention is well suited to achieving the stated objectives and advantages, as well as those inherent therein. The methods, variations, and compositions described herein as representing preferred embodiments are exemplary and not intended to be limiting of scope. Variations and other uses therein will be conceived by those skilled in the art, and they are encompassed within the spirit of the invention and defined by the scope of the claims.

[0611] Unless otherwise specified, the definitions provided herein are not intended to limit the meaning as commonly understood by those skilled in the art.

[0612] The invention described herein can be suitably practiced in the absence of any one or more elements or limitations not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” and “containing,” for example, should be interpreted broadly and without limitation. Furthermore, the terminology and wording used herein have been used as descriptive rather than restrictive terms, and are not intended to exclude any equivalents of the shown and described features or portions thereof, but it should be recognized that various modifications are possible within the scope of the claimed invention. Therefore, it should be understood that although the invention has been expressly disclosed through preferred embodiments and optional features, modifications and variations of the invention embodied herein can be made by those skilled in the art, and such modifications and variations are considered to fall within the scope of the invention.

[0613] This invention has been described broadly and generally herein. Each of the more narrower contents and subclasses falling within the general disclosure also forms part of this invention. This includes describing the invention generally by removing any incidental or negative limiting conditions from said class, regardless of whether the excluded contents are specifically described herein.

[0614] Other embodiments fall within the scope of the following claims. Furthermore, where features or aspects of the invention are described in the Markush group, those skilled in the art will recognize that the invention is therefore also described in the context of any single member or subgroup of the Markush group.

Claims

1. K ATP Use of channel openers in the preparation of a medicament used in a method of treating reduced lean body mass in subjects with Prader-Willi syndrome, wherein the K ATP Channel openers are diazoxides or their pharmaceutically acceptable salts.

2. The use as claimed in claim 1, wherein after administration of the drug for at least 10 weeks, the subject's lean body mass or lean body mass / fat mass ratio increases by at least 2%.

3. The use as claimed in claim 1, wherein after administration of the drug for at least 10 weeks, the subject's lean body mass or lean body mass / fat mass ratio increases by at least 3%.

4. The use as claimed in claim 1, wherein after administration of the drug for at least 10 weeks, the subject's lean body mass or lean body mass / fat mass ratio increases by at least 4%.

5. The use as described in claim 1, wherein the drug further comprises at least one other active ingredient.

6. The use as claimed in claim 1, wherein the method further comprises administering human growth hormone to the subject.

7. The use as described in claim 6, wherein the human growth hormone is administered by injection.

8. The use as claimed in claim 1, wherein the subject has been treated with growth hormone, and wherein the method includes co-administering the drug to the subject in addition to the growth hormone.

9. The use as claimed in claim 1, wherein the subject has been treated by administration of the drug, and wherein the method includes, in addition to the drug, co-administering an effective amount of growth hormone to the subject.

10. The use as claimed in claim 1, wherein the subject’s overeating symptoms are reduced by at least 10% after administration of the drug for at least 10 weeks.

11. The use as claimed in claim 1, wherein the subject’s overeating symptoms are reduced by at least 20% after at least 10 weeks of administration of the drug.

12. The use as claimed in claim 1, wherein the subject’s overeating symptoms are reduced by at least 30% after at least 10 weeks of administration of the drug.

13. The use as claimed in claim 1, wherein the circulating concentration of IGF-1 in the subject does not increase after at least 10 weeks of administration of the drug. 14.K ATP The use of a channel opener in the preparation of a drug, said drug, in a method of treating aggressive behavior in a subject suffering from Prad-Willi syndrome, wherein said K ATP Channel openers are diazoxides or their pharmaceutically acceptable salts.

15. The use as claimed in claim 14, wherein the method further comprises applying a second therapeutic product, wherein the second product is designed to further reduce the one or more aggressive behaviors. 16.K ATP Use of a channel opener in the preparation of a medicament used in a method of treating hyperghrelinemia in subjects with Prader-Willi syndrome, wherein the K ATP Channel openers are diazoxides or their pharmaceutically acceptable salts.

17. The use as described in any one of claims 1-16, wherein the drug is administered twice daily.

18. The use as described in any one of claims 1-16, wherein the drug is administered once daily.

19. The use as described in any one of claims 1-16, wherein the application is performed for one year or longer.

20. The use as described in any one of claims 1-16, wherein the diazoxide or a pharmaceutically acceptable salt thereof is administered orally.

21. The use as claimed in any one of claims 1-16, wherein the pharmaceutically acceptable salt is diazoxidecholine.

22. The use as described in claim 21, wherein the diazoxide choline is administered orally.

23. The use as described in any one of claims 1-16, wherein the drug comprises the drug that affects K. ATP At least one excipient that determines the release rate of the channel opener.

24. The use as claimed in any one of claims 1-16, wherein the drug comprises delaying the K ATP At least one excipient released by the channel opener.

25. The use according to any one of claims 1-16, wherein the medicament comprises at least one excipient selected from polyoxyethylene and hydroxypropyl methylcellulose.

26. The use according to any one of claims 1-16, wherein the medicament further comprises at least one other active ingredient selected from liraglutide, topiramate, naltrexone, melanocortin-4 receptor agonists and antidepressants.

27. The use as described in claim 26, wherein the antidepressant is a monoamine oxidase inhibitor, a tricyclic antidepressant, or a tetracyclic antidepressant.

28. The use as described in claim 27, wherein the monoamine oxidase inhibitor is selected from isocarboxazid, phenelzine sulfate, and transphenylcyclopropane sulfate; the tricyclic antidepressant is selected from doxepin, clomipramine, amitriptyline, maprine, desipramine, nortriptyline, desipramine, trimipramine, imipramine, and protriptyline; and the tetracyclic antidepressant is selected from mianserin, mirtazapine, maprotiline, oxaprazin, demiquamamine, leprotriptyline, triflucarbene, sprotiline, clotamethasone, azithromycin, alprazolam, and pyridindole.

29. The use as described in any one of claims 1-16, wherein the drug is formulated for administration to the subject for at least 10 weeks.

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