CN101043879A

CN101043879A - Pharmaceutical formulations of potassium atp channel openers and uses thereof

Info

Publication number: CN101043879A
Application number: CN 200580035520
Authority: CN
Inventors: 尼尔·M·科文; 肯尼思·B·卡施金
Original assignee: Essentialis Inc
Current assignee: Essentialis Inc
Priority date: 2004-08-25
Filing date: 2005-08-25
Publication date: 2007-09-26

Abstract

Provided are immediate or prolonged administration of certain potassium ATP (KATP) channel openers to a subject to achieve novel pharmacodynamic, pharmacokinetic, therapeutic, physiological, metabolic and compositional outcomes in the treatment of diseases or conditions involving KATP channels. Also provided are pharmaceutical formulations, methods of administration and dosing of KATP channel openers that achieve these outcomes and reduce the incidence of adverse effects in treated individuals. Further provided are method of co-administering KATP channel openers with other drugs to treat diseases of humans and animals.

Description

The pharmaceutical preparation of potassium ATP channel openers and application thereof

Invention field

The present invention relates to be used for the treatment of multiple disease and illness such as diabetes and fat potassium ATP (K _ATP) pharmaceutical preparation and the application thereof of channel opener.

Background of invention

Following description about background of invention only is provided in order to help to understand the present invention, and is not admitted to describe or form prior art of the present invention.

ATP sensitive potassium (K _ATP) passage is by combining cellular metabolism and playing an important role in multiple tissue with bioelectric.This K _ATPPassage has been confirmed as two kinds of uncorrelated proteinic eight aggressiveness complex with stoichiometry assembling in 4: 4.First kind is that the duct forms subunit: Kir6.x, and it forms the K of inner rectification ⁺Passage; Second kind is ABC (ATP is in conjunction with box) transporter, also is considered to sulfonylureas receptor (SURx) (people such as Babenko, Annu.Rev.Physiol., 60:667-687 (1998)).It is the K of many types that the Kir6.x duct forms subunit _ATPPassage is common, and have two infer pass through that orifice ring (H5) connects stride film district (being defined as TM1 and TM2).The subunit that comprises the SUR receptor comprises a plurality of film district and two nucleotide-binding folds of striding.

According to K _ATPThe tissue positioned of passage, they are to exist with the different subtype that is produced by the multiple combination assembling of SUR and Kir subunit or subspecies.The combination of SUR1 and Kir6.2 subunit (SUR1/Kir6.2) typically forms lipocyte and B cells of pancreas type K _ATPPassage, and the combination of SUR2A/Kir6.2 and SUR2B/Kir6.2 or Kir6.1 typically forms heart-type and smooth muscle type K respectively _ATPPassage (people such as Babenko, Annu.Rev.Physiol., 60:667-687 (1998)).Evidence suggests that also described passage can comprise the Kir2.x subunit.This class potassium channel can be suppressed by ATP in the cell, is activated by nucleoside diphosphate in the cell.Described K _ATPPassage can with the metabolism state of cell and plasmalemma potential be got in touch and play a crucial role in regulating cellular activity by this way.In most of excitatory cell, K _ATPPassage is closed under normal physiological conditions and is open when this tissue is subjected to metabolism harm (as: as (ATP: when ADP) ratio descends).This has promoted K+ outflow and cell hyperpolarization, thereby prevents voltage maneuverability Ca ²⁺Passage (VOCs) is opened.(Prog?Res?Research，(2001)31：77-80)。

Potassium channel openers (PCOs or KCOs) (being also referred to as passage activator or channel agonist) is a different chemical compound on one group of structure, and described chemical compound does not have the K that their antagonisms of tangible connection are suppressed by the intracellular nucleic thuja acid _ATPThe common pharmacophore of the ability of passage.Diazoxide is at pancreatic beta cell moderate stimulation K _ATPA kind of PCO of passage (seeing people such as Trabe, Pfluegers Arch kEur J Physiol, 407,493-99 (1986)).Pinacidil and chromakalim (see people such as Escande, Biochem Biophys Res Commun, 154,620-625 (1988) for the PCOs of activation sarolemma potassium channel; Babenko waits the people, J Biol Chem, 275 (2), 717-720 (2000)).Reactivity to diazoxide has shown first nucleotide-binding fold (NBF1) of striding film district (TMD6-11) and SUR1 subunit that is present in the 6th to the 11st prediction.

Diazoxide is for having formula 7-chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide (empirical formula C ₈H ₇ClN ₂O ₂S) non-diuretic benzothiadiazine derivatives is used for the treatment of two kinds of various disease indications with three kinds of different dosage form supply the markets: hyperinsulinemia hypoglycemia 1) hypertensive emergency and 2).Hypertensive emergency can use Hyperstat IV---a kind of diazoxide preparation (regulating pH value to 11.6) treatment that is used for the intravenous injection use with sodium hydroxide.Hyperstat IV is excessive with treatment malignant hypertension or sulfonylureas with dosage administration in peripheral vein of injecting.In this purposes, diazoxide plays the potassium channel of open vascular smooth muscle, in tranquillization horizontal stable transmembrane potential and prevent the effect that vascular smooth muscle shrinks.

The hyperinsulinemia hypoglycemia can use Proglycem---and a kind of can be used for, treat to the diazoxide of the oral medicinal form of baby, child and adult's administration.Its oral suspensions that can be used as a kind of chocolate mint flavored uses, and described oral suspensions comprises hydrochloric acid, poloxamer 188, propyl parabene and the water of 7.25% ethanol, Sorbitol, chocolate mass spice, propylene glycol, aluminium-magnesium silicate, sodium carboxymethyl cellulose, mint flavouring, sodium benzoate, methyl parahydroxybenzoate, adjusting pH value.Diazoxide also can be used as to have and comprises lactose and magnesium stearate at the capsule of the diazoxide of interior 50 or 100mg and use.

Some experimental preparations of diazoxide are tested in the human and animal.These be included in drug influence kinetics and the pharmacokinetics research oral solution and as antihypertensive exploitation but never commercial tablet (is seen people such as Calesnick, J.Pharm.Sci.54:1277-1280 (1965); People such as Reddy, AAPS Pharm Sci Tech 4 (4): 1-98,9 (2003); United States Patent (USP) 6,361,795).

The current oral formulations of diazoxide is marked as: administration every day two or three times, 8 or 12 hours at interval.The most of patient who accepts diazoxide is administered three times every day.The commodity of diazoxide and experimental preparation are released to feature with the quick medicament after the absorption that discharges fully in about 2 hours.

The current oral formulations that is used for the treatment of the diazoxide of purposes causes the adverse side effect of certain limit, comprise: dyspepsia, feel sick diarrhoea, fluid retention, edema, the minimizing of sodium, chloride and urate excretion rate, hyperglycemia, vomiting, stomachache, intestinal obstruction, tachycardia, cardiopalmus and headache (seeing the drug packaging description of current Proglycem).The oral medication of diazoxide is used to experience the individuality of severe disease, and wherein the treatment failure causes significant M ﹠ M.Because the treatment benefit is significantly tolerated the described adverse side effect of oral administration.The described adverse side effect of oral diazoxide has limited this medicine in the practicality by the dosage treatment adiposis patient of the label range of every day 3 to 8mg/kg.

Reported the effect of diazoxide in diabetes and fat animal model (as: fat and thin Zucker rat).See, for example, people such as Alemzadeh (Endocrinology 133:705-712 (1993), people such as Alemzadeh (Metabolism 45:334-341 (1996)), people such as Alemzadeh (Endocrinology 140:3197-3202 (1999)), people such as Stanridge (FASEB J 14:455-460 (2000)), people such as Alemzadeh (Med Sci Monit 10 (3): BR53-60 (2004)), (Endocrinology 145 (12): 3476-3484 (2004)) for Alemzadeh and Tushaus, 194-199 (1995)) and people (Endocrinology141:3630-3637 (2000)) such as Surwit people such as Aizawa (J ofPharma Exp Ther 275 (1):.

Reported the effect of diazoxide in the mankind that suffer from obesity or diabetes.See that for example, (Diabetes 28 (4): 287-291 (1979) for Wigand and Blackard; Evaluation of diazoxideon insulin receptors), people such as Ratzmann (Int J Obesity 7 (5): 453-458 (1983); Glucose tolerance and insulin sensitivity in moderately obese patients), people such as Marugo (Boll Spec It Biol Sper 53:1860-1866 (1977); Moderate dose diazoxidetreatment on weight loss in obese patients), people such as Alemzadeh (J Clin EndocrMetab 83:1911-1915 (1998); Low dose diazoxide treatment on weight loss inobese hyperinsulinemic patients), people such as Guldstrand (Diabetes and Metabolism28:448-456 (2002); Diazoxide in obese type II diabetic patients), (Diabetes Care 27 (9): 2191-2197 (2004) for people such as Ortqvist; Beta-cell function measured bycirculating C-peptide in children at clinical onset of type 1 diabetes), (Diabetes Care 21 (3): 427-430 (1998) for people such as Bjork; Effect of diazoxide on residualinsulin secretion in adult type I diabetes patients) and people such as Qvigstad, (DiabeticMedicine 21:73-76 (2004)).

United States Patent (USP) the 5th; the method of a kind of normalization individuality (fasting glucose of acting normally and insulin level and in oral glucose tolerance test performance blood sugar level to improve and be selected from insulin level at least a in the insulin peak of insulin peak, increase of delay and the insulin peak that secondary improves unusual) blood glucose and insulin level has been described for 284, No. 845.According to this reference, described method is included in each before the meal to carry out the administration of diazoxide from about 0.4 to the amount of effective normalization blood glucose of about 0.8mg/kg body weight and insulin level.

United States Patent (USP) the 6th, 197 has been described for No. 765 and have been used that diazoxide is used for the treatment of X syndrome and the complication that causes comprises hyperlipemia, hypertension, central obesity, hyperinsulinemia and glucose intolerance.According to this reference, diazoxide disturbs islet function by eliminating the endogenous insulin secretion, causes being equivalent to insulin defective and the hyperglycemia level that relies on the diabetics of exogenous insulin administration for normalization diabetics blood sugar level.

United States Patent (USP) the 2nd, 986 has been described for No. 573 and to be used for the treatment of hypertensive diazoxide and alkali metal salt.

United States Patent (USP) the 5th, 629 has been described the diazoxide that is used for partial ophthalmic drug delivery No. 045.

WO 98/10786 has described diazoxide and has comprised purposes in the relative obesity at the treatment X syndrome.

U.S. Patent Publication has been described for No. 2003/0035106 to contain and has been useful on the diazoxide that reduces the chemical compound that contains the fat food consumption.

U.S. Patent Publication has been described the purposes that in Bariatric Cox-2 inhibitor adds diazoxide for No. 2004/0204472.

U.S. Patent Publication has been described for No. 2002/0035106 and has been used to reduce the K that contains the fat food consumption _ATPChannel opener comprises the purposes of diazoxide and slaine.

Summary of the invention

The invention provides K _ATPThe pharmaceutical preparation of channel opener and be used for the treatment of multiple disease and illness comprises diabetes and fat purposes.But described preparation is a feature with biological utilisation.Be used for K of the present invention _ATPChannel opener carries out having after the administration of described chemical compound following any one or multiple character in vivo: (1) open SUR1/Kir6.2 potassium channel; (2) in conjunction with K _ATPThe SUR1 subunit of passage; And (3) suppress the insulin release of glucose induction.Preferably, K _ATPChannel opener is the K with whole 3 kinds of character _ATPChannel opener.K as defined above _ATPChannel opener preferably has the structure of chemical compound of the formula I-VII of following elaboration.

K by formula I definition _ATPChannel opener is as follows:

Formula I

Wherein:

R ^1aAnd R ^1b, when occurring, be independently selected from low alkyl group, the cycloalkyl of hydrogen, low alkyl group, replacement, cycloalkyl, the amino of replacement and the amino that replaces;

R ^2aAnd R ^2b, when occurring, be independently selected from hydrogen and low alkyl group;

X is 1,2 or 3 atomic links, wherein each atom is independently selected from carbon, sulfur and nitrogen, and each atom is randomly replaced by the amino of the lower alkoxy of the cycloalkyl of the low alkyl group of halogen, hydroxyl, low alkyl group, replacement, lower alkoxy, cycloalkyl, replacement, replacement, amino and replacement;

Its medium ring A and B are saturated, monounsaturated, polyunsaturated or aromatics independently of one another;

And all biological equivalent, comprise its salt, prodrug and isomer.

In specific embodiment, formula I can be included in the two keys between 1 and 2 or 2 and 3 that encircles A.When two keys appear at 1 and 2 interdigits of ring A, R ^2aDo not exist and R ^1aAnd R ^1bOne of do not exist.When two keys appear at 2 and 3 interdigits of ring A, R ^2bDo not exist and R ^1aAnd R ^1bOne of do not exist.In a preferred embodiment, R ^1aAnd R ^1bBe not amino.In another embodiment preferred, ring B does not comprise any hetero atom.

By formula II definition is the K of the subgenus of formula I _ATPChannel opener is as follows:

Formula II

Wherein:

R ¹Be selected from low alkyl group, cycloalkyl, cycloalkyl, the amino of replacement and the amino that replaces of hydrogen, low alkyl group, replacement;

R ^2aBe selected from hydrogen and low alkyl group;

Its medium ring B is saturated, monounsaturated, polyunsaturated or aromatics;

And all biological equivalent, comprise its salt, prodrug and isomer.

In the particular of formula II, X is C (R ^a) C (R ^b), R wherein ^aAnd R ^bBe independently selected from lower alkoxy, amino, sulfonamido, sulfamoyl, sulfonyl of cycloalkyl, lower alkoxy, the replacement of low alkyl group, cycloalkyl, the replacement of hydrogen, halogen, low alkyl group, replacement etc.In other embodiments, R ^aAnd R ^bBe independently selected from amine, alkyl sulphinyl, alkyl sulphonyl, alkyl sulfonyl amino of amino, the replacement of sulfonamido, the replacement of sulfonyl, the replacement of sulfinyl, the replacement of alkylthio group, sulfinyl, sulfonyl, the replacement of mercapto, alkylthio group, the replacement of oxygen base, the replacement of hydroxyl, replacement etc.In an embodiment preferred, R ¹Be not amino.In another embodiment preferred, ring B does not comprise any hetero atom.

By the formula III definition is the K of the subgenus of formula I _ATPChannel opener is as follows:

Formula III

Wherein:

R ^2bBe selected from hydrogen and low alkyl group;

Its medium ring B is saturated, monounsaturated, polyunsaturated or aromatics;

And all biological equivalent, comprise its salt, prodrug and isomer.

In the particular of formula III, X is C (R ^a) C (R ^b), R wherein ^aAnd R ^bBe independently selected from lower alkoxy, amino, sulfonamido, sulfamoyl, sulfonyl of cycloalkyl, lower alkoxy, the replacement of low alkyl group, cycloalkyl, the replacement of hydrogen, halogen, low alkyl group, replacement etc.In other embodiments, R ^aAnd R ^bBe independently selected from amine, alkyl sulphinyl, alkyl sulphonyl, alkyl sulfonyl amino of amino, the replacement of sulfonamido, the replacement of sulfonyl, the replacement of sulfinyl, the replacement of alkylthio group, sulfinyl, sulfonyl, the replacement of mercapto, alkylthio group, the replacement of oxygen base, the replacement of hydroxyl, replacement etc.In an embodiment preferred, R ¹Be not amino.In another embodiment preferred, ring B does not comprise any hetero atom.

By formula IV definition is the K of the subgenus of formula I _ATPChannel opener is as follows:

Formula IV

Wherein:

R ¹Be selected from low alkyl group, cycloalkyl, the amino of hydrogen, low alkyl group, replacement and the rudimentary amino that replaces;

R ^2aBe selected from the low alkyl group of hydrogen, low alkyl group and replacement;

R ³Be selected from low alkyl group, the amino of hydrogen, halogen, low alkyl group, replacement and the amino that replaces;

R ⁴Be selected from low alkyl group, the amino of hydrogen, halogen, low alkyl group, replacement and the amino that replaces;

And all biological equivalent, comprise its salt, prodrug and isomer.

In the particular of formula IV, R ¹Be low alkyl group (preferred ethyl or methyl); R ^2aBe hydrogen; And R ³And R ⁴Be halogen independently of one another.

In the preferred embodiment of formula IV, R ¹Be not amino.

In another embodiment of formula IV, R ¹Be methyl; R ^2aBe hydrogen; R ³Be selected from the cycloalkyl of amino, cycloalkyl and replacement of low alkyl group, amino, the replacement of hydrogen, halogen, low alkyl group, replacement; And R ⁴Be chlorine.

By formula V definition is the K of the subgenus of formula I _ATPChannel opener is as follows:

Formula V

Wherein:

R ^2bBe selected from the low alkyl group of hydrogen, low alkyl group and replacement;

And all biological equivalent, comprise its salt, prodrug and isomer.

In the particular of formula V, R ¹Be low alkyl group (preferred ethyl or methyl); R ^2bBe hydrogen; And R ³And R ⁴Be halogen independently of one another.

In the preferred embodiment of formula V, R ¹Be not amino.

In another embodiment of formula V, R ¹Be methyl; R ^2bBe hydrogen; R ³Be selected from the cycloalkyl of amino, cycloalkyl and replacement of low alkyl group, amino, the replacement of hydrogen, halogen, low alkyl group, replacement; And R ⁴Be chlorine.

K by formula VI definition _ATPChannel opener is as follows:

Formula VI

Wherein:

R ¹Be selected from low alkyl group, cycloalkyl, cycloalkyl, the amino of replacement and the rudimentary amino that replaces of hydrogen, low alkyl group, replacement, or R ¹Can with R ⁵Or R ⁶Be combined to form other ring;

R ⁵Be selected from low alkyl group, the amino of hydrogen, halogen, hydroxyl, low alkyl group, replacement, amino, sulfonyl, sulfamoyl and the sulfonamido of replacement, or R ⁵Can with R ¹Or R ⁶Be combined to form other ring;

R ⁶Be selected from low alkyl group, the amino of hydrogen, halogen, low alkyl group, replacement, amino, sulfonyl, sulfamoyl and the sulfonamido of replacement, or R ⁶Can with R ¹Or R ⁵Be combined to form other ring;

R wherein ¹With R ⁵, or R ¹With R ⁶, or R ⁵With R ⁶The ring that is combined to form is saturated, monounsaturated, polyunsaturated or aromatics;

R wherein ¹With R ⁵, or R ¹With R ⁶, or R ⁵With R ⁶The ring that is combined to form is randomly replaced by the amino of the low alkyl group of halogen, hydroxyl, low alkyl group, replacement, amino, replacement, sulfonyl, sulfamoyl and sulfonamido;

And all biological equivalent, comprise its salt, prodrug and isomer.

In an embodiment preferred, R ¹It is not amino substituent group.

In another embodiment of formula VI, R ⁵With R ⁶Be combined to form 6 yuan of rings.In another embodiment, R ⁵With R ⁶Be combined to form 6 yuan of rings, wherein have a nitrogen at least.Preferably, by R ⁵With R ⁶The ring that forms does not contain any hetero atom.

K by formula VII definition _ATPChannel opener is as follows:

Formula VII

Wherein:

And all biological equivalent, comprise its salt, prodrug and isomer.

In an embodiment preferred, R ¹It is not amino substituent group.

Unless otherwise noted, K among the application _ATPChannel opener has the K that one or more also preferably have whole three kinds of following character after should being understood that to refer to the administration of carrying out described chemical compound in vivo _ATPChannel opener: (1) open SUR1/Kir6.2 potassium channel; (2) in conjunction with K _ATPThe SUR1 subunit of passage; And (3) suppress the insulin release of glucose induction.Described K _ATPChannel opener preferably has the structure of any compound of formula I-VII; Or more preferably, R wherein ¹It is not the structure that amino and its medium ring B or its equivalent do not contain any compound of any heteroatomic formula I-VII; Or more preferably, the structure of any compound of formula II or III; Or more preferably, R wherein ¹It is not the structure that amino and its medium ring B or its equivalent do not contain any compound of any heteroatomic formula II or III; Or more preferably, described structure is a diazoxide.The invention still further relates to the structural variant or for example derivant, salt, prodrug or the isomer of biochemical equivalents of any compound of formula I-VII.Be used for other K of the present invention _ATPChannel opener comprises BPDZ62, BPDZ73, NN414, BPDZ154.

Via K _ATPChannel opener is by the analyzed in vitro of the insulin release of glucose induction, can be as people such as De Tullio, J.Med.Chem., the use rat Langerhans islet that 46:3342-3353 (2003) proposes or as people such as Bj  rklund, Diabetes, the human islets of langerhans of the use that 49:1840-1848 (2000) proposes is measured.

The invention provides K _ATPThe preparation of channel opener and equivalent thereof, for example controlled-release pharmaceutical formulation.In one embodiment, described controlled release preparation is formulated into and is used for oral administration.Described preparation contains in single-dose dosage between 10 to 100mg, between 25 to 100mg, between 100 to 200mg, between 200 to 300mg, between 300 to 500mg or the K between 500 to 1000mg _ATPChannel opener.In certain embodiments, the K that in preparation, contains _ATPThe dosage of channel opener can be based on being determined that promptly, described preparation can contain the K of every kg weight in patients 0.1-20mg in single-dose dosage by the patient's of administration body weight _ATPChannel opener, or the K of every kg weight in patients 0.1-0.5mg _ATPChannel opener, or the K of every kg weight in patients 0.5-1mg _ATPChannel opener, or the K of every kg weight in patients 1-2mg _ATPChannel opener, or the K of every kg weight in patients 2-5mg _ATPChannel opener, or the K of every kg weight in patients 5-10mg _ATPChannel opener, or the K of every kg weight in patients 10-15mg _ATPChannel opener, or the K of every kg weight in patients 15-20mg _ATPChannel opener.

The present invention also provides and has contained the K that obtains by at least a following method _ATPThe controlled-release pharmaceutical formulation of channel opener: (a) granularity refinement comprises pulverizing, spray drying or other micronization technology; (b) use described K _ATPThe pharmaceutical salts of channel opener; (c) make spent ion exchange resin; (d) use inclusion complex, for example cyclodextrin; (e) with described K _ATPChannel opener with comprise the solubilizing agent of low viscosity hypromellose, low viscosity methylcellulose or the excipient or the compacting together of its compositions of similar functions; (f) before formulated, with described K _ATPChannel opener and salt associate; (g) use described K _ATPThe solid dispersion of channel opener; (h) use self-emulsifying drug delivery systems; (i) in described preparation, add one or more surfactants; (j) use nanoparticle; Or (k) these methods of coupling.

The present invention also provides and has contained K _ATPThe controlled-release pharmaceutical formulation of channel opener, it comprises at least a remarkable inhibition K _ATPThe passage activator discharges the composition of (until through after the stomach) from described preparation.As used in the present invention, " significantly suppress " meaning is at stomach between transit period, and medicine is lower than 15% release from described preparation, more preferably is lower than 10% release at least, or more preferably is lower than 5% release at least.The mensuration that discharges can be with reference to USP standard, uses digestion instrument through verification to carry out external gastric solubleness and goes out to detect.(American Pharmacopeia, the 711st chapter (2005)).

The present invention also provides K _ATPThe oral drug preparation of channel opener, it comprises at least a remarkable inhibition K _ATPChannel opener discharges the composition of (until through after the stomach) from described preparation.A kind ofly be selected from following composition and significantly suppress drug release between transit period by in described preparation, containing: (a) as the pH sensitive polymer or the copolymer of the pressed coated on the tablet to be implemented in stomach; (b) as the pH sensitive polymer or the copolymer of the thin film on the tablet; (c) as the pH sensitive polymer or the copolymer of the thin film of encapsulated system; (d) be used for the pH sensitive polymer or the copolymer of encapsulate microgranule; (e) as the non-soluble polymer or the copolymer of the pressed coated on the tablet; (f) as the non-soluble polymer or the copolymer of the thin film on the tablet; (g) as the non-soluble polymer of the thin film of encapsulated system; (h) be used for the non-soluble polymer of microgranule; (i) in osmotic pump system, introduce described preparation; (j) use the system that controls by ion exchange resin; And (k) these methods of coupling, wherein said pH sensitive polymer or copolymer degradation resistant under acid condition.

The present invention also provides K _ATPThe controlled-release pharmaceutical formulation of channel opener, wherein said preparation comprise and impelling during 2-4 after the administration hour or at K during 4-8 after the administration hour or during 8-24 after the administration hour _ATPChannel opener continues at least a composition of release.These preparations are feature to have one of following ingredients: (a) pH sensitivity polymeric coatings; (b) hydrogel coating; (c) film coating, the diffusion rate of its control medicine from coated substrate; (d) can lose the substrate of separating, medicine piller, granule or the microgranule of its control drug release rate (e) polymer coating, its can be further by encapsulate or be pressed into tablet; (f) contain the osmotic pump system of described medicine; (g) the coated tablet form of the compacting of described medicine; Or (h) combination of these methods.

As used in the present invention, the described substrate of separating of losing is the core of tablet formulation, and when contacting hydrous environment, it begins disintegrating procedue, and this has promoted medicine to discharge from described substrate.Control the release rate of medicine by the dissolubility of medicine and the disintegrate rate of substrate from described tablet.

Above-mentioned preparation also can contain one or more other pharmaceutically active agents (rather than K _ATPChannel opener), described pharmaceutically active agents can be used for treating and is selected from following illness: obesity, prediabetes, diabetes, hypertension, depression, cholesterol rising, fluid retention, other fat relevant comorbidities, ischemic and reperfusion injury, epilepsy, schizophrenia, mania or other mental sickness.

The present invention also provides K _ATPA kind of controlled-release pharmaceutical formulation of channel opener, wherein cause at least a following result: (a) suppress the fasting insulin secretion to individual administration fat, overweight or that have obesity to be inclined to, (b) suppress the zest insulin secretion, (c) increase energy expenditure, (d) increase fatty beta oxidation, or (e) appetite-suppressing was crossed Sheng lasting about 24 hours.

The present invention also provides K _ATPA kind of controlled-release pharmaceutical formulation of channel opener, wherein cause at least a following result: (a) suppress the fasting insulin secretion to individual administration fat, overweight or that have obesity to be inclined to, (b) suppress glucose zest insulin secretion, (c) increase energy expenditure, (d) increase fatty beta oxidation, or (e) appetite-suppressing was crossed Sheng lasting about 18 hours.

The present invention also provides K again _ATPA kind of controlled-release pharmaceutical formulation of channel opener, described controlled-release pharmaceutical formulation is when being delivered medicine to obesity, overweight or cause following at least a kind of result when obesity tendency individual arranged: (a) suppress the fasting insulin secretion, (b) suppress glucose zest insulin secretion, (c) increase energy expenditure, (d) increase fatty beta oxidation, or (e) appetite-suppressing was crossed Sheng lasting about 24 hours.

The present invention also provides K _ATPA kind of controlled-release pharmaceutical formulation of channel opener, described controlled-release pharmaceutical formulation is when being delivered medicine to obesity, overweight or cause at least a following result when obesity tendency individual arranged: (a) suppress the fasting insulin secretion, (b) suppress glucose zest insulin secretion, (c) increase energy expenditure, (d) increase fatty beta oxidation, or (e) appetite-suppressing was crossed Sheng lasting about 18 hours.

The invention provides a kind of method for the treatment of hypoglycemia, described method comprises K _ATPThe oral administration of the controlled release preparation of channel opener.

The present invention also provides a kind of obesity, overweight or the method for the comorbidities that obesity is relevant in the individuality of obesity tendency is arranged for the treatment of, and described method comprises the K that treats effective dose _ATPThe solid oral dosage form of channel opener or K _ATPThe administration of the controlled-release pharmaceutical formulation of channel opener.In an embodiment preferred, administration is to be no more than twice in per 24 hours, or per 24 hours once.

It is a kind of fat, overweight or have and realize the method that loses weight in the individuality of obesity tendency that the present invention also provides, and described method comprises the K that treats effective dose _ATPThe solid oral dosage form of channel opener or K _ATPThe administration of the controlled-release pharmaceutical formulation of channel opener.In an embodiment preferred, administration is to be no more than twice in per 24 hours, or per 24 hours once.Dosage every day of administration is preferably 50-180mg.In some embodiments, when beginning this method, the Body Mass Index that described obese individuals has is greater than 30kg/m ², or greater than 35kg/m ², or greater than 40kg/m ², or greater than 50kg/m ², or greater than 60kg/m ²

The present invention also provides a kind of obesity, overweight or the method that loses weight of the individuality of obesity tendency is arranged of keeping, and described method comprises the K that treats effective dose _ATPThe solid oral dosage form of channel opener or K _ATPThe administration of the controlled-release pharmaceutical formulation of channel opener.In case take place in the obese individuals to lose weight to a certain degree, preferably keep body weight, otherwise weight recovery.In an embodiment preferred, administration is to be no more than twice in per 24 hours, or per 24 hours once.

The present invention also provides a kind of to be increased overweight, fat or the method for energy expenditure of the individuality of obesity tendency is arranged, and described method comprises the K that treats effective dose _ATPThe solid oral dosage form of channel opener or K _ATPThe administration of the controlled-release pharmaceutical formulation of channel opener.In an embodiment preferred, administration is to be no more than twice in per 24 hours, or per 24 hours once.In some embodiments, when beginning this method, the Body Mass Index that described individuality has is greater than 20kg/m ², or greater than 25kg/m ², or greater than 30kg/m ², or greater than 35kg/m ², or greater than 40kg/m ², or greater than 50kg/m ², or greater than 60kg/m ²

The present invention also provides a kind of to be increased overweight, fat or the method for fatty beta oxidation of the individuality of obesity tendency is arranged, and described method comprises the K that carries out effective dose _ATPThe solid oral dosage form of channel opener or K _ATPThe administration of the controlled-release pharmaceutical formulation of channel opener.In an embodiment preferred, administration is to be no more than twice in per 24 hours, or per 24 hours once.In some embodiments, when beginning this method, the Body Mass Index that described individuality has is greater than 20kg/m ², or greater than 25kg/m ², or greater than 30kg/m ², or greater than 35kg/m ², or greater than 40kg/m ², or greater than 50kg/m ², or greater than 60kg/m ²

The present invention also further provides a kind of and has reduced overweight, fat or the method for interior fat of the individuality of obesity tendency is arranged, and described method comprises the K that carries out effective dose _ATPThe solid oral dosage form of channel opener or K _ATPThe administration of the controlled-release pharmaceutical formulation of channel opener.In an embodiment preferred, administration is to be no more than twice in per 24 hours, or per 24 hours once.

The present invention also further provides a kind of delay or has stoped the prediabetes individuality to be converted into the method for diabetes, and described method comprises the K that carries out effective dose _ATPChannel opener or K _ATPThe administration of the controlled-release pharmaceutical formulation of channel opener.In an embodiment preferred, administration is to be no more than twice in per 24 hours, or per 24 hours once.

The present invention also provides a kind of method of recovering the NGT of prediabetes individuality, and described method comprises the K that carries out effective dose _ATPChannel opener or K _ATPThe administration of the controlled-release pharmaceutical formulation of channel opener.In an embodiment preferred, administration is to be no more than twice in per 24 hours, or per 24 hours once.

The present invention also provides a kind of method of recovering the NGT of diabetic individual, and described method comprises the K that carries out effective dose _ATPChannel opener or K _ATPThe administration of the controlled-release pharmaceutical formulation of channel opener.In an embodiment preferred, administration is to be no more than twice in per 24 hours, or per 24 hours once.

The present invention also further provides a kind of method that postpones or stop individual diabetes process, and described method comprises the K that carries out effective dose _ATPChannel opener or K _ATPThe administration of the controlled-release pharmaceutical formulation of channel opener.In an embodiment preferred, administration is to be no more than twice in per 24 hours, or per 24 hours once.

The method that the present invention also provides a kind of prevention or treatment weight increase, glucose tolerance reduces or the dyslipidemia relevant with the use psychosis treated the patient, described method comprises the K that carries out effective dose _ATPChannel opener or K _ATPThe controlled-release pharmaceutical formulation of channel opener in company with administration.In an embodiment preferred, administration is to be no more than twice in per 24 hours, or per 24 hours once.

The present invention also provides a kind of obesity or bulimiac method for the treatment of following patient: Prader-Willi syndrome (Prader-Willi Syndrome) patient, the Froehlich syndrome (Froelich ' sSyndrome) patient, Cohen syndrome (Cohen Syndrome) patient, Sa Mite syndrome (Summit Syndrome) patient, alstrom syndrome (Alstrom Syndrome) patient, Bauer wise man gloomy syndrome (Borjeson Syndrome) patient or Ahmedabad-other Dare syndrome (Summit Syndrome) patient, described method comprises the K that carries out effective dose _ATPChannel opener or K _ATPThe administration of the controlled-release pharmaceutical formulation of channel opener.In an embodiment preferred, administration is to be no more than twice in per 24 hours, or per 24 hours once.

The present invention also provide a kind of be used for the treatment of suffer from the I type, the patient's of II type, III type or IV type hyperlipoproteinemia obesity and the method that triglyceride increases, described method comprises the K that carries out effective dose _ATPChannel opener or K _ATPThe administration of the controlled-release pharmaceutical formulation of channel opener.In an embodiment preferred, administration is to be no more than twice in per 24 hours, or per 24 hours once.

The present invention also provides a kind of and has been reduced in the disease for the treatment of the curee because of carrying out K _ATPThe administration of channel opener and the method for the incidence rate of adverse reaction that causes, described method obtains via any following manner: (a) use a kind of dosage form, it has reduced C with respect to present diazoxide oral administration mixed suspension or capsule product when administration _MaxThereby, reduced the incidence rate of the adverse side effect related with peak drug concentration; (b) use a kind of dosage form, it is delayed to and just discharges after the stomach transhipment is finished, thereby has reduced the incidence rate that discharges the adverse side effect that is associated with medicine under one's belt; (c) predose is in inferior treatment level and increases every day dosage until reaching therapeutic dose in progressively mode, and wherein number of steps is 2 to 10, with the incidence rate of the adverse side effect that is reduced in the of short duration generation of treatment initial stage; (d) use minimal effective dose obtaining ideal therapeutic effect, thereby reduce the incidence rate of the dependent adverse side effect of dosage; Or (e) in every day, optimize the administration time of dosage with relative each meal.

The method that the present invention also provides a kind of weight increase, dyslipidemia or glucose tolerance that prevents to use the patient of psychosis treatment to reduce, described method comprises carries out K _ATPThe administration of the pharmaceutical preparation of channel opener.

The present invention also further comprises the method that a kind of weight increase, dyslipidemia or glucose tolerance for the treatment of the patient who uses the psychosis treatment reduces, and described method comprises carries out K _ATPThe administration of the pharmaceutical preparation of channel opener.

The present invention also provides a kind of treatment to be reduced to the method for the disease of feature with obesity, bulimia nerovsa, dyslipidemia or energy expenditure, described disease comprises: (a) Prader-Willi syndrome, (b) Froehlich syndrome, (c) Cohen syndrome, (d) Sa Mite syndrome, (e) alstrom syndrome, (f) the gloomy syndrome of Bauer wise man, (g) Ahmedabad-other Dare syndrome, or (h) I, II, III and IV type hyperlipoproteinemia, described method comprises carries out K _ATPThe administration of the pharmaceutical preparation of channel opener.

The present invention also provides K _ATPA kind of pharmaceutical preparation of channel opener, it also comprises except that K _ATPThe pharmaceutically active agents that channel opener is outer.In said preparation, the other drug activating agent can be used for treating and is selected from following illness: obesity, prediabetes, diabetes, hypertension, depression, cholesterol rising, fluid retention or other comorbiditieses relevant with obesity, ischemic and reperfusion injury, epilepsy, schizophrenia, mania and other mental diseases.

The K that contains described herein _ATPThe preparation of channel opener provides compliance, usefulness and the safety that improves, and the coupling preparation with other reagent is provided.Described coupling preparation comprises K _ATPChannel opener and one or more have the coupling preparation of other pharmaceutically active agents additional or similar activity or target.Other can with K _ATPChannel opener is in conjunction with the obesity that is used for the treatment of the individuality that the obesity tendency is arranged or keep its pharmaceutically active agents that loses weight to comprise, but be not limited to, sibutramine, orlistat, phentermine, Rimonabant, diuretic, antuepileptic or other treatment purposes comprise slimming pharmaceutically active agents.In case take place in the obese individuals to lose weight to a certain degree, preferably keep body weight, otherwise weight recovery.Other can with K _ATPThe pharmaceutically active agents of channel opener combined treatment type 2 diabetes mellitus or prediabetes comprises: acarbose, miglitol, metformin, repaglinide, Nateglinide, rosiglitazone (rosiglitizone), pioglitazone (proglitizone), ramipril, metaglidasen, or any other improves the pharmaceutically active agents of insulin sensitivity or glucose utilization or glycemic control, and wherein its binding mode is not increase insulin secretion.Other can with K _ATPThe pharmaceutically active agents of the comorbidities that channel opener combined treatment obesity is relevant comprises the medicine that is used for low cholesterol, the medicine that is used to bring high blood pressure down, the anti-inflammatory drug of non-cox-2 inhibitor, antidepressants, the medicine that is used for the treatment of urinary incontinence, or the conventional other drug that is used for the treatment of the disease situation, compare in overweight or obese patient with the individuality of normal type, the sickness rate of these diseases increases, and described medicine includes but not limited to: be used for the treatment of atherosclerosis, osteoarthritis, intervertebral disk hernia, the degeneration of knee joint and hip, breast carcinoma, carcinoma of endometrium, cervical cancer, colon cancer, leukemia and carcinoma of prostate, hyperlipemia, asthma/RAD, cholelithiasis, gastroesophageal reflux disease (GERD), obstructive sleep apnea, obesity hypoventilation syndrome, recurrent ventral hernia, the medicine of menoxenia and infertility.

In this article, term " treatment effectively " or " effective dose " expression effectively prevent, alleviate or improve one or more symptoms of disease or medical disorder, and/or prolong the curee's who is treated the material of survival or the consumption of material.

Disease or illness and the route of administration separately that to be treated considered in term " pharmaceutically acceptable " expression, and the material of being identified does not have and causes that quite careful doctor avoids carrying out to the patient character of the administration of described material.For example, it is aseptic substantially needing such material usually, as is used for injection.

As used in the present invention, term " compositions " refers to therapeutic purposes are suitable for the preparation of animal subject administration to expection, and it contains at least a pharmaceutical active compounds and at least a pharmaceutically acceptable carrier or excipient.Other terms used in the present invention define hereinafter.

Adipose cell: a kind of animal connective tissue cell, it is specifically designed to the synthetic of fat and stores.

Agonist: a kind of chemical compound, it has the affinity of pair cell receptor and stimulates common physiologically active by naturally occurring material incentive in the cell receptor place, triggers biochemical response.The agonist of receptor also can be considered to the activator of receptor.

Approximately: being used for the meaning of the present invention is to add deduct 10% at quantitative term.

Fatty tissue: the main tissue of forming by adipose cell.

Teenager: the age 10 was to 19 years old people.

Adiponectin: produce and special excretory a kind of proteohormone by the adipose cell of regulating lipid and glucose metabolism.Adiponectin influences the response of health to insulin.Adiponectin also has for the anti-inflammatory effect of lining at the cell of blood vessel wall.

By giving the symptom of certain drug composition for improved particular disorder: refer to any alleviating (no matter being persistent or temporary transient), stablize or changing of can being impelled by the administration of described compositions or be associated.

Analog: a kind of chemical compound, it is structurally similar to another chemical compound, but has an atom difference at least.

Antagonist: a kind of material, it trends towards offsetting the effect of another material, and as a kind of medicine, it combines with cell receptor and does not cause biological respinse.

Atheromatous plaque: because atherosclerotic effect, cumulative cholesterol and fatty material in blood vessel.

The bariatrician operation: the operation technique of certain limit, it is designed to help processing or treatment of obesity and class edge disease thereof.

β cell tranquillization: temporarily the β cell is in a kind of situation, wherein exists because insulin secretion is suppressed the metabolic stress minimizing that is caused.

Bilamellar: a kind of composition of pharmaceutical preparation, its lamination by two kinds of different materials is formed.

Bioavailability: refer to amount or degree that effective substances is gone up in treatment, it discharges from pharmaceutical preparation, and the drug effect site of expecting in health becomes and can utilize.The amount of drug release and degree can be established by pharmacokinetic parameter, and described pharmacokinetic parameter is the area (AUC) under blood or the plasma drug level-time graph and the peak value blood or the plasma concentration (C of medicine for example _Max).

Bioequivalent: when carrying out administration with identical molar dose under similar condition, active substance becomes utilizable speed and degree when not having significant difference in the drug effect site, and two kinds of preparations of described identical active substance are bioequivalent." preparation " can comprise the free alkali of described active substance or the different salt of described active substance in its definition.Can be via reaching external method proof bioequivalence in some bodies.These methods with the descending of preference, comprise pharmacokinetics research, drug influence dynamics research, clinical research and in vitro study.Especially, use the statistics standard, measure for example blood or the area under plasma drug level-time graph (AUC) and the peak value blood or the plasma concentration (C of medicine with pharmacokinetics _Max) the expression bioequivalence.

Cannabined receptor: the receptor in Endocannabinoids (EC) system relevant with food intake and tobacco dependence.The blocking-up Cannabined receptor can reduce to the dependency of Nicotiana tabacum L. with to the addiction of food.

The associating: refer between two or more projects or among any associating.Described associating can be two or more independently projects, for example two kinds of compositionss or two kinds of aggregations.Can be its mixing, for example one mixing of two or more projects, or its any variation.

Compositions: refer to any mixture.It can be solution, suspension, liquid, powder, paste, aqueous, non-water or its combination in any.

Compressed tablet: tablet by exerting pressure to the small pieces substrate of certain volume and forming in mould.

The coated tablet of compacting: by adding the tablet that coating forms via compacting to the compressed tablet heart that contains pharmaceutical actives.

Derivant: a kind of via modifying or replacing and the chemical substance of deriving and obtaining from another material.

Every day dosage: the medicine total amount of during 24 hours, taking in, no matter take in single dose or multidose.

Diazoxide: 7-chloro-3-methyl-2-H-1,2,4-benzothiadiazine 1,1 dioxide has empirical formula C ₈H ₇C ₁N ₂O ₂S and 230.7 molecular weight.

Encapsulated system: a kind of architectural feature that in capsule for medicine for example, contains medicine.The gel that mixes medicine also is considered to a kind of encapsulated system.

Equivalent: the amount that in analysis or when curee's administration, produces the medicaments derivative of answering with true quantitative non-drug derivative equivalent.

Fatty acid synthase: the main enzyme of multienzyme complex, its catalysis S-acetyl-coenzyme-A, malonyl CoA and NADPH form cetylate.

Gastric lipase: a kind of secretion, the triglyceride hydrolysis that its catalysis is edible to the gastrointestinal enzyme.

Fluidizer: the composition of a kind of non-activity of pharmaceutical preparation, it prevents the caking at the procedure of processing mesostroma.

Hyperinsulinemia: very high blood insulin level, it is different from insulism (by the too much insulin of islet secretion).Hyperinsulinemia can be the result of many illness, for example obesity and gestation.

Insulism: by the too much insulin of islet secretion.

Hyperlipemia: be shown in for example generic term that improves of the concentration of cholesterol, triglyceride and lipoprotein of any or whole lipids in the blood plasma.

Bulimia nerovsa: picked-up is greater than the food of optimal number.

The composition of pharmaceutical composition: refer to one or more materials that are used for pharmaceutical compositions.Composition can refer to active component (medicament) or other materials in the described compositions.Composition can comprise water and other solvents, salt, buffer, surfactant, water, nonaqueous solvent and correctives.

Insulin resistant: a kind of illness, wherein the tissue of health has reduced their responses to insulin.

Ischemia injury:, common because the arterial blood supply is obstructed or insufficient blood flow causes histanoxia by the tissue injury that hypoxia causes.

Ketoacidosis: in bodily tissue and body fluid, follow ketoboidies to accumulate the acidosis of (ketoacidosis), as diabetic acidosis.

Test kit: the association that refers to packing.The association of a packing can randomly comprise a label or some labels, the explanation and/or the reagent that use with described association.

Kir:K _ATPThe duct of passage forms subunit.Also be construed to K _ATPThe inward rectification subunit of passage.Generally exist and seldom as the Kir2.x subspecies with Kir6.x.

K _ATPPassage: a kind of duct by the associating sulfonylureas receptor of 4 copies and 4 copies forms the ATP sensitive potassium-channel of the cross-cell membrane that subunit Kir forms.Exciting described passage can cause the film hyperpolarization.

The product (16kD) of leptin: ob (obesity) locus.It is found in the mammiferous blood plasma and plays hormonal action, can reduce food intake and increase energy expenditure.

Lipogenesis: new lipid mainly is the generation of triglyceride.It relies on the multiple different enzyme and the effect of transport molecule.

Steatolysis: the comprehensive function by plurality of enzymes reduces fat.

Lipoprotein lipase: a kind of enzyme of hydrolase, its catalyzing glycerol three esters and water reaction produce diglyceride (diacylglyerol) and a kind of fatty acid anion.Triglyceride in this enzyme hydrolysis Chylomicron, very low density lipoprotein (VLDL), the low density lipoprotein, LDL, and diglyceride.

Lubricant: the composition of a kind of non-activity of pharmaceutical preparation, it makes material flow in different procedure of processings, particularly tabletting.

Microgranule: the granule that forms in the development process of pharmaceutical preparation, it can carry out coating before generating final dosage form.

Obesity: owing to fat in health is excessively accumulated the weight increase that exceeds skeleton and psychological need limit that causes.Formal being defined as has greater than 30kg/m ²Body Mass Index.

Obesity tendency: individual because genetic predisposition or previous obesity medical history are on the average risk of the obesity that becomes.

The comorbidities that obesity is relevant: any disease or the illness of animal or human's class that sickness rate increases in fat or overweight individuality.Such illness comprises: hypertension, prediabetes, type 2 diabetes mellitus, osteoarthritis and cardiovascular disease.

The release of infiltration control: a kind of pharmaceutical preparation, wherein the release of active medicine mainly obtains by the expandable composition of the described preparation of hydration.

Overweight: individual body weight is higher than the ideal body weight for their height, but does not reach the standard as fat classification.In the mankind, use Body Mass Index (kg/m ²), overweight individuality has the Body Mass Index between 25 to 30.

Fat oxidation: a series of reactions that relate to the acyl coenzyme A chemical compound, experience beta-oxidation and thioclastic cleavage whereby, follow the formation of S-acetyl-coenzyme-A, be the main path of fatty acid metabolism in the living tissue.

Pharmaceutical composition: refer to a kind of compositions, it contains a kind of medicament and one or more other compositions, and it is used for the administration to the curee by preparation.Described medicament refers to active ingredient in pharmaceutical.Typical active component is effective to the treatment of disease or illness.For example, the medicament that can be included in the pharmaceutical composition comprises the medicament that is used for the treatment of obesity or diabetes.Pharmaceutically active agents can be known as " pharmaceutical actives ".

Drug effect: refer to observed effect after expection is used for the treatment of disease or disease or is used to improve the administration of medicament of its symptom.

Drug influence kinetics function: by the effect of drug effect mediation.

Pharmacokinetics effect: the effect relevant with medicine absorption in vivo, distribution, metabolism and elimination.

Polymorph: have identical chemical constitution but the chemical compound of different crystal structure.

Preceding adipose cell: a kind of CFU-GM of adipose cell.

Prediabetic: a kind of illness, it is in before the diagnosis of type 2 diabetes mellitus.Type 2 diabetes mellitus is a kind of form of diabetes, and it is a feature with insulin insensitivity or opposing.

Prodrug: refer to a kind of chemical compound, when by metabolism, produce required reactive compound.Typically, described prodrug is a non-activity, or is lower than the activity of reactive compound, but favourable processing, administration or metabolic character can be provided.For example, some prodrugs are esters of reactive compound; Between metabilic stage, described ester group cracking produces active medicine.In addition, some prodrugs are produced reactive compound by enzyme activation, or produce the chemical compound of described reactive compound behind further chemical reaction.

Long term administration (long-term basis): continue the administration of pharmaceutically acceptable preparation of the medicine of 7 days or more days.Typically, long term administration continued at least two weeks, preferably at least one month, and even more preferably at least two months (that is at least 8 weeks).

Dissolution formulation: a kind of pharmaceutical preparation, it can discharge whole pharmaceutical actives substantially from described preparation in 10 minutes behind oral administration.

Delivery formulations (lasting), (or " sustained release formulation "): a kind of preparation of pharmaceutical preparation, it is behind animals administer, provides the release of the active medicine of time expand than identical pharmaceutical actives preparation, causes fast Absorption.Similarly term is that prolongation discharges, the gentle slow release of long-term release is put.In various situations, from definition, described preparation has the release rate of the minimizing of active substance.

Delivery formulations (delay), (or " preparation that postpones release "): the goods that postpone to discharge are to modify to discharge, but are not that prolongation discharges.After they are included in administration, some times of the drug release of discontinuous quantity (as enteric coated goods), and show lag time, during this lag time, less absorption takes place or do not absorb.

Delivery formulations (control), (or " preparation of sustained release "): the preparation of pharmaceutical preparation, its delay that can be included in pharmaceutical actives after the administration discharge and are used for continuing the mode sustained release that discharges by described.

Salt: by neutrality, alkalescence or the acid compound of combined acid or acid group and alkali or the formation of alkali root.

Solid oral dosage form: be designed to the pharmaceutical preparation of oral administration, comprise capsule and tablet.

Curee: refer to animal, comprise mammal, as the mankind.

Sulfonylureas receptor: K _ATPA kind of composition of passage, itself and sulfonylurea, other K _ATPChannel antagonist, diazoxide and other K _ATPChannel agonist interacts.

Tablet: form the pharmaceutical preparation of the size and dimension that is suitable for oral administration by the substrate that contains pharmaceutical actives and excipient that makes certain volume.

Heat generates: the physiological process of heat production in vivo.

Threshold concentration: changed required medicine minimal circulation concentration by the specific metabolism of performance in the human or animal body for the treatment of, physiology or composition.

Treatment: expression improves or changes valuably in addition any way of the symptom of illness, disease or disease or other indications.

Triglyceride: the depot fat of animal and human's class fatty tissue, mainly form by the glyceride of satisfied fatty acid.

Type 1 diabetes: a kind of chronic disease wherein because the β cell is destroyed, makes islets of langerhans produce and seldom or not produces insulin.

Uncoupling protein: a kind of protein families, it allows to carry out in the mitochondrion oxidation and produces ATP, and the phosphorylation of not following usually.

Interior fat: be mainly seen in the human adipose tissue under intravital subcutaneous fat and the Musclar layer.

Detailed Description Of The Invention

The invention provides specific K _ATPThe pharmaceutical preparation of channel opener, described pharmaceutical preparation can obtain novel drug influence kinetics, pharmacokinetics, therapeutics, physiology and metabolic result when to curee's administration.The present invention also provides specific K _ATPThe pharmaceutical preparation of channel opener, medication and dosage when obtaining the therapeutics result, have reduced adverse reaction rate.

Especially, being used for the beneficial property that the pharmaceutical preparation of oral administration shows by preparation comprises: sorbefacient continuity, the pharmacokinetics of treat patient and the dynamic (dynamical) response of drug influence, impel patient's compliance and improve the security feature of described goods, as passing through the frequency of minimizing serious adverse reaction.The present invention also provides by carrying out the administration of described preparation, treatment human and animal's the metabolic and the method for other diseases.

The chemical compound of formula II and III, formula IV and V and formula VI and VII, for example diazoxide (hereinafter) can be the proton tautomerism body.The proton tautomerism body is the only hydrogen atom isomer different with position of double bond each other.Described hydrogen atom and two key dislocation between carbon atom and hetero atom (for example N).Therefore, when described nitrogen substituent group was hydrogen, the chemical constitution of described two isomeries was used interchangeably.

The specific K that can be used for preparation of the present invention _ATPChannel opener comprises those in formula I to VII arbitrarily.Typical described chemical compound comprises: diazoxide, BPDZ62, BPDZ73, NN414 and BPDZ154 (seeing, for example: people such as Schou, Bioorg.Med.Chem., 13,141-155 (2005)).Suffer among the patient of pancreas insulinoma suffering from hyperinsulinar patient neutralization, compd B PDZ154 also is a kind of effective K _ATPThe passage activator.Synthetic people such as Cosgrove, J.Clin.Endocrinol.Metab., 87, the 4860-4868 (2002) of seeing of BPDZ chemical compound.

The analog of diazoxide comprises 3-isopropylamino-7-methoxyl group-4H-1,2, and 4-benzothiadiazine 1, the 1-dioxide, it is selectivity Kir 6.2/SUR 1 channel opener (seeing people such as Dabrowski, Diabetes, 51,1896-1906 (2002)).Comprise the diazoxide that the 2-alkyl replaces (seeing people such as Ouedraogo for example, Biol.Chem., 383,1759-1768 (2002)); These channel openers show active reduction and show that in the vascular smooth muscle tissue activity increases in suppressing insulin release.In addition, the diazoxide that the 2-alkyl replaces does not work as traditional potassium channel activator usually, and shows as Ca ²⁺The probability of blocker.

Other diazoxide analog are included in people such as Schou, Bioorg.Med.Chem., and 13, described in the 141-155 (2005), illustrate hereinafter.

R ¹, R ²And R ³For:

a)H，Cl，NHCH(CH ₃) ₂

b)CF ₃，H，NHCH(CH ₃) ₂

c)H，Cl，NHCH ₂CH ₂CH(CH ₃) ₂

D) H, Cl, NH-cyclobutyl

The diazoxide analog that has different alkyl substituents 3 (being expressed as R3 hereinafter) of molecule is described in people such as Bertolino, Receptors and Channels, 1,267-278 (1993).

R ³, R ⁶And R ⁷For: i) nC ₇H ₁₅, H, Cl

a)H，H，CH ₃ j)nC ₃H ₇，Cl，H

b)H，H，Cl k)nC ₄H ₉，Cl，H

c)CH ₃，Cl，H l)nC ₅H ₁₁，Cl，H

d)CH ₂Cl，H，Cl m)nC ₇H ₁₅，Cl，H

e)NH ₂，H，?H n)nC ₃H ₇，Cl，Cl

f)CH ₂CH ₂Cl，H，Cl?o)nC ₄H ₉，Cl，Cl

g)nC ₄H ₉，H，Cl p)nC ₅H ₁₁，Cl，Cl

h)nC ₅H ₁₁，H，Cl q)nC ₇H ₁₅，Cl，Cl

r)H，Cl，H

The K of formula I-VII and related compound _ATPChannel activity can be measured by transmembrane potential research, as people such as Schou, and Bioorg.Med.Chem., 13, people such as 141-155 (2005) and Dabrowski, Diabetes, 51, described in the 1896-1906 (2002).

To from the measurement of the glucose zest suppression of insulin release of β TC6 cell in people such as Schou, Bioorg.Med.Chem., 13, describe to some extent among the 141-155 (2005).Specific K _ATPThe ability that channel opener inhibition insulin discharges from the rat Langerhans islet of cultivating can be by people such as Ouedraogo, Biol.Chem., and 383, the method that 1759-1768 (2002) describes realizes.

Detect K by the diaphragm of monitoring macroscopic electric current inside out from the Kir6.2 of Xenopus laevis (Xenopus) ovum coexpression and SUR1, SUR2A or SUR2B _ATPChannel opener is to recombinant K _ATPThe activation of passage.The film of expressing SUR can be by known method preparation.See, for example, people such as Dabrowski, Diabetes, 51,1896-1906 (2002).

Can be used for determining K in conjunction with experiment _ATPChannel opener is in conjunction with the ability of SUR1, SUR2A and SUR2B.See, for example, people such as Schwanstecher, EMBO J., 17,5529-5535 (1998).

As SUR1 and the chimeric preparation of SUR2A that people such as Babenko describe, the pharmacological characteristics (that is: sulfonyl sensitivity and to the responsiveness of diazoxide or other potassium channel openerses) that makes it possible to SUR1/Kir6.2 and SUR2A/Kir6.2 potassium channel compares.See people such as Babenko, J.Biol.Chem., 275 (2), 717-720 (2000).The K of sulfonylureas receptor and inner rectification ⁺Passage be cloned in people such as Isomoto, J.Biol.Chem., 271 (40), 24321-24324 (1996); People such as D ' hahan, PNAS, 96 (21), 12162-12167 has description in (1999).

Human SUR1 and the intergenic difference of human SUR2 be people such as Aguilar-Bryan, Physiological Review, and 78 (1), have among the 227-245 (1998) and describe and explanation.

" halogen " and " halogen " refers to all halogens, i.e. chlorine (Cl), fluorine (F), bromine (Br) or iodine (I).

" hydroxyl " and " hydroxyl " refers to-the OH group.

" the oxygen base of replacement " refers to-OR ^fGroup, wherein R ^fAralkyl, cycloalkyl, cycloalkyl, the heterocyclic radical (heterocyclyl) of replacement or the heterocyclic radical that replaces for the heteroaryl of the aryl of the alkyl of alkyl, replacement, aryl, replacement, heteroaryl, replacement, aralkyl, replacement.

" mercaptan of replacement " refers to-the SR group, and wherein R is heteroaryl, the aralkyl of aryl, heteroaryl, the replacement of acyl group, aryl, the replacement of alkyl, acyl group, the replacement of alkyl, replacement, aralkyl, cycloalkyl, cycloalkyl, the heterocyclic radical (heterocyclyl) of replacement or the heterocyclic radical that replaces of replacement.

" alkyl " refer to contain from 1 to 10, the deutero-group of alkane of preferred 1 to 6 carbon atom.Alkyl comprises straight chained alkyl, branched alkyl and cycloalkyl, as methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group etc.The straight or branched alkyl contains from 1-10, preferred 1 to 6, more preferably 1-4, more preferably 1-2 carbon atom also.Described alkyl can be connected any available position and generate stable chemical compound.

" alkyl of replacement " is for independently by 1 or a plurality of as 1; the alkyl that 2 or 3 groups or substituent group replace; described group or substituent group such as halogen; hydroxyl; the optional alkoxyl that replaces; the optional alkylthio group that replaces; alkyl sulphinyl; alkyl sulphonyl; the optional amino that replaces; the optional acylamino-that replaces; amidino groups; the urea that is replaced by alkyl randomly; randomly the N-list that is replaced by alkyl replaces or N; the dibasic sulfamoyl of N-; alkyl sulfonyl amino; carboxyl; heterocycle; the heterocycle that replaces; nitro; cyano group; mercaptan; sulfonamidos etc., described group or substituent group can be connected any available position and generate stable chemical compound.Especially, " fluorine replaces " refer to by 1 or a plurality of as 1,2 or 3 fluorine atom replace." randomly fluorine replaces " expression substituent group (if existence) is a fluorine.

" low alkyl group " refers to the alkyl with 1-6 carbon atom.

" low alkyl group of replacement " is a kind of low alkyl group, and it is by 1 or a plurality of as 1,2 or 3 aforesaid group or substituent group replacement, and described group or substituent group can be connected any available position and generate stable chemical compound.

" cycloalkyl " refers to for each ring has 3-8, the more preferably monocyclic, bicyclic or tricyclic carbon-loop system of saturated or undersaturated, the non-aromatics of 3-6 ring members, as cyclopropyl, cyclopenta, cyclohexyl, adamantyl etc." ring alkylidene " is the cycloalkyl of bivalence.

" alkoxyl " expression-OR ^fGroup, wherein R ^fBe low alkyl group.

" alkoxyl of replacement " expression-OR ^fGroup, wherein R ^fBe the low alkyl group that replaces.

" alkylthio group " or " thio alkoxy " refers to-the S-R group, and wherein R is a low alkyl group.

" alkylthio group of replacement " or " thio alkoxy of replacement " refers to-the S-R group, wherein the low alkyl group of R for replacing.

" sulfinyl " expression-S (O)-group.

" sulfonyl " expression-S (O) ₂-group.

" sulfinyl of replacement " expression-S (O)-R group, wherein R is the aralkyl of heteroarylalkyl, aralkyl or replacement of heteroaryl, heteroarylalkyl, the replacement of aryl, heteroaryl, the replacement of heterocyclic radical alkyl, aryl, the replacement of heterocyclic radical, heterocyclic radical alkyl, the replacement of cycloalkyl-alkyl, heterocyclic radical, the replacement of cycloalkyl, cycloalkyl-alkyl, the replacement of low alkyl group, cycloalkyl, the replacement of low alkyl group, replacement.

" sulfonyl of replacement " expression-S (O) ₂-R group, wherein R is the aralkyl of heteroarylalkyl, aralkyl or replacement of heteroaryl, heteroarylalkyl, the replacement of aryl, heteroaryl, the replacement of heterocyclic radical alkyl, aryl, the replacement of heterocyclic radical, heterocyclic radical alkyl, the replacement of cycloalkyl-alkyl, heterocyclic radical, the replacement of cycloalkyl, cycloalkyl-alkyl, the replacement of low alkyl group, cycloalkyl, the replacement of low alkyl group, replacement.

" sulfonamido " expression-NRS (O) ₂-group, wherein R is hydrogen or low alkyl group.

" sulfonamido of replacement " expression-NR ^aS (O) ₂-R ^bGroup, wherein R ^aBe hydrogen or low alkyl group and R ^bAralkyl for heteroarylalkyl, aralkyl or the replacement of the heteroaryl of the aryl of the heterocyclic radical of the cycloalkyl of the low alkyl group of low alkyl group, replacement, cycloalkyl, replacement, heterocyclic radical, replacement, aryl, replacement, heteroaryl, replacement, heteroarylalkyl, replacement.

" amino " or " amine " expression-NH ₂Group." divalent amines " expression-NH-group." divalent amines of replacement " expression-NR-group, wherein R is the sulfonyl of acyl group, sulfonyl or replacement of heteroaryl, acyl group, the replacement of aryl, heteroaryl, the replacement of low alkyl group, aryl, the replacement of low alkyl group, replacement.

" amino of replacement " or " amine of replacement " expression-NR ⁱR ^jGroup, wherein R ⁱAnd R ^jBe acyl group, the sulfonyl of heteroaryl, acyl group, the replacement of aryl, heteroaryl, the replacement of low alkyl group, aryl, the replacement of hydrogen, low alkyl group, replacement, the sulfonyl or the cycloalkyl of replacement independently, yet, R ⁱAnd R ^jOne of at least be not hydrogen.R ⁱR ^jCombine the heterocycle or the hetero-aromatic ring that can form optional replacement with nitrogen.

" alkyl sulphinyl " expression-S (O) R ^PGroup, wherein R ^PBe the optional alkyl that replaces.

" alkyl sulphonyl " expression-S (O) ₂R ^PGroup, wherein R ^PBe the optional alkyl that replaces.

" alkyl sulfonyl amino " expression-NR ^qS (O) ₂R ^PGroup, wherein R ^PBe the optional alkyl that replaces, and R ^qBe hydrogen or low alkyl group.

Contain K _ATPThe pharmaceutical preparation of channel opener comprises the free alkali of described medicine or the salt of described medicine.Such salt can have one or more following characteristics: (1) during synthetic and preparation, the stability in solution; (2) stability in solid-state; (3) compatibility of the excipient that uses in producing with tablet formulation; (4) when being exposed to mimic or real stomach and duodenum condition, produce K in a large number _ATPChannel opener; (5) the enough little particle release K from being easy to dissolve and absorb _ATPChannel opener; (6) when mixing pharmaceutical preparation, provide absorption greater than 80% dosage; (7) and K _ATPThe free alkali of channel opener is compared, and does not show the toxicological risk of increase; (8) can be allocated into the acceptable drug preparation to treat human obesity and other diseases; (9) be that FDA accepts the basis as pharmaceutical preparation; (10) can be by recrystallization to improve purity; (11) can be used for forming described K _ATPThe cocrystallization of two or more salt of channel opener; (12) has the hygroscopicity of qualification to improve stability; Or (13) in described salt synthetic, can control the salifiable synthetic or crystallization condition of shape, and the salifiable synthetic or crystallization condition of described shape can change and produce different crystal structure (polymorph).

K _ATPChannel opener can be formulated into pharmaceutically acceptable salt.Pharmaceutically acceptable salt is nontoxic salt at them by the consumption of administration and concentration.Such salt pref can not hinder its performance physiological effect to promote its pharmacological use by the physical behavior that changes chemical compound.Beneficially altering in the physical property comprises the administration of reduction fusing point with the promotion through mucous membrane, and increases dissolubility to promote the administration of hanging down effective dose of described medicine.

Pharmaceutically acceptable salt comprises acid-addition salts, for example those of sulfur-bearing hydrochlorate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, mesylate, esilate, benzene sulfonate, tosilate, cyclohexyl-n-sulfonate and quinate.Pharmaceutically acceptable salt can obtain from acid, and described acid is hydrochloric acid, maleic acid, sulphuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethyl sulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, cyclohexyl sulfamic acid, fumaric acid and quinic acid for example.

Pharmaceutically acceptable salt also comprises base addition salts, for example when acidic functionality such as carboxylic acid or phenol exist, contain those of benzathine benzylpenicillin, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine and zinc.For example, see Remington ' s Pharmaceutical Sciences, the 19th edition, Mack Publishing Co., Easton, PA, the 2nd volume, the 1457th page, 1995.Such salt can use suitable corresponding alkali to be prepared.

Pharmaceutically acceptable salt can be by the preparation of following method: for example at suitable solvent as containing the free alkali form of dissolved compound in suitable aqueous acid or the water-alcohol solution, and then separate by evaporating described solution.In another embodiment, by in organic solvent, making free alkali and acid reaction prepare salt.

The pharmaceutically acceptable salt of different chemical compounds can be used as complex and exists.The example of complex comprises that the 8-Chlorotheophyline complex (is similar to as dimenhydrinate: 8-Chlorotheophyline diphenhydramine (1: 1) complex; All draw numb bright) and multiple cyclodextrin inclusion complexes.

K _ATPThe specific salt of the salt of channel opener and diazoxide can comprise; but be not limited to second hydrochloric acid; acetonide; acetyl group; adipate; aspartate; benzene sulfonate; diacetin; biatrate; bromide; butoxide; butyrate; calcium; camsilate; caproate; carbonate; citrate; cyprionate; decaroate; diacetate; dimegulumine; dinitrate; dipotassium; dipropionate; disodium; disulphide; ethanedisulphonate; enanthate; estolate; etabonate; ethylsuccinate; fumarate; furoate; gluceptate; gluconate; six acetonides; hippurate; hyclate; hydrobromate; hydrochloride; isethionate; Lactobionate; malate; maleate; meglumine; Celfume; Methylsulfate; metrizoic acid salt; cefamandole nafate; naphthalene sulfonate; nitrate; oleate; palmitate; pounce on the nurse hydrochlorate; phenpropionate; phosphate; pivalate; sulfonation divinylbenzene-Ethenylbenzene copolymer (polistirex); Polygalacturonate; probutate; propionate; glucarate; Glycine sodium; sodium phosphate; podium succinate; state; succinate; sulfate; sulfonate; sulfosalicylate; tartrate; tebutate; terephalate; terephthalate; toluene fulfonate; trifluoroacetate; trihydrate; trisilicate; trometamol; valerate or xinafoate.

Preparation provided by the invention demonstrates some or all following characteristics: they stablized (1) 1 year in that room temperature is minimum; (2) they make be easy to oral; (3) they impel the compliance of patient to dosage; (4) after administration, they impel the high concentration of pharmaceutical actives to absorb all the time; (5) once a day or behind twice the oral administration, they allow K _ATPChannel opener discharges at one section lasting time range, so that described K _ATPThe circulation composition of channel opener or its metabolic active metabolite is not less than treatment valid density; (6) they can not rely on by the individual gastrointestinal tract pH value of treatment and obtain these results; And (7) they are delayed to the stomach transhipment and finish or finish substantially just release.

Can be provided as the preparation of oral administration design, for example as capsule or tablet.Capsule or tablet formulation comprise multiple heterogeneity.A kind of is to improve K _ATPThe composition that channel opener absorbs.Another kind of through the release of the time remaining above 2 hours medicine.The third is finished just until the stomach transhipment and discharges substantially.

Compare with the preparation of these medicines before, preparation disclosed by the invention demonstrates K _ATPThe dissolubility of the improvement of channel opener and absorption.These useful character obtain by following any one or several different methods: (1) reduces the granularity of described preparation by pulverizing, spray drying or other micronization technology; (2) use described K _ATPThe pharmaceutical salts of channel opener; (3) in described preparation, make spent ion exchange resin; (4) use inclusion complex, as using cyclodextrin; (5) with described K _ATPChannel opener is with the excipient that comprises low viscosity hypromellose, low viscosity methylcellulose (metylcellulose) or similar functions or its compositions compacting; (6) before preparation, described K associates _ATPChannel opener and salt; (7) use described K _ATPThe solid dispersion of channel opener; (8) use self-emulsifying drug delivery systems; (9) in described preparation, add one or more surfactants; (10) in described preparation, use nanoparticle; Or these methods of (11) coupling.Preferably, as described K _ATPWhen channel opener was the salt of diazoxide, described salt was not sodium salt.

By using one or more methods to obtain K _ATPChannel opener discharges at one section lasting time durations (2-24 hour), and described method includes but not limited to: (1) uses pH sensitivity polymeric coatings; (2) use hydrogel; (3) use film coating, the diffusion rate of its control medicine from coated substrate; (4) use can be lost the substrate of separating, its control drug release rate; (5) use medicine piller, granule or the microgranule of polymer coating, its can be further by encapsulate or be pressed into tablet; (6) use osmotic pump system; Or (7) use the coated tablet of compacting; Or the combination of (8) these methods.

In preparation provided by the invention, obtain to finish K until the stomach transhipment by any several mechanism _ATPChannel opener discharges from the delay of described preparation.Used pH sensitive polymer or copolymer when it is applied in around the drug matrices, work as a kind of effective barrier, so that discharge active matter at pH 3.0 or lower pH value, and in pH 5.5 or higher pH value instability.This feasible release of controlling reactive compound under one's belt, in case but said preparation has been transferred into small intestinal, and it is with rapid release.The substitute of pH sensitive polymer or copolymer is non-water-soluble polymer or copolymer.Can be by controlling in gastric environment with water-insolube and water-soluble mixture of polymers coating to the opposing degree that discharges.In the method, blended polymer or copolymer do not have pH sensitivity.An example of pH sensitive copolymers is Eudragit (acrylic resin) methacrylic acid copolymer, comprises Eudragit L100, S100 or L100-55 solid, L30 D-55 or FS 30D dispersion, or L12,5 or S 12,5 organic solutions.

The polymer that postpones to discharge can be applied to tablet by spray coating (as thin film) or pressed coated.If what use is capsule, so described polymer can be applicable on the capsular surface, or is applied to the microgranule of described medicine, its can be then by encapsulate for example in capsule or gel.If described capsule is by coating, it will resist disintegrate after the stomach transhipment so.If microgranule is by coating, capsule disintegrate but will discharge small amount of drug even not have medicine to be released under one's belt so is after the complete stomach transhipment of free microgranule.At last, use can be used for postponing medicine release under one's belt as the osmotic pump system of the hydrogel of swellable.The hydrogel of swellable is at administration post-absorption moisture.The swelling of gel causes medicine to shift from absorption system.The time limit of drug release and speed depend on the gel of use, and the speed of moisture arrival gel, and it can be controlled by the openings of sizes that fluid in system is flowed through.See people such as Dong among the Drug Delivery Technologies online article, " L-OROS ^SOFTCAP ^TMFor Controlled Release of Non-Aqueous Liquid Formulations ".

Therefore, in preparation provided by the invention, obtain to finish K until the stomach transhipment by any several mechanism _ATPChannel opener discharges from the delay of preparation of the present invention, and described mechanism includes, but are not limited to: the pH sensitive polymer or the copolymer that (a) are used as the pressed coated on the tablet; (b) as the pH sensitive polymer or the copolymer of the thin film on the tablet; (c) as the pH sensitive polymer or the copolymer of the thin film of encapsulated system; (d) be used for the pH sensitive polymer or the copolymer of encapsulate microgranule; (e) as the non-soluble polymer or the copolymer of the pressed coated on the tablet; (f) as the non-soluble polymer or the copolymer of the thin film on the tablet; (g) as the non-soluble polymer of the thin film of encapsulated system; (h) be used for the non-soluble polymer of microgranule; (i) in osmotic pump system, mix described preparation; Or (j) use system by ion exchange resin control; Or (k) these methods of coupling, wherein said pH sensitive polymer or copolymer degradation resistant under acid condition.

The invention provides the preparation that is designed for (per 24 hours) single administration every day.These can contain the K between 25 to 500mg _ATPChannel opener.The preparation that is designed for (per 24 hours) twice administration every day also is provided.These can contain the K between 25 to 250mg _ATPChannel opener.

Preparation provided by the invention has shown the safety that the pharmaceutical preparation of administration improves.Improvement in these safeties takes place by at least two kinds of mechanism.The first, the release that postpones active medicine is finished until the stomach transhipment, and this can reduce the incidence rate of a series of gastrointestinal tract adverse side effects, and that described gastrointestinal tract adverse side effect comprises is nauseating, vomiting, dyspepsia, stomachache, diarrhoea and intestinal obstruction.The second, by active medicine surpassed 2 hours or reach longer time of 24 hours during continue to discharge, compare with the viewed peak drug concentration of identical dosage of the oral formulations that uses any non-lasting release or controlled release, peak drug concentration reduces.The reduction of this peak drug concentration can impel partially or completely because the untoward reaction of peak drug concentration decision alleviates.These untoward reaction comprise: with sodium, chloride and urate excretion rate reduce relevant fluid retention, edema, hyperglycemia and relevant ketoacidosis progress may, cataract and non-ketoacidosis hyperosmolar coma, headache, tachycardia and cardiopalmus.

The present invention also provides K _ATPThe controlled release preparation of channel opener, it has a kind of feature every among the A-D that is shown in Table 1.

Table 1: the feature of controlled release preparation and character

A. unit dosage forms: tablet or capsule

B. dosage/unit: 10-100mg

100-200mg

200-300mg

300-500mg

500-2000mg

C. dosed administration every day (24 hours) once

Twice of every day (24 hours)

D. release time: 2-4 hour

4-8 hour

8-24 hour

For example: controlled release composition can be the K that contains 25-100mg _ATPThe tablet of channel opener, such tablet is administered once with the controlled release time that obtains 2-4 hour every day.All these preparations also can comprise postpone the feature that pharmaceutical actives discharges again basically after stomach transhipment is finished.

In addition, any preparation of above-mentioned table 1 can comprise at least a K of improvement _ATPThe dissolubility of channel opener or absorbing features.

Controlled release preparation provided by the invention comprises reactive compound (K _ATPChannel opener) and substrate, described substrate contains swollen gellant behind the contacting hydrous liquid.The reactive compound of embedding slowly is being released in the body after the gel stripping in gel.Described reactive compound can be dispersed in the substrate fifty-fifty or the medicine pocket (pocket of drug) that can be used as in the substrate exists.For example, described medicine can be formulated into the granule that is dispersed in the substrate.In addition, described drug particles also can comprise substrate, thereby, provide primary matrix and second level substrate, described in No. the 4th, 880,830, the United States Patent (USP) of Rhodes.

Described gellant is preferably polymeric material, it can comprise, for example, any pharmaceutically acceptable water solublity or water-insoluble release polymer such as Xanthan gum, gelatin, cellulose ethers, arabic gum, carob gum, guar gum, carboxy vinyl polymer, agar, acacin, the tragakanta, aluminium-magnesium silicate, sodium alginate or alginic acid, polyvinylpyrrolidone, polyvinyl alcohol, or film forming polymer such as methylcellulose (MC), carboxymethyl cellulose (CMC), hydroxypropyl emthylcellulose, hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl-cellulose (HEC), ethyl cellulose (EC), the mixture of acrylic resin or above-mentioned material (is seen, for example United States Patent (USP) the 5th, 415, No. 871).

The gellant of described substrate also can be the dispersive natural gum of heterogeneity, comprises heteropolysaccharide composition and homopolysaccharide composition, and it generates as United States Patent (USP) the 5th, 399, the quick shaping of describing in No. 359 and regid gel.Described substrate also can comprise cross-linking agent (crossing agent) as monovalence or polyvalent metal cation with the hardness of substrate as described in the further increase with reduce its dissolution, thereby further slow down drug release.Can use consumption for the definite described cross-linking agent that will add of conventional method of those of ordinary skill.

The substrate of described controlled release composition also can comprise the acceptable accessories known to one or more those skilled in the art, i.e. pharmaceutical adjunct.Described adjuvant for example comprises, binding agent: polyvinylpyrrolidone, gelatin, gelatinized corn starch, microcrystalline Cellulose; Diluent (or filler): starch, sucrose, dextrose, lactose, fructose, xylitol, sorbitol, sodium chloride, dextrin, calcium phosphate, calcium sulfate; And lubricant: stearic acid, magnesium stearate, calcium stearate, Precirol (trade mark) and fluidizer such as Talcum or silicon dioxide colloid.

The substrate of described controlled release composition also can comprise hydrophobic substance, the hydration of its gellant that slows down and do not destroy the hydrophilic nmature of substrate, as United States Patent (USP) the 5th, 399, No. 359 describe.Described hydrophobic polymer can comprise, for example alkylcellulose such as ethyl cellulose, other hydrophobic fibre materials, from acrylate or methacrylate derived polymers or copolymer, the copolymer of acrylate and methacrylate, zein, wax, lac, hydrogenated vegetable oil, wax and waxiness material such as Brazil wax, spermaceti, candelilla wax, cocoa butter, cetostearyl alcohol (cetosteryl alcohol), Cera Flava, ceresine, paraffin, myristyl alcohol, stearyl alcohol, hexadecanol and stearic acid, and any other pharmaceutically acceptable hydrophobic substance well known by persons skilled in the art.

The amount of mixing the hydrophobic substance of described controlled release composition be can effectively slow down gellant hydration and do not destroy the amount of the hydrophilic substrate of formation behind the liquid around be exposed to.In some preferred embodiments, described hydrophobic substance is comprised in the described substrate with about 1% to about 20% amount by weight, and replaces the pharmaceutical adjunct of respective amount.The solvent that is used for hydrophobic substance can be aqueous solvent or organic solvent, or its mixture.

The example of the commercially available alkylcellulose that gets is Aquacoat ^(aqueous dispersion of the ethyl cellulose that can obtain from FMC) and Surelease ^(aqueous dispersion of the ethyl cellulose that can obtain from Colorcon).The example that is suitable for use as the commercially available acrylic polymer that gets of hydrophobic substance comprises Eudragit ^RS and RL ((as 1: 20 or 1: the 40) acrylate of quaternary ammonium compound and the copolymer of methacrylate) with low content.

Described controlled release composition also can be entered reactive compound and/or postpone the release of described reactive compound via the film coating to postpone liquid by coating.Described film coating can provide stomach repellence and enteral deliquescent feature by the described compositions of opposing in gastral quick stripping.By weight, described film coating generally accounts for about 5-15% of controlled release composition.Preferably, the sheet heart accounts for the about 90% of described compositions by weight, and residue 10% is provided by coating.Described coating can be a film coating well known in the art, comprises compositions, polymer, starch of gel, wax, fat, emulsifying agent, fat and emulsifying agent etc.

Polymer and copolymer can be used as film coating.Solution coating and dispersion coating can be used for reactive compound is carried out coating separately or with substrate combination.As known in the art, described coating preferably is applied to as the medicine of solid piece heart material or the compositions of medicine and substrate.

The solution that is used for coating can comprise the polymer of organic solvent and aqueous solvent system, and generally comprises that also one or more are used as the chemical compound of plasticizer.The polymer that can be used for coated composition comprises, for example methylcellulose (Methocel ^A; The Dow chemical company), molecular weight is 1,000 and 4,000, the hydroxypropyl emthylcellulose (Methocel between 000 ^E; Dow chemical company or Pharmacoat ^Shin Etsu), molecular weight is 2,000 and 2,000, hydroxypropyl emthylcellulose between 000, ethyl cellulose, cellulose acetate, cellulose triacetate, cellulose acetate-butyrate, CAP, cellulose acetate trimellitate (Eastman Kodak), carboxymethylethylcellulose (Duodcel ^), hydroxypropyl methyl cellulose phthalate, ethyl cellulose, methylcellulose, and common cellulose derivative, polymethylacrylic acid-methacrylic acid copolymer (1: 1 EudragitL100 of A type; 1: 2 Eudragit S100 of Type B; And 1: 1 Eudragit L100-55 of C type, aqueous dispersion 30% solid, Eudragit L30D), poly-(methyl) acrylate: poly-(ethyl acrylate: methyl methacrylate 2: 1), Eudragit NE30D aqueous dispersion 30% solid, poly-amino methyl acrylate E100, poly-(chlorination trimethyl ammonium ethyl-methyl acrylate) ammonium methacrylate copolymer, EudragitRL30D and Eudragit RS30D, carboxy vinyl polymer, polyvinyl alcohol, glucosan, scleroglucan, mannan and xanthan gum.

Aqueous polymer dispersion comprises Eudragit L30D and RS/RL30D, and NE30D, poly-(the vinyl acetate phthalate ester) of the CAP of the ethyl cellulose of the ethyl cellulose of Aquacoat trade mark, Surelease trade mark, the N-10F ethyl cellulose of EC trade mark, Aquateric trade mark, Coateric trade mark and the acetic acid hydroxypropyl methyl cellulose succinate of Aqacoat trade mark.Major part is latex, pseudo-gums milk powder end or micronized powder medium in these dispersions.

Plasticizer can be included in the described coating with elasticity and the stability of improving described polymeric film and the variation that prevents polymer penetration during long term storage.Described variation can influence drug release rate.Suitable conventional plasticizers comprises; ethyl phthalate for example; glycerol triacetate; single-acetyl triglyceride; citroflex A-4; CitroflexA-2; Oleum Ricini; citrate; Dibutyl phthalate; dibutyl sebacate; ethyl oxalate; diethyl malate; DEF; ethyl phthalate; diethyl succinate; diethyl malonate; diethyl tartrate.; dimethyl phthalate; glycerol; glycerol; glyceryl triacetate; tributyrin; mineral oil and lanolin alcohol; vaseline and lanolin alcohol; phthalic acid ester; Polyethylene Glycol; propylene glycol; Oleum Brassicae campestris; Oleum sesami; the glycerol triethyl; tributyl citrate; triethyl citrate and triethyl group acetyl group citrate, or above-mentioned two or more mixture arbitrarily.The plasticizer that can be used for the water coating comprises, for example propylene glycol, Polyethylene Glycol (PEG400), glycerol triethyl, polyoxyethylene sorbitan monoleate, triethyl citrate and dextrotartaric acid diethylester.

The mixture that contains hydroxypropyl emthylcellulose and moisture ethyl cellulose (as the Aquacoat trade mark) can be used for microgranule is carried out coating as the coating solution of plasticizer as polymer, dibutyl sebacate.(Aquacoat is the aqueous polymer dispersion of ethyl cellulose and contains sodium lauryl sulphate and hexadecanol).Preferably, described plasticizer accounts for about 1-2% of described compositions.

Except that polymer, described coatings can include the adjuvant that helps prepare described coating solution.Described adjuvant can comprise lubricant or wetting agent.The examples of suitable lubricants that is used for the film coating as adjuvant comprises, for example Talcum, calcium stearate, silicon dioxide colloid, glycerol, magnesium stearate, mineral oil, Polyethylene Glycol and zinc stearate, aluminium stearate or above-mentioned two or more mixture arbitrarily.Suitable wetting agent comprises, sodium lauryl sulphate for example, arabic gum, benzalkonium chloride, cetomacrogol emulsifying wax, cetostearyl alcohol, hexadecanol, cholesterol, diethanolamine, docusate sodium, sodium stearate, emulsifing wax, glyceryl monostearate, hydroxypropyl cellulose, lanolin alcohol, lecithin, mineral oil, monoethanolamine, poloxamer, polyoxyethylene alkyl ether, castor oil derivatives, the polyoxyethylene sorbitan aliphatic ester, Myrj 45, propylene glycol alginate, sorbitan ester, stearyl alcohol and triethanolamine, or above-mentioned two or more mixture arbitrarily.

Specified tablet or capsule preparations can comprise with the bariatrician medicine and (remove K in the table 1 _ATPChannel opener is outer) the coupling preparation.Spendable bariatrician medicine comprises, but be not limited to, Sibutramine hydrochloride (5-30mg/ unit), orlistat (50-360mg/ unit), phentermine hydrochloride or resin complexation thing (Unit 15 to 40mg/), zonisamide (Unit 100 to 600mg/), topiramate (Unit 64 to 400mg/), Naltrexone Hydrochloride (Unit 50 to 600mg/), Rimonabant (Unit 5 to 20mg/), ADP356 (Unit 5 to 25mg/), ATL962 (Unit 20 to 400mg/), or AOD9604 (Unit 1 to 10mg/).These preparations are preferably used once every day.For twice administration every day, K _ATPThe amount of channel opener is half consumption in the preparation that is included in once a day, and the bariatrician medicine of co-formulated is the appointment consumption half.Alternative bariatrician medicine can comprise: selectivity 5-hydroxy tryptamine 2c receptor stimulating agent, dopamine antagonist, cannabinoid-1 receptor antagonist, the leptin analog, leptin transporter and/or leptin receptor promoter, the peptide antagonists that neuropeptide tyrosine is relevant with agouti, the transcript promoter that former and cocaine of opium melanophore cortin and amfetamine are regulated, the melanotropin analog, the melanocortin-4 receptor agonist, and those influence insulin metabolism/active reagent, it comprises protein-tyrosine phosphatase-1B inhibitor, peroxisome proliferation-activated receptors-receptor antagonist, fugitive bromocriptine (bromocriptine), somatostatin agonist (octreotide), and adiponectin, gastrointestinal-nervous pathway medicament, comprise and strengthen the cholecystokinin activity, (extendin 4 to strengthen the glucagon-like-peptide-1 activity, liraglutide, inhibitors of dipeptidyl IV), and strengthen protein YY3-36 active those and reduce stomach hungry plain (ghrelin) active those, also has the dextrin analog, can increase medicament (" selectivity " β-3 stimulants/agonist of resting metabolic rate, uncoupling protein homolog, and thryoid receptor agonist), the melanin concentrating hormone antagonists, the phytostanol analog, amylase inhibitor, growth hormone fragment, synthetic dehydroepiandrosterone sulfate analog, the active antagonist of adipose cell 11B hydroxyl steroid dehydrogenase type I, the corticotropin releasing hormone agonist, the synthetic inhibitor of fatty acid, carboxyl peptide enzyme inhibitor, indone/indanol, amino sterol and other gastrointestinal lipase inhibitors.

Specified tablet or capsule preparations can comprise with Remedies for diabetes and (remove K in the table 1 _ATPChannel opener is outer) the coupling preparation.Spendable Remedies for diabetes comprises, but be not limited to acarbose (Unit 50 to 300mg/), miglitol (Unit 25 to 300mg/), metformin hydrochloride (Unit 300 to 2000mg/), repaglinide (1-16mg/ unit), Nateglinide (Unit 200 to 400mg/), rosiglitazone (Unit 5 to 50mg/), metaglidasen (Unit 100 to 400mg/), or improve insulin sensitivity or improve glucose utilization and any medicine of picked-up.Preferably use these preparations once a day.For twice administration every day, K _ATPThe amount of channel opener is half consumption in the preparation that is included in once a day, and the Remedies for diabetes of co-formulated is the appointment consumption half.

Specified tablet or capsule preparations can comprise the coupling preparation with pravastatin in the table 1.Spendable pravastatin includes, but not limited to pravastatin or simvastatin or atorvastatin or fluvastatin or rosuvastatin or lovastatin (whole Unit 10 to 80mg/).Preferably use these preparations once a day.For twice administration every day, K _ATPThe preferred Unit 25 to 200mg/ of the amount of channel opener, and the pravastatin of co-formulated is the appointment consumption half.

Specified tablet or capsule preparations can comprise the coupling preparation with the treating depression medicine in the table 1.Spendable treating depression medicine comprises, but be not limited to citalopram hydrobromate (Unit 10 to 80mg/), hydrobromic acid escitalopram (Unit 5 to 40mg/), fluvoxamine maleate (Unit 25 to 300mg/), paroxetine hydrochloride (Unit 12.5 to 75mg/), fluoxetine Hydrochloride (Unit 30 to 100mg/), sertraline hydrochloride (Unit 25 to 200mg/), amitriptyline hydrochloride (Unit 10 to 200mg/), desipramine hydrochloride (Unit 10 to 300mg/), psychostyl (Unit 10 to 150mg/), duloxetine hydrochloride (Unit 20 to 210mg/), VENLAFAXINE HCL (Unit 37.5 to 150mg/), W-1544a (Unit 10 to 30mg/), bupropion hydrochloride (Unit 200 to 400mg/) or mirtazapine (Unit 7.5 to 90mg/).Preferably use these preparations once a day.For twice administration every day, K _ATPThe amount of channel opener preferably includes half consumption in preparation once a day, and the treating depression medicine of co-formulated is the appointment consumption half.

Specified tablet or capsule preparations can comprise the coupling preparation with the hypertension therapeutic medicine in the table 1.Spendable hypertension therapeutic medicine comprises, but be not limited to, enalapril maleate (Unit 2.5 to 40mg/), captopril (Unit 2.5 to 150mg/), lisinopril (Unit 10 to 40mg/), benazepril hydrochloride (Unit 10 to 80mg/), quinapril hydrochloride (Unit 10 to 80mg/), perindopril elbumin (peridopril erbumine) (Unit 4 to 8mg/), ramipril (Unit 1.25 to 20mg/), trandolapril (Unit 1 to 8mg/), fosinopril sodium (Unit 10 to 80mg/), moexipril hydrochloride (Unit 5 to 20mg/), Losartan (Unit 25 to 200mg/), irbesartan (Unit 75 to 600mg/), valsartan (Unit 40 to 600mg/), Candesartan Cilexetil (Unit 4 to 64mg/), Olmesartan medoxamil (Unit 5 to 80mg/), telmisartan (Unit 20 to 160mg/), methanesulfonic acid Eprosartan (Unit 75 to 600mg/), atenolol (Unit 25 to 200mg/), propranolol hydrochloride (Unit 10 to 180mg/), the metoprolol tartrate, succinate or fumarate (whole Unit 25 to 400mg/), nadolol (Unit 20 to 160mg/), betaxolol hydrochloride (Unit 10 to 40mg/), M B 17803A (Unit 200 to 800mg/), pindolol (Unit 5 to 20mg/), bisoprolol fumarate (Unit 5 to 20mg/), nifedipine (Unit 15 to 100mg/), felodipine (Unit 2.5 to 20mg/), Amlodipine Besylate Tablet (Unit 2.5 to 20mg/), nicardipine (Unit 10 to 40mg/), nisoldipine (Unit 10 to 80mg/), terazosin hydrochloride (Unit 1 to 20mg/), Carclura (Unit 4 to 16mg/), minipress (Unit 2.5 to 10mg/) or alfuzosin hydrochloride (Unit 10 to 20mg/).Preferably use these preparations once a day.For twice administration every day, K _ATPThe amount of channel opener is half consumption in the preparation that is preferably included in once a day, and the hypertension therapeutic medicine of co-formulated is the appointment consumption half.

Specified tablet or capsule preparations can comprise that the coupling preparation that has diuretic is with the treatment edema in the table 1.Spendable diuretic comprises, but be not limited to amiloride hydrochloride (Unit 1 to 10mg/), spironolactone (Unit 10 to 100mg/), triamterene (Unit 25 to 200mg/), bumetanide (Unit 0.5 to 4mg/), furosemide (Unit 10 to 160mg/), etacrynic acid or sodium etacrynate (whole Unit 10 to 50mg/), tosemide (Unit 5 to 100mg/), chlortalidone (Unit 10 to 200mg/), indapamide (Unit 1 to 5mg/), hydrochlorothiazide (Unit 10 to 100mg/), chlorothiazide (Unit 50 to 500mg/), bendroflumethiazide (Unit 5 to 25mg/), hydroflumethiazide (Unit 10 to 50mg/), methyclothiazide (Unit 1 to 5mg/) or polythiazide (Unit 1 to 10mg/).Preferably use these preparations once a day.For twice administration every day, K _ATPThe amount of channel opener is preferably half consumption in the preparation that is included in once a day, and the diuretic of co-formulated is the appointment consumption half.

Specified tablet or capsule preparations can comprise and treat the coupling preparation of the medicine of inflammation or pain in the table 1.The medicine that can be used for treating inflammation or pain comprises, but be not limited to, aspirin (Unit 100 to 1000mg/), tramadol hydrochloride (Unit 25 to 150mg/), gabapentin (Unit 100 to 800mg/), acetaminophen (Unit 100 to 1000mg/), carbamazepine (Unit 100 to 400mg/), ibuprofen (Unit 100 to 1600mg/), ketoprofen (Unit 12 to 200mg/), fenoprofen sodium (Unit 100 to 600mg/), flurbiprofen sodium or flurbiprofen (both equal Unit 50 to 200mg/), or in these medicines arbitrarily and compositions steroid or aspirin.Preferably use these preparations once a day.For twice administration every day, K _ATPThe amount of channel opener is preferably half consumption in the preparation that is included in once a day, and the diuretic of co-formulated is the appointment consumption half.

Specified tablet or capsule preparations can comprise the coupling preparation of the medicine of the comorbidities relevant with treatment of obesity in the table 1, the diabetes that are used for the treatment of that comprise those above-mentioned detailed descriptions, cholesterol, depression, the medicine of hypertension and edema, or be used for the treatment of atherosclerosis, osteoarthritis, intervertebral disk hernia, the degeneration of knee joint and hip, breast carcinoma, carcinoma of endometrium, cervical cancer, colon cancer, leukemia and carcinoma of prostate, hyperlipemia, asthma/reactive airway disorders, cholelithiasis, GERD (gastroesophageal reflux disease), obstructive sleep apnea, obesity hypoventilation syndrome, recurrent ventral hernia, the medicine of menoxenia and infertility.

Specified tablet or capsule preparations can comprise the coupling preparation with antipsychotic drug in the table 1, and described compositions is used for the treatment of is treated individual mental disease and treatment or prevention and treated individual weight increase, dyslipidemia or glucose tolerance and reduce.The medicine that can be used for treating multiple mental disease comprises, but be not limited to lithium or its salt (Unit 250 to 2500mg/), carbamazepine or its salt (Unit 50 to 1200mg/), valproate, valproic acid or divalproex sodium (Unit 125 to 2500mg/), lamotrigine (Unit 12.5 to 200mg/), olanzapine (Unit 5 to 20mg/), clozapine (Unit 12.5 to 450mg/) or risperidone (Unit 0.25 to 4mg/).These preparations preferably are intended to be administered once every day.For twice administration every day, K _ATPThe amount of channel opener is preferably half consumption in the preparation that is included in once a day, and the psychosis of co-formulated is the appointment consumption half.

Specified tablet or capsule preparations can comprise and the coupling preparation for the treatment of or prevent the medicine of ischemic or reperfusion injury in the table 1.Can be used for treating or preventing the medicine of ischemic or reperfusion injury to comprise; but be not limited to; low molecular weight heparin (reaches heparin (dalteparin); Enoxaparin; edegliparin.; booth is pricked heparin (tinzaparin) or danaparoid); ancrod; Pentoxifylline; nimodipine; flunarizine; ebselen; tirilazad; clomethiazole; (GYKI 5246 for the AMPA agonist; NBQX; YM90K; zonampanel or MPQX); SYM 2081; selfotel; Cerestat; CP-101,606; nor-dextromethorphan; dextromethorphan; MK-801; NPS 1502; remacemide; ACEA 1021; GV150526; the eliprodil ifenprodil; lubeluzole; naloxone; the nalfemene citicoline; 1-acetyl group carnitine; nifedipine; resveratrol; nitrone derivative; clopidogrel; dabigatran; prasugrel; troxoprodil; AGY-94806 or KAI-9803.

Continuously once a day or provide preparation to fat or overweight curee's administration twice, cause K _ATPThe circulation composition of channel opener is enough to induce and loses weight.Preferential loss by body fat loses weight.When carrying out the administration of described preparation when combining with the caloric diet of minimizing, other losing weight takes place.

The invention provides as single dose to fat, overweight or the K of curee's administration of obesity tendency arranged _ATPThe channel opener agent formulation, it causes on an empty stomach or the irritating insulin secretion of glucose was suppressed about 24 hours or about 18 hours approximately.

The invention provides as single dose to fat, overweight or the K of curee's administration of obesity tendency arranged _ATPThe channel opener agent formulation, it causes energy expenditure to increase about 24 hours or about 18 hours.

The invention provides as single dose to fat, overweight or the K of curee's administration of obesity tendency arranged _ATPThe channel opener agent formulation, it causes the beta-oxidation of fat to increase about 24 hours or about 18 hours.

The invention provides as single dose to fat, overweight or the K of bulimiac curee's administration of obesity tendency arranged _ATPThe channel opener agent formulation, it causes bulimia nerovsa to be suppressed about 24 hours or about 18 hours.

To curee every day (per 24 hours) once or twice the preparation of successive administration cause K _ATPThe circulation composition of channel opener is enough to induce the insulin sensitivity of β cell tranquillization or improvement or both all to have.The improvement of described β cell tranquillization and insulin sensitivity can impel effective treatment type 1 diabetes, type 2 diabetes mellitus and prediabetes.The such β cell tranquillization and the improvement of insulin sensitivity can impel the curee's of type 2 diabetes mellitus and prediabetes NGT that efficient recovery is arranged.

K _ATPThe different pharmaceutical preparation of channel opener serves many purposes, and includes but not limited to: (1) treatment of obesity; (2) whose body weight that is liable to obesity of prevention increases; (3) treatment hyperinsulinemia or insulism; (4) treatment hypoglycemia; (5) treatment hyperlipemia; (6) treatment type 2 diabetes mellitus; (7) protection type 1 diabetes patient's pancreas function; (8) treatment metabolism syndrome (or X syndrome); (9) prevent diabetes changes diabetes in earlier stage into; (10) correction impels the defective of the insulin secretion and the insulin sensitivity of prediabetes and type 2 diabetes mellitus; (11) treatment polycystic ovary syndrome; (12) prevention ischemic or reperfusion injury; (13) treatment reduces with the curee's of psychosis treatment weight increase, dyslipidemia or glucose tolerance; (14) prevention reduces with the curee's of psychosis treatment weight increase, dyslipidemia or glucose tolerance; And the following any disease of (15) treatment, wherein hyperlipemia, hyperinsulinemia, hunger disease, hyperlipemia, bulimia nerovsa or obesity are to impel the severity of following disease or the factor of progress, described disease includes but not limited to, Prader-Willi syndrome, Froehlich syndrome, Cohen syndrome, Sa Mite syndrome, alstrom syndrome, the gloomy syndrome of Bauer wise man, Ahmedabad-other Dare syndrome, or I, II, III and IV type hyperlipoproteinemia.

In one embodiment, with K _ATPPer 24 hours single administrations of the solid oral dosage form of channel opener lose weight to induce in overweight or obese individuals.In other embodiments, described individuality (a) is not the type 1 diabetes patient, (b) is not the type 2 diabetes mellitus patient, (c) does not suffer from chronic, recurrence or drug-induced hypoglycemia, (d) does not have metabolism syndrome, or (e) does not suffer from malignant hypertension.

In one embodiment, with K _ATPThe solid oral dosage form of channel opener is per to be delivered medicine to overweight 24 hours twice or obese individuals loses weight to induce.This treatment can be to induce the independent treatment that loses weight.In other embodiments, described overweight or obese individuals (a) does not have insulin secretion type tumor, (b) do not suffer from polycystic ovary syndrome, (c) not the type 1 diabetes patient, (d) not the type 2 diabetes mellitus patient, (e) do not have metabolism syndrome, (f) do not suffer from chronic, recurrence or drug-induced hypoglycemia, (g) do not use haloperidol treatment schizophrenia, or (h) do not suffered from malignant hypertension.In other embodiments, described overweight or fat teenager (a) be not diagnosed as suffers from 1 type or type 2 diabetes mellitus, (b) does not suffer from chronic, recurrence or drug-induced hypoglycemia, or (c) has not been diagnosed as and suffers from metabolism syndrome.

In another embodiment, with K _ATPThe solid oral dosage form of channel opener delivers medicine to overweight per 24 hours three times or obese individuals loses weight to induce.This treatment can be to induce the independent treatment that loses weight.In other embodiments, described overweight or obese individuals (a) does not have insulin secretion type tumor, (b) do not suffer from polycystic ovary syndrome, (c) not the type 1 diabetes patient, (d) not the type 2 diabetes mellitus patient, (e) do not have metabolism syndrome, or (f) do not suffer from chronic, recurrence or drug-induced hypoglycemia.

In another embodiment, with K _ATPThe solid oral dosage form of channel opener delivers medicine to overweight or fat teenager per 24 hours three times and loses weight to induce.This treatment can be to induce the independent treatment that loses weight.In other embodiments, described overweight or fat teenager is (a) 1 type or type 2 diabetes mellitus patient, (b) does not suffer from chronic, recurrence or drug-induced hypoglycemia, or (c) does not have metabolism syndrome.

In another embodiment, with K _ATPThe solid oral dosage form of channel opener delivers medicine to overweight or fat adult per 24 hours three times and loses weight to induce, described adult (a) does not accept glucagon injection, Lithyronine or furosemide simultaneously, (b) do not use haloperidol treatment schizophrenia, or (c) do not suffered from malignant hypertension.

In another embodiment, with K _ATPThe solid oral dosage form of channel opener delivers medicine to overweight per 24 hours four times or obese individuals loses weight to induce.

In another embodiment, with K _ATPThe solid oral dosage form of channel opener is by 50 to 275mg dosage every day, delivers medicine to overweight per 24 hours one, two, three or four time or obese individuals loses weight to induce.In yet another embodiment, described overweight or fat individuality (a) is not the type 1 diabetes patient, (b) is not the type 2 diabetes mellitus patient, (c) does not suffer from chronic, recurrence or drug-induced hypoglycemia, or (d) does not have metabolism syndrome.

In another embodiment, with K _ATPThe solid oral dosage form of channel opener is by 130 to 275mg dosage every day, delivers medicine to overweight per 24 hours one, two, three or four time or obese individuals loses weight to induce.In yet another embodiment, described overweight or fat individuality (a) is not the type 1 diabetes patient, (b) is not the type 2 diabetes mellitus patient, (c) does not suffer from chronic, recurrence or drug-induced hypoglycemia, or (d) does not have metabolism syndrome.

In other embodiments, with K _ATPThe solid oral dosage form of channel opener delivers medicine to for per 24 hours one, two, three or four time overweight or has the individuality of obesity tendency to lose weight with maintenance, in case this is because take place to lose weight to a certain degree in the obese individuals, preferably keep body weight, otherwise weight recovery.In yet another embodiment, described K _ATPDosage every day of channel opener is 50 to 275mg.

In other embodiments, with K _ATPThe solid oral dosage form of channel opener delivers medicine to, and individuality overweight, fat or that have obesity to be inclined to increases energy expenditure with (a), (b) increases the beta oxidation of fat, or (c) reduces the circulation triglyceride concentration.

In other embodiments, with K _ATPThe solid oral dosage form long term administration of channel opener in have in requisition for individuality initial body fat reduces 25%, 50% or 75% to induce just.

In another embodiment, with K _ATPThe solid oral dosage form long term administration of channel opener in have in requisition for individuality inducing the preferential loss of (a) body fat, or (b) the preferential loss of interior fat.

In other embodiments, with K _ATPThe solid oral dosage form of channel opener per 24 hours one, two or three time, by every day dosage 50 to 275mg continue medication in individuality, induce just with (a) that initial body fat reduces 25%, 50% or 75%, (b) the preferential loss of inductor fat, or (c) induce the preferential loss of interior fat.

In another embodiment, with K _ATPThe solid oral dosage form of channel opener delivers medicine to individual with the preferential loss of inductor fat with induce the minimizing of circulation triglyceride.

In another embodiment, with K _ATPThe solid oral dosage form of channel opener and following medicine co-administered are with overweight, fat or have to induce in the individuality of obesity tendency and lose weight and/or comorbidities that treatment of obesity is relevant, and described medicine is: the diuretic of sibutramine, orlistat, Rimonabant, appetite suppressant, antidepressants, antuepileptic, non-furosemide, by being different from K _ATPThe mechanism of channel opener is induced the medicine that loses weight, is induced the medicine (but non-metformin, furosemide or Lithyronine) that loses weight by the mechanism that is different from the KATP channel opener, or the medicine of blood pressure lowering.In more embodiments, described individuality (a) overweight, fat or that have obesity to be inclined to is the type 1 diabetes patient, (b) is not the type 2 diabetes mellitus patient, (c) does not suffer from chronic, recurrence or drug-induced hypoglycemia, or (d) does not have metabolism syndrome.

In another embodiment, carry out K to individuality overweight, fat or that have obesity to be inclined to _ATPThe anti-inflammatory agent of the solid oral dosage form of channel opener and antidepressants, hypotensor, pravastatin, high density lipoprotein increasing medicine, non-Cox-2 inhibitor, reduce the medicine co-administered of circulation triglyceride, lose weight and/or comorbidities that treatment of obesity is relevant to induce.In more embodiments, described individuality (a) overweight, fat or that have obesity to be inclined to is not the type 1 diabetes patient, (b) not the type 2 diabetes mellitus patient, (c) do not suffer from chronic, recurrence or drug-induced hypoglycemia, or (d) do not have metabolism syndrome.

In another embodiment, overweight, fat or have in the individuality of obesity tendency, carry out K _ATPThe medicine co-administered of the anti-inflammatory agent of the solid oral dosage form of channel opener and hypotensor, pravastatin, high density lipoprotein increasing medicine, non-Cox-2 inhibitor, reduction circulation triglyceride, to keep the relevant comorbidities of body weight and/or treatment of obesity, in case this is because take place to lose weight to a certain degree in the obese individuals, preferably keep body weight, otherwise weight recovery.In other embodiments, described individuality (a) overweight, fat or that have obesity to be inclined to is not the type 1 diabetes patient, (b) not the type 2 diabetes mellitus patient, (c) do not suffer from chronic, recurrence or drug-induced hypoglycemia, or (d) do not have metabolism syndrome.

In other embodiments, K _ATPThe tablet formulation of channel opener is used for the K with the treatment effective dose _ATPChannel opener to have in requisition for overweight, fat or have the individuality of obesity tendency to carry out administration, make β cell tranquillization with (a), (b) treatment 1 type or type 2 diabetes mellitus, or (c) recurrence of prevent diabetes.

In other embodiments, with K _ATPThe solid oral dosage form of channel opener or tablet formulation lose weight and/or treatment of obesity and the relevant comorbidities of obesity to induce with the adult or the teenager of phentermine or derivatives thereof co-administered in obesity.In other embodiments, with K _ATPThe solid oral dosage form of channel opener or tablet formulation and phentermine or derivatives thereof co-administered in the adult of obesity or teenager with treatment have in requisition for patient's metabolism syndrome.

In other embodiments, with K _ATPThe pharmaceutically acceptable preparation of channel opener (with 50 to 275mg/ days dosage) and phentermine or derivatives thereof (dosage every day with 15 to 37.5mg) co-administered lose weight, treat metabolism syndrome or induce in overweight or fat individuality and lose weight and comorbidities that treatment of obesity is relevant to induce.In another embodiment, with tablet formulation and phentermine or derivatives thereof co-administered metabolism syndrome with the treatment patient.

In another embodiment, with K _ATPThe dissolution formulation of channel opener be used for Xiang Youxiang in requisition for the patient treatment effective dose is provided.

In other embodiments, with K _ATPChannel opener with the dosage of per 24 hours 125mg to 275mg to not being that type 2 diabetes mellitus people and the overweight or obese individuals that is not in the hypoglycemia treatment at night are carried out administration.

In other embodiments, with K _ATPChannel opener is formulated as tablet for oral administration or capsule.Described tablet or capsule can be prepared with metformin.In another embodiment, with K _ATPChannel opener is formulated as oral suspensions, and also can be with described oral suspensions encapsulate in another embodiment.

In another embodiment, with K _ATPThe pharmaceutical salts of channel opener is prepared as tablet for oral administration or capsule, or as oral suspensions or as oral administration solution, or conduct is by the oral administration solution of encapsulate.If described opener is a diazoxide, described salt preferably is not sodium salt.

In another embodiment, with K _ATPChannel opener is formulated in the pharmaceutical preparation that is suitable for oral administration with hydrochlorothiazide, chlorothiazide, cyclothiazide, benzthiazide, metyclothiazide, bendroflumethiazide, hydroflumethiazide, trichlormethiazide or polythiazide.

When after the mankind or animal carry out the administration of preparation provided by the invention, observe some or all following effects: (1) is reduced adipose cell and is produced lipoprotein lipase; (2) lipolysis of increase adipose cell; (3) reduce adipose cell and express fatty acid synthase; (4) activity of the glyceraldehyde phosphate dehydrogenase of reduction adipose cell; (5) a small amount of or do not have new triglyceride to be synthesized and by storage of adipocytes; (6) improved β ₃Adrenoreceptor (β ₃AR) expression also improves adrenergic function in the adipose cell; (7) the glucose zest insulin secretion of reduction B cells of pancreas; (8) alleviate insulinemia; (9) improve blood sugar level; (10) expression of uncoupling protein 1 in the increase adipose cell; (11) heat production in the increase white adipose tissue and the brown adipose tissue; (12) reduce plasma triglyceride concentration; (13) reduce circulation leptin concentration; (14) rise of Insulin receptor INSR; (15) improve glucose uptake; (16) alleviate adipose cell proliferation; (17) alleviate the adipose cell hypertrophy; (18) reduce the conversion ratio of preceding adipose cell to adipose cell; (19) reduce the bulimia nerovsa incidence rate; (20) enhancing is because of the protection of CNS, heart and the hetero-organization thereof of ischemic and reperfusion injury; (21) improve insulin sensitivity; (22) improve the CSF insulin concentration; (23) improve the circulation adiponectin concentration; (25) reduce the circulation triglyceride concentration; (26) increase the beta cell tranquillization.

Threshold concentration of the present invention comprises by oral formulations, controlled release preparation, percutaneous preparation or intranasal preparation medicine as intravenous formulations, instant-free and delivers medicine to K overweight or that obese individuals produced _ATPThe circulation composition of channel opener, it causes: the inhibition of the fasting insulin level that (1) can be surveyed; (2) using K _ATPIn same individual, suppress at least 20% fasting insulin level before the channel opener treatment from base line measurement; (3) using K _ATPIn same individual, suppress at least 30% fasting insulin level before the channel opener treatment from base line measurement; (4) using K _ATPIn same individual, suppress at least 40% fasting insulin level before the channel opener treatment from base line measurement; (5) using K _ATPIn same individual, suppress at least 50% fasting insulin level before the channel opener treatment from base line measurement; (6) using K _ATPIn same individual, suppress at least 60% fasting insulin level before the channel opener treatment from base line measurement; (7) using K _ATPIn same individual, suppress at least 70% fasting insulin level before the channel opener treatment from base line measurement; (8) using K _ATPIn same individual, suppress at least 80% fasting insulin level before the channel opener treatment from base line measurement; (9) lose weight; (10) energy expenditure of raising tranquillization; Or (11) improve fat or oxidation of fatty acids.Threshold effect of the present invention comprises the K that individuality produced that is delivered medicine to the obesity tendency by the intranasal preparation of the percutaneous preparation of the extended release preparation of the controlled release preparation of the oral formulations of the instant-free of the intravenous formulations of medicine or medicine or medicine or medicine or medicine or medicine _ATPThe circulation composition of channel opener, it causes: (1) loses weight and (2) keep body weight.Threshold effect of the present invention comprises that the intranasal preparation by the percutaneous preparation of the extended release preparation of the controlled release preparation of the oral formulations of the instant-free of the intravenous formulations of medicine or medicine or medicine or medicine or medicine or medicine delivers medicine to the K that the prediabetes individuality is produced _ATPThe circulation composition of channel opener, it can prevent the conversion to diabetes.Threshold effect of the present invention comprises that the intranasal preparation by the percutaneous preparation of the sustained release formulation of the controlled release preparation of the oral formulations of the instant-free of the intravenous formulations of medicine or medicine or medicine or medicine or medicine or medicine delivers medicine to the K that individuality produced that suffers from type 1 diabetes _ATPThe circulation composition of channel opener, it causes β cell tranquillization.

By carrying out K to individuality overweight, fat or that have obesity to be inclined to _ATPMaintenance that the long term administration of channel opener produces or slimming model of action (as the invention provides) include, but are not limited to following one or more: (1) improves energy expenditure; (2) improve fat and oxidation of fatty acids; (3) lipolysis in the enhancing fatty tissue; (4) increase via the glucose uptake of organizing, increase insulin sensitivity; (5) improve the Beta-3 adrenergic response.By carrying out K to individuality fat or that have obesity to be inclined to _ATPMaintenance or slimming model of action that the long term administration of channel opener produces also can comprise appetite-suppressing.

Carry out K to the overweight or fat mankind or animal _ATPThe long term administration of the pharmaceutical preparation of channel opener causes significant and persistent losing weight, and comprises some or all following effects: the preferential loss of (1) body fat; (2) initial body fat mass reduces greater than 25%; (3) initial body fat mass reduces greater than 50%; (4) initial body fat mass reduces greater than 75%; (5) significantly improve REE; (6) improve fat and oxidation of fatty acids; (7) bring high blood pressure down; (8) reduce adipose cell and produce lipoprotein lipase; (9) lipolysis of increase adipose cell; (10) reduce adipose cell and express fatty acid synthase; (11) activity of the glyceraldehyde phosphate dehydrogenase of reduction adipose cell; (12) a small amount of or do not have new triglyceride to be synthesized and via storage of adipocytes; (13) improve β ₃Adrenoreceptor (β ₃AR) expression also improves adrenergic function in the adipose cell; (14) the glucose zest insulin secretion of reduction B cells of pancreas; (15) alleviate insulinemia; (16) improve blood sugar level; (17) expression of uncoupling protein 1 in the increase adipose cell; (18) heat production in the increase white adipose tissue and the brown adipose tissue; (19) reduce plasma triglyceride concentration; (20) reduce circulation leptin concentration; (21) rise of Insulin receptor INSR; (22) improve glucose uptake; (23) alleviate adipose cell proliferation; (24) alleviate the adipose cell hypertrophy; (25) reduce the conversion ratio of preceding adipose cell to adipose cell; (26) reduce bulimiac incidence rate; (27) the at first most active fatty tissue of metabolism (internal organs) loss in succession, the fatty tissue loss that the metabolic activity that continues is less; (28) improve the circulation adiponectin concentration; (29) improve the cerebrospinal fluid insulin level; (30) Insulin mRNA and the insulin content of raising islets of langerhans; Or (31) improve the metabolic efficiency of insulin.

To the mankind or animal that the obesity tendency is arranged, comprise that the individuality of the various types of Bariatric operations of experience carries out K _ATPThe long term administration of channel opener agent formulation causes the lasting maintenance of body weight, comprises some or all following effects: (1) increases REE; (2) increase fat and oxidation of fatty acids; (3) bring high blood pressure down; (4) lipoprotein lipase of reduction adipose cell produces; (5) steatolysis of raising adipose cell; (6) reduce the adipocyte fatty acid synthase expression; (7) activity of the glyceraldehyde phosphate dehydrogenase of reduction adipose cell; (8) a small amount of or do not have new triglyceride to be synthesized and by storage of adipocytes; (9) improved β ₃Adrenoreceptor (β ₃AR) expression also improves adrenergic function in the adipose cell; (10) reduced the glucose zest insulin secretion of B cells of pancreas; (11) alleviate insulinemia; (12) improve blood sugar level; (13) expression of uncoupling protein 1 in the increase adipose cell; (14) heat production in the increase white adipose tissue and the brown adipose tissue; (15) reduce plasma triglyceride concentration; (16) reduce circulation leptin concentration; (17) rise of Insulin receptor INSR; (18) improve glucose uptake; (19) alleviate adipose cell proliferation; (20) alleviate the adipose cell hypertrophy; (21) reduce the conversion ratio of preceding adipose cell to adipose cell; And (22) reduce bulimiac incidence rate; (23) improve the circulation adiponectin concentration; (24) improve the cerebrospinal fluid insulin level; (25) Insulin mRNA and the insulin content of raising islets of langerhans; Or (26) improve the metabolic efficiency of insulin.

The mankind or animal to prediabetes or type 1 diabetes carry out K _ATPInstant or the long term administration of the preparation of channel opener can prevent beta cell failure, improves glycemic control and prevent diabetes in earlier stage to the conversion of diabetes, and comprise some or all following effects: (1) increases REE; (2) increase fat and oxidation of fatty acids; (3) bring high blood pressure down; (4) generation of the lipoprotein lipase of reduction adipose cell; (5) steatolysis of raising adipose cell; (6) reduce the adipocyte fatty acid synthase expression; (7) activity of the glyceraldehyde phosphate dehydrogenase of reduction adipose cell; (8) a small amount of or do not have new triglyceride to be synthesized and by storage of adipocytes; (9) improve β ₃Adrenoreceptor (β ₃AR) expression also improves adrenergic function in the adipose cell; (10) the glucose zest insulin secretion of reduction B cells of pancreas; (11) alleviate insulinemia; (12) improve blood sugar level; (13) expression of uncoupling protein 1 in the increase adipose cell; (14) heat production in the increase white adipose tissue and the brown adipose tissue; (15) reduce plasma triglyceride concentration; (16) reduce circulation leptin concentration; (17) rise of Insulin receptor INSR; (18) improve glucose uptake; (19) alleviate adipose cell proliferation; (20) alleviate the adipose cell hypertrophy; (21) reduce the conversion ratio of preceding adipose cell to adipose cell; (22) reduce bulimiac incidence rate; (23) improve the circulation adiponectin concentration; (24) improve the cerebrospinal fluid insulin level; (25) Insulin mRNA and the insulin content of raising islets of langerhans; Or (26) improve the metabolic efficiency of insulin.

Carry out K to being in the dangerous of myocardial infarction or apoplexy or experience recovery blood flow the mankind or animal to the operation technique of heart or brain _ATPInstant or the long term administration of channel opener agent formulation can improve the therapeutic outcome behind the surgical operation, or improves tissue survival behind restoration of blood flow after myocardial infarction or apoplexy take place, alleviate tissue and press down and time and the character of change inflammatory response.

Pharmaceutical preparation provided by the invention is designed to the illness that treatment of obesity, hyperlipemia, hypertension, weight maintenance, type 1 diabetes, prediabetes, type 2 diabetes mellitus or any weight alleviate, and reduces circulation triglyceride or β cell tranquillization and impels therapeutic outcome that K to dosage is provided _ATPThe drug influence kinetics of channel opener and the crucial excursion in the pharmacokinetic response, this variation comprise following one or more: the drug influence kinetic effect that (1) postpones dosage is to greater than 24 hours, as measured by suppressing insulin secretion; (2) provide the huge uptake of active pharmaceutical ingredient in the small intestinal; (3) provide the huge uptake of active pharmaceutical ingredient in the large intestine; (4) compare with the present oral suspensions or the capsule product of the active pharmaceutical ingredient of identical dosage, cause lower C _Max(5) provide circulation composition to reach 24 hours or the longer time from the non-binding active pharmaceutical ingredient more than the threshold concentration of single-dose dosage; Reach (6) and compare, provide and treated individual more consistent drug absorption with present capsule preparations.

The drug combination preparation that is designed for treatment series of human and animal illness of the present invention comprises coupling K _ATPChannel opener and following medicine: (1) diuretic, (2) hypotensor, (3) appetite suppressant, (4) cannabinoid receptor antagonists, (5) medicine of inhibition gastric lipase effect, (6) be used to induce any medicine that loses weight, (7) pravastatin, (8) reduce the medicine in conjunction with the cholesterol of LDL, and (9) improve the medicine of insulin sensitivity, (10) improve the medicine of glucose utilization or picked-up, (11) medicine of reduction atheromatous plaque incidence rate, the medicine that (12) reduce inflammation, (13) antidepressants, (14) antuepileptic, or (15) psychosis.

The present invention uses K _ATPThe incidence rate that the pharmaceutical preparation treatment mankind of channel opener or animal can reduce adverse side effect, described adverse side effect includes but not limited to, edema, fluid retention, the excretion rate of sodium, chloride and uric acid reduces, hyperglycemia, ketoacidosis is felt sick, vomiting, it is bad to liquefy, intestinal obstruction and headache.Minimizing on these adverse side effect occurrence frequencies is by following acquisition: (1) individual predose is in inferior therapeutic dose and increases every day dosage until reaching therapeutic dose in progressively mode, is 2 to 10 at the natural law that reaches that step of effective dose wherein; (2) use minimal effective dose to obtain ideal treatment effect; (3) use a kind of pharmaceutical preparation, it is delayed to and just discharges active matter after the stomach transhipment is finished; (4) use a kind of pharmaceutical preparation, it is delayed to and just discharges active matter after the stomach transhipment is finished; (5) use a kind of pharmaceutical preparation, it is compared with the oral suspensions or the capsule preparations of the instant-free of identical dosage, causes lower circulation peak drug concentration; And (6) are in the administration timing of the administration same day and relative each meal optimization dosage.

The present invention uses K _ATPThe pharmaceutical preparation treatment of channel opener suffers from rad-Willie syndrome, the Froehlich syndrome, Cohen syndrome, the Sa Mite syndrome, alstrom syndrome, the gloomy syndrome patient of Bauer wise man, Ahmedabad-other Dare syndrome and I type, the II type, the patient of III type or IV type hyperlipoproteinemia, cause some or all following therapeutic outcomes: (1) loses weight, (2) reduce the speed of weight increase, (3) appetite-suppressing is crossed Sheng, (4) reducing glucose tolerance reduces, the incidence rate of prediabetes or diabetes, (5) incidence rate of reduction congestive heart failure, (6) alleviating hypertension and (7) reduce the incidence rate of the death of all reasons.

The present invention uses K _ATPThe curee of the pharmaceutical preparation treatment prediabetes of channel opener, cause some or all following therapeutic outcomes: (1) loses weight, (2) recover NGT, (3) delay advances to the speed of diabetes, (4) hypertension alleviates and (5) reduce the incidence rate of the death of all reasons.

The present invention uses K _ATPThe curee of the pharmaceutical preparation treatment diabetes of channel opener, cause some or all following therapeutic outcomes: (1) loses weight, (2) recover NGT, (3) delay advances to the speed of diabetes, (4) improve glucose tolerance, (5) hypertension alleviates and (6) reduce the incidence rate of the death of all reasons.

Overweight, fat or medicine and K are arranged in the disease treatment of the mankind of obesity tendency or animal subject _ATPThe preparation co-administered of channel opener comprises K _ATPThe pharmaceutically acceptable preparation of channel opener and following a kind of acceptable preparation co-administered: (1) sibutramine, (2) orlistat, (3) Rimonabant, (4) appetite suppressant, (5) be used for inducing any medicine that loses weight at fat and overweight individuality, (6) non-thiazide diuretic, (7) medicine of cholesterol reducing, (8) medicine of rising HDL cholesterol, (9) medicine of reduction LDL cholesterol, (10) medicine that brings high blood pressure down, (11) antidepressant medicine, (12) improve the medicine of insulin sensitivity, (13) improve the medicine of glucose utilization and picked-up, (14) antiepileptic, (15) anti-inflammatory drug, or (16) reduce the medicine of circulation triglyceride.

In the curee's who treats or prevent to treat with antipsychotic drug weight increase, dyslipidemia or glucose tolerance reduce, medicine and K _ATPThe preparation co-administered of channel opener comprises K _ATPThe pharmaceutically acceptable preparation of channel opener and following a kind of acceptable preparation co-administered: lithium; Carbamazepine; Valproic acid and divalproex sodium; And lamotrigine; Usually be classified as the antidepressants of oxidase inhibitor, comprise isocarbossazide, W-1544a and tranylcypromine sulfate; The tricyclic antidepressants antidepressant drug comprises doxepin, clomipramine, amitriptyline, maprotiline, desipromine, nortryptyline, desipramine, doxepin, trimeprimine, imipramine and protriptyline; Fourth Ring class antidepressant drug, comprise mianserin, mirtazapine, maprotiline, oxaprozin, delequamine, levoprotline, three flucarbrils, setiptiline, lortalamine, azipramine, aptazapine maleate and pirlindole, and major tranquilizer comprises paloproxidol, perphenazine, thioridazine, risperidone, clozapine, olanzapine and chlorpromazine with the psychosis that is not true to type.

In one embodiment, K _ATPChannel opener carries out administration as the capsule of oral suspensions or instant-free or tablet or controlled release preparation or percutaneous preparation or intranasal preparation to overweight or fat individuality, thereby a period of time that continues to prolong reaches and keeps the required threshold concentration of appropriateness reduction fasting insulin level.Preferably, K _ATPThe fasting insulin level that makes channel opener reduces at least 20%, and 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%.Usually use glucose tolerance test (OGTT) to measure the fasting insulin level.After overnight fasted, the patient takes in the glucose of known quantity.Initial glucose level is determined by the trial test glucose level of measuring in blood and the urine.Glucose be consumed reach three hours after, measure the blood insulin level by blood drawing per hour.In the fasting glucose test, the plasma glucose value of glucose load after 2 hours shows that greater than the individuality of 200mg/dl its glucose tolerance reduces.

In another embodiment, with K _ATPChannel opener carries out administration as the capsule of oral suspensions or instant-free or tablet or controlled release preparation or percutaneous preparation or intranasal preparation to overweight or fat individuality, reaches and keeps inducing the required threshold concentration that loses weight with a period of time that continues to prolong.

In another embodiment, with K _ATPChannel opener carries out administration as the capsule of oral suspensions or instant-free or tablet or controlled release preparation or percutaneous preparation or intranasal preparation to overweight or fat individuality, reaches and keeps inducing the required threshold concentration of raising rest energy expenditure with a period of time that continues to prolong.

In another embodiment, with K _ATPChannel opener carries out administration as the capsule of oral suspensions or instant-free or tablet or controlled release preparation or percutaneous preparation or intranasal preparation to overweight or fat individuality, reaches and keeps improving fatty and the required threshold concentration of fatty acid oxidation with a period of time that continues to prolong.

In another embodiment, with K _ATPChannel opener carries out administration as the capsule of oral suspensions or instant-free or tablet or controlled release preparation or percutaneous preparation or intranasal preparation to the individuality that the obesity tendency is arranged, and reaches and keeps inducing the required threshold concentration that loses weight with a period of time that continues to prolong.

In another embodiment, with K _ATPChannel opener carries out administration as the capsule of oral suspensions or instant-free or tablet or controlled release preparation or percutaneous preparation or intranasal preparation to the individuality that the obesity tendency is arranged, and reaches and keeps keeping the required threshold concentration of body weight with a period of time that continues to prolong.

In another embodiment, with K _ATPChannel opener carries out administration as the capsule of oral suspensions or instant-free or tablet or controlled release preparation or percutaneous preparation or intranasal preparation to overweight or fat individuality, reaches and is kept above the drug level of inducing the required threshold concentration that loses weight with a period of time that continues to prolong.

In another embodiment, with K _ATPChannel opener carries out administration as the capsule of oral suspensions or instant-free or tablet or controlled release preparation or percutaneous preparation or intranasal preparation to overweight or fat individuality, reduce body fat with a period of time that continues to prolong and surpass 25%, more preferably at least 50%, and more preferably at least 75%.

In another embodiment, with K _ATPChannel opener carries out administration as the capsule of oral suspensions or instant-free or tablet or controlled release preparation or percutaneous preparation or intranasal preparation to overweight or fat individuality, with the preferential calm body of interior fat that reduces of a period of time that continues to prolong.

In another embodiment, with K _ATPChannel opener carries out administration as the capsule of oral suspensions or instant-free or tablet or controlled release preparation or percutaneous preparation or intranasal preparation to overweight or fat individuality, reduces the calm body of interior fat and other fat deposit with a period of time that continues to prolong.

In another embodiment, with K _ATPChannel opener carries out administration as the capsule of oral suspensions or instant-free or tablet or controlled release preparation or percutaneous preparation or intranasal preparation to the overweight or fat individuality with normal insulin, reaches and is kept above the drug level of inducing the required threshold concentration that loses weight with a period of time that continues to prolong.

In another embodiment, with K _ATPChannel opener carries out administration as the capsule of oral suspensions or instant-free or tablet or controlled release preparation or percutaneous preparation or intranasal preparation to the prediabetes individuality, reaches and is kept above the drug level that prevention changes the required threshold concentration of diabetes into a period of time that continues to prolong.

In another embodiment, with K _ATPChannel opener carries out administration as the capsule of oral suspensions or instant-free or tablet or controlled release preparation or percutaneous preparation or intranasal preparation to the type 1 diabetes individuality, reaches and is kept above the drug level of inducing the required threshold concentration of β cell tranquillization with a period of time that continues to prolong.

In another embodiment, with the K of single dose _ATPThe pharmaceutically acceptable preparation of channel opener to have in requisition for individual administration, cause the circulation composition of active medicine to be enough to continue 24 hours or the longer time reduces insulin secretion.

In another embodiment, with K _ATPThe pharmaceutically acceptable preparation of channel opener with time expand to have in requisition for individuality carry out per administration that was no more than once in 24 hours, it causes the circulation composition of active medicine to be enough to the continuous decrease insulin secretion.

In another embodiment, with the K of single dose _ATPThe pharmaceutically acceptable preparation of channel opener to have in requisition for individual administration, cause the circulation composition of active medicine to be enough to continue 24 hours or the longer time is improved non-esterified fatty acid in the circulation.

In another embodiment, with K _ATPThe pharmaceutically acceptable preparation of channel opener with time expand to have in requisition for individuality carry out per administration that was no more than once in 24 hours, it causes the circulation composition of active medicine to be enough to continue to improve non-esterified fatty acid in the circulation.

In another embodiment, with the K of single dose _ATPThe pharmaceutically acceptable preparation of channel opener to have in requisition for individual administration, cause the circulation composition of active medicine to be enough to continue 24 hours or the longer time is treated the circulation hypoglycemia.

In another embodiment, with K _ATPThe pharmaceutically acceptable preparation of channel opener with time expand to have in requisition for individuality carry out per administration that was no more than once in 24 hours, it causes the circulation composition of active medicine to be enough to the continued treatment hypoglycemia.

In another embodiment, with K _ATPThe pharmaceutically acceptable preparation of channel opener with time expand to have in requisition for individuality carry out per administration that was no more than once in 24 hours, it causes the circulation composition of active medicine to be enough to successive induction losing weight.

In another embodiment, with K _ATPThe pharmaceutically acceptable preparation of channel opener with time expand to have in requisition for individuality carry out per administration that was no more than once in 24 hours, it causes the circulation composition of active medicine to be enough to continue to keep body weight, in case this is because take place to lose weight to a certain degree in the obese individuals, preferably keep body weight, otherwise weight recovery.

In another embodiment, with K _ATPThe pharmaceutically acceptable preparation of channel opener with time expand to have in requisition for individuality carry out per administration that was no more than once in 24 hours, it causes the circulation composition of active medicine to be enough to continue to reduce the circulation triglyceride.

In another embodiment, with the K of single dose _ATPThe pharmaceutically acceptable preparation of channel opener to have in requisition for individual administration, cause the circulation composition of active medicine to be enough to continue 24 hours or the longer time reduces or the prevention circulation in ischemic or reperfusion injury.

In another embodiment, with K _ATPThe pharmaceutically acceptable preparation of channel opener with time expand to have in requisition for individuality carry out per administration that was no more than once in 24 hours, it causes the circulation composition of active medicine to be enough to continuous decrease or prevention ischemic or reperfusion injury.

In another embodiment, the pharmaceutically acceptable preparation with the diazoxide or derivatives thereof reduces K _ATPThe frequency of the untoward reaction of channel opener treatment, with its every day to have in requisition for individual administration, wherein known initial dose is in inferior therapeutic dose and then progressively increases every day dosage until the arrival therapeutic dose.

In another embodiment, use K _ATPThe pharmaceutically acceptable preparation of channel opener has reduced K _ATPThe frequency of the untoward reaction of channel opener treatment, with its every day to have in requisition for individual administration, wherein active component is transported until stomach and is just discharged from preparation after finishing.

In another embodiment, use K _ATPThe pharmaceutically acceptable preparation of channel opener has reduced K _ATPThe frequency of the untoward reaction of channel opener treatment, with its every day to have in requisition for individual administration, wherein the largest loop concentration of active component be lower than same dose by use oral suspensions or capsule preparations administration realized.

In another embodiment, use K _ATPThe pharmaceutically acceptable preparation of channel opener has reduced K _ATPThe frequency of the untoward reaction of channel opener treatment, with its every day to have in requisition for individual administration, wherein known initial dose is in inferior therapeutic dose and then progressively increases every day dosage until arriving therapeutic dose, described active component just discharges from preparation after stomach transhipment is finished, and wherein the largest loop concentration of active component be lower than same dose by using oral suspensions or capsule preparations administration realized.

In another embodiment, use K _ATPThe pharmaceutically acceptable preparation of channel opener has reduced K _ATPThe frequency of the untoward reaction of channel opener treatment, with its every day to have in requisition for overweight or obese individuals administration, wherein known initial dose is in inferior therapeutic dose and then progressively increases every day dosage until arriving therapeutic dose, described active component just discharges from preparation after the stomach transhipment is finished, wherein the largest loop concentration of active component be lower than same dose by using oral suspensions or capsule preparations administration realized, and wherein maximal dose is lower than 2.5mg/kg/ days.

In another embodiment, use K _ATPThe pharmaceutically acceptable preparation of channel opener has reduced K _ATPThe frequency of the untoward reaction of channel opener treatment, with every day to have in requisition for overweight or obese individuals administration, wherein known initial dose is in inferior therapeutic dose and then progressively increases every day dosage until arriving therapeutic dose, described active component just discharges from preparation after the stomach transhipment is finished, wherein the largest loop concentration of active component be lower than same dose by using oral suspensions or capsule preparations administration realized, and wherein maximal dose is lower than 1.75mg/kg/ days.

In another embodiment, by once carrying out K in per 24 hours _ATPThe treatment of overweight or obese individuals is optimized in the administration of the pharmaceutically acceptable preparation of channel opener at losing weight, wherein provide nearly zero level to discharge for continuing at least 12 hours the release improvement of active component from described preparation.

In another embodiment, by once carrying out K in per 24 hours _ATPThe treatment of overweight or obese individuals is optimized in the administration of the pharmaceutically acceptable preparation of channel opener at losing weight, wherein provide nearly zero level to discharge for continuing at least 18 hours the release improvement of active component from described preparation.

In another embodiment, by once carrying out K in per 24 hours _ATPThe treatment of overweight or obese individuals is optimized in the administration of the pharmaceutically acceptable preparation of channel opener at losing weight, wherein with the release improvement of active component from described preparation for continuing to provide at least 12 hours the drug level that raises in the circulation.

In another embodiment, by once carrying out K in per 24 hours _ATPThe treatment of overweight or obese individuals is optimized in the administration of the pharmaceutically acceptable preparation of channel opener at losing weight, wherein with the release improvement of active component from described preparation for continuing to provide at least 18 hours the drug level that raises in the circulation.

In another embodiment, by once carrying out K in per 24 hours _ATPThe treatment of overweight or obese individuals is optimized in the administration of the pharmaceutically acceptable preparation of channel opener at losing weight, wherein the release improvement of active component from described preparation is coupling basal insulin secretion pattern.

In another embodiment, use K _ATPThe pharmaceutically acceptable preparation of channel opener has reduced K _ATPThe frequency of the untoward reaction of channel opener treatment, with its every day to have in requisition for the individual administration that obesity tendency is arranged, wherein known initial dose is in inferior therapeutic dose and then progressively increases every day dosage until arriving therapeutic dose, described active component just discharges from preparation after the stomach transhipment is finished, wherein the largest loop concentration of active component be lower than same dose by using oral suspensions or capsule preparations administration realized, and wherein maximal dose is lower than 2.5mg/kg/ days.

In another embodiment, use K _ATPThe pharmaceutically acceptable preparation of channel opener has reduced K _ATPThe frequency of the untoward reaction of channel opener treatment, with its every day to have in requisition for the individual administration that obesity tendency is arranged, wherein known initial dose is in inferior therapeutic dose and then progressively increases every day dosage until arriving therapeutic dose, described active component just discharges from preparation after the stomach transhipment is finished, wherein the largest loop concentration of active component be lower than same dose by using oral suspensions or capsule preparations administration realized, and wherein maximal dose is lower than 1.75mg/kg/ days.

In another embodiment, the treatment of individuality of obesity tendency is arranged by once carrying out K in per 24 hours _ATPThe administration of the pharmaceutically acceptable preparation of channel opener comes at keeping body weight optimization, wherein provides nearly zero level to discharge for continuing at least 12 hours the release improvement of active component from described preparation.

In another embodiment, by once carrying out K in per 24 hours _ATPThe administration of the pharmaceutically acceptable preparation of channel opener has the treatment of the individuality of obesity tendency at keeping body weight to optimize, and wherein provides nearly zero level to discharge for continuing at least 18 hours the release improvement of active component from described preparation.

In another embodiment, by once carrying out K in per 24 hours _ATPThe administration of the pharmaceutically acceptable preparation of channel opener has the treatment of the individuality of obesity tendency at keeping body weight to optimize, and wherein the release of active component from described preparation is improved to continuing to provide at least 12 hours the drug level of continuous rising in the circulation.

In another embodiment, by once carrying out K in per 24 hours _ATPThe administration of the pharmaceutically acceptable preparation of channel opener has the treatment of the individuality of obesity tendency at keeping body weight to optimize, and wherein the release of active component from described preparation is improved to continuing to provide at least 18 hours the drug level of continuous rising in the circulation.

In another embodiment, by once carrying out K in per 24 hours _ATPThe administration of the pharmaceutically acceptable preparation of channel opener has the treatment of the individuality of obesity tendency at keeping body weight to optimize, and wherein the release of active component from described preparation is improved, and mates basal insulin secretion pattern.

In another embodiment, carry out K to overweight or fat individuality _ATPThe pharmaceutically acceptable preparation of channel opener and the co-administered of sibutramine lose weight to induce.

In another embodiment, carry out K to overweight or fat individuality _ATPThe pharmaceutically acceptable preparation of channel opener and the co-administered of orlistat lose weight to induce.

In another embodiment, carry out K to overweight or fat individuality _ATPThe pharmaceutically acceptable preparation of channel opener and the co-administered of Rimonabant lose weight to induce.

In another embodiment, carry out K to overweight or fat individuality _ATPThe pharmaceutically acceptable preparation of channel opener and the co-administered of appetite suppressant lose weight to induce.

In another embodiment, carry out K to overweight or fat individuality _ATPThe pharmaceutically acceptable preparation of channel opener and the co-administered of antidepressants lose weight to induce.

In another embodiment, carry out K to overweight or fat individuality _ATPThe pharmaceutically acceptable preparation of channel opener and the co-administered of antuepileptic lose weight to induce.

In another embodiment, carry out K to overweight or fat individuality _ATPThe pharmaceutically acceptable preparation of channel opener and the co-administered of non-thiazide diuretic lose weight to induce.

In another embodiment, carry out K to overweight or fat individuality _ATPThe pharmaceutically acceptable preparation of channel opener with induce the medicine co-administered that loses weight to lose weight by the mechanism that is different from diazoxide to induce.

In another embodiment, to overweight, have obesity tendency or obese individuals to carry out K _ATPThe pharmaceutically acceptable preparation of channel opener and hypotensor co-administered are to induce the comorbidities relevant with treatment of obesity that lose weight.

In another embodiment, to overweight, have obesity tendency or obese individuals to carry out K _ATPThe pharmaceutically acceptable preparation of channel opener and the medicine co-administered of cholesterol reducing are to induce the comorbidities relevant with treatment of obesity that lose weight.

In another embodiment, to overweight, have obesity tendency or obese individuals to carry out K _ATPThe medicine co-administered of the cholesterol that the pharmaceutically acceptable preparation of channel opener is related with rising HDL is to induce the comorbidities relevant with treatment of obesity that lose weight.

In another embodiment, to overweight, have obesity tendency or obese individuals to carry out K _ATPThe pharmaceutically acceptable preparation of channel opener and the medicine co-administered that improves insulin sensitivity are to induce the comorbidities relevant with treatment of obesity that lose weight.

In another embodiment, to overweight, have obesity tendency or obese individuals to carry out K _ATPThe pharmaceutically acceptable preparation of channel opener and anti-inflammatory agent co-administered are to induce the comorbidities relevant with treatment of obesity that lose weight.

In another embodiment, to overweight, have obesity tendency or obese individuals to carry out K _ATPThe pharmaceutically acceptable preparation of channel opener and the medicine co-administered that reduces the circulation triglyceride are to induce the comorbidities relevant with treatment of obesity that lose weight.

In another embodiment, with K _ATPChannel opener is formulated in the pharmaceutically acceptable preparation with sibutramine, with described preparation to overweight, obesity tendency or obese individuals administration are arranged to induce the comorbidities relevant that lose weight with treatment of obesity.

In another embodiment, with K _ATPChannel opener is mixed with pharmaceutically acceptable preparation with the activating agent that orlistat or other suppress the gastric lipase effects, with described preparation to overweight, obesity tendency or obese individuals administration are arranged to induce the comorbidities relevant that lose weight with treatment of obesity.

In another embodiment, with K _ATPChannel opener is mixed with pharmaceutically acceptable preparation with non-thiazide diuretic, with described preparation to overweight, obesity tendency or obese individuals administration are arranged to induce the comorbidities relevant that lose weight with treatment of obesity.

In another embodiment, with K _ATPChannel opener is mixed with pharmaceutically acceptable preparation with appetite suppressant, with described preparation to overweight, obesity tendency or obese individuals administration are arranged to induce the comorbidities relevant that lose weight with treatment of obesity.

In another embodiment, with K _ATPChannel opener is mixed with pharmaceutically acceptable preparation with cannabinoid receptor antagonists, with described preparation to overweight, obesity tendency or obese individuals administration are arranged to induce the comorbidities relevant that lose weight with treatment of obesity.

In another embodiment, with K _ATPChannel opener is mixed with pharmaceutically acceptable preparation with anti-gallbladder steroid class activating agent, with described preparation to overweight, obesity tendency or obese individuals administration are arranged to induce the comorbidities relevant that lose weight with treatment of obesity.

In another embodiment, with K _ATPChannel opener is mixed with pharmaceutically acceptable preparation with the antihypertensive active agent, with described preparation to overweight, obesity tendency or obese individuals administration are arranged to induce the comorbidities relevant that lose weight with treatment of obesity.

In another embodiment, with K _ATPChannel opener is mixed with pharmaceutically acceptable preparation with the insulin-sensitizing activity agent, with described preparation to overweight, obesity tendency or obese individuals administration are arranged to induce the comorbidities relevant that lose weight with treatment of obesity.

In another embodiment, with K _ATPChannel opener is mixed with pharmaceutically acceptable preparation with agent having ahtiphlogistic activity, with described preparation to overweight, obesity tendency or obese individuals administration are arranged to induce the comorbidities relevant that lose weight with treatment of obesity.

In another embodiment, with K _ATPChannel opener is mixed with pharmaceutically acceptable preparation with the antidepressant activity agent, with described preparation to overweight, obesity tendency or obese individuals administration are arranged to induce the comorbidities relevant that lose weight with treatment of obesity.

In another embodiment, with K _ATPChannel opener is mixed with pharmaceutically acceptable preparation with the antiepileptic activity agent, with described preparation to overweight, obesity tendency or obese individuals administration are arranged to induce the comorbidities relevant that lose weight with treatment of obesity.

In another embodiment, with K _ATPChannel opener is mixed with pharmaceutically acceptable preparation with the activating agent that reduces the atheromatous plaque incidence rate, with described preparation to overweight, obesity tendency or obese individuals administration are arranged to induce the comorbidities relevant that lose weight with treatment of obesity.

In another embodiment, with K _ATPChannel opener is mixed with pharmaceutically acceptable preparation with the activating agent of triglyceride reducing circulation composition, with described preparation to overweight, obesity tendency or obese individuals administration are arranged to induce the comorbidities relevant that lose weight with treatment of obesity.

Overweight, fat or have in the individuality of obesity tendency, by carrying out the K of effective dose _ATPThe administration of the solid oral dosage form of channel opener realizes the minimizing of circulation triglyceride.

K _ATPThe solid oral dosage form of channel opener can be used for to overweight or have obesity tendency have in requisition for individuality treat the K of effective dose _ATPThe administration of channel opener in case this is because take place to lose weight to a certain degree in the obese individuals, is preferably kept body weight, otherwise weight recovery.

A kind ofly in overweight or obese individuals, induce initial body fat loss just can pass through K greater than 25% method _ATPThe long term administration of the solid oral dosage form of channel opener realizes.

A kind ofly in overweight or obese individuals, induce initial body fat loss just can pass through K greater than 50% method _ATPThe long term administration of the solid oral dosage form of channel opener realizes.

A kind ofly in overweight or obese individuals, induce initial body fat loss just can pass through K greater than 75% method _ATPThe long term administration of the solid oral dosage form of channel opener realizes.

A kind of method of the preferential loss of interior fat of inducing in overweight or obese individuals can be passed through K _ATPThe long term administration of the solid oral dosage form of channel opener realizes.

A kind of method that the loss of inductor fat and circulation triglyceride reduce in overweight or obese individuals can be passed through K _ATPThe long term administration of the solid oral dosage form of channel opener realizes.

The present invention is described with reference to following non-restrictive example.

Embodiment

A. the preparation that contains the potassium ATP channel activator:

1. compressed tablet preparation

With the ethyl cellulose of the diazoxide or derivatives thereof of about 15-30% by weight and the hydroxypropyl emthylcellulose of about 55-80% by weight, about 3-10wt/vol% be less than 3% magnesium stearate (as lubricant) and Talcum (as fluidizer) by weight separately and mix.Described mixture is used to prepare people such as Reddy, the compressed tablet of describing among AAPS Pharm Sci Tech 4 (4): the 1-9 (2003).Can use the thin film that is used for microgranule as described below that described tablet is carried out coating.

The tablet that contains 100mg diazoxide or derivatives thereof also will contain have an appointment 400mg hydroxypropyl cellulose and 10mg ethyl cellulose.The tablet that contains 50mg diazoxide or derivatives thereof also will contain have an appointment 200mg hydroxypropyl cellulose and 50mg ethyl cellulose.The tablet that contains 25mg diazoxide or derivatives thereof also will contain have an appointment 100mg hydroxypropyl cellulose and 2.5mg ethyl cellulose.

2. the coated particle preparation of the encapsulate of diazoxide

According to well-known method (seeing that for example United States Patent (USP) the 6th, 022, No. 562), diazoxide or derivatives thereof encapsulate is become microgranule.The diameter that contains the diazoxide or derivatives thereof combines individually or with one or more adjuvants that are fit at 100 to 500 microns microgranule, granulator auxiliary form down and then with its screening for having the independent microgranule of suitable granularity.Use commercially available instrument to use thin film that microgranule is carried out coating (as: Uniglatt Spray CoatingMachine (Uniglatt spraying robot)) by spray drying.This thin film contains ethyl cellulose, cellulose acetate, polyvinylpyrrolidone and/or polyacrylamide.The coating solution that is used for thin film can contain plasticizer, and it can be Oleum Ricini, ethyl phthalate, triethyl citrate and salicylic acid.This coating solution also can comprise lubricant, and it can be magnesium stearate, enuatrol or polyoxyethylene sorbitan monolaurate.This coating solution also can comprise adjuvant, as Talcum, silica sol or the two the mixture with 1.5 to 3% interpolations by weight, to prevent film coating granule caking.

3. the preparation that is used for the tablet form of the diazoxide of controlled release or derivant

Before mixing, make active component and hydroxypropyl emthylcellulose (Dow Methocel K4M P) by ASTM 80 mesh screens.Form mixture by 1 part of diazoxide or derivatives thereof to 4 part hydroxypropyl emthylcellulose.After fully mixing, slowly adding is as the alcoholic solution of the ethyl cellulose of enough volumes of granulating agent.In final preparation, about 1/10 part of the amount of every ethyl cellulose.The ball piece that the described granulating agent of mixing is obtained sieves by 22/44 sieve mesh.The pellet that obtains is 40 ℃ of dryings 12 hours, and then room temperature preservation in exsiccator 12 hours.In case dry, the pellet that remains on 44 sieve meshes is mixed with 15% concentrate (by the pellet of 44 sieve meshes).Talcum and magnesium stearate are added by the weight that accounts for 2% separately as fluidizer and lubricant.Add coloring agent again.Use singles hole tablet press machine to suppress described tablet.

4. the preparation of compressed tablet form of the diazoxide or derivatives thereof of controlled release is provided

With the diazoxide or derivatives thereof with the weight that accounts for 20-40% and weight account for 30% hydroxypropyl emthylcellulose (Dow Methocel KlOOLV P) and the weight trickle lactose that accounts for 20-40% mix.Add water this mixture is made granule.The wet described granulate mixture and of milling then 110 ℃ of dryings 12 hours.The dried described dried mixture of milling.After milling, add weight and account for 25% ethyl cellulose resin (Dow Ethocel 10FP or Ethocel 100FP), the interpolation weight that continues accounts for 0.5% magnesium stearate.Add coloring agent again.Use singles hole tablet press machine suppress described tablet (people such as Dasbach, in November, 2002 10-14 day AAPS can exhibition paste).

5. the preparation of compression coated tablets form of the diazoxide or derivatives thereof of controlled release is provided

By 100mg diazoxide or derivatives thereof is mixed with 10mg ethyl cellulose (Dow Ethocel10FP), or pass through 75mg diazoxide or derivatives thereof is mixed with 25mg lactose and 10mg ethyl cellulose (Dow Ethocel 10FP), or by 50mg diazoxide or derivatives thereof is mixed and prepares core tablet with 50mg lactose and 10mg ethyl cellulose (Dow Ethocel 10FP).Use the concave surface mould to pressurize automatically and form described core tablet.The pressed coated that use is made up of the oxirane (Union Carbide OLYOX WSR Coagulant) of 400mg suppresses it to 3000psi (people such as Dasbach, poster is in October, 2003 26-30 day AAPS meeting).

6. use the controlled release preparation of the diazoxide or derivatives thereof of osmotic pressure controlled release system.

The diazoxide or derivatives thereof is prepared as osmotic pressure adjustment release system.Usually, with two kinds of compositions, and order about that active medicine discharges expandable hydrogel and the diazoxide or derivatives thereof fits in semipermeable double shells.After assembling, boring is to impel activating agent to discharge after the hydration of hydrogel in shell.

Be suitable for, design and be shaped and produce as follows as the dosage form of osmotic drug delivery system: at first, to the homogeneous mixture of polyethylene glycol oxide, diazoxide or derivatives thereof and hydroxypropyl emthylcellulose, provide the compositions of diazoxide or derivatives thereof by mixed together.Then, what slowly add dry weight heavily is the degeneration dehydrated alcohol of a volume of 70%, follows to continue to mix above 5 minutes.With described prepared fresh wet granular by 20 sieve meshes screenings, drying at room temperature 16 hours, and once more by the screening of 20 sieve meshes.At last, sized granules and weight being accounted for 0.5% magnesium stearate mixed 5 minutes.

Described hydrogel composition is by being prepared as follows: at first, weight is accounted for 69% polyethylene glycol oxide, weight account for 25% sodium chloride and weight and account for 1% ferrum oxide respectively by the screening of 40 sieve meshes.Then, the composition of all screenings and weight being accounted for 5% hydroxypropyl emthylcellulose mixes and generates homogeneous mixture.Then, in described mixture, the weight that slowly adds dry weight equals the degeneration dehydrated alcohol of a volume of 50%, follows to continue to mix 5 minutes.Described prepared fresh wet granular by 20 sieve meshes screenings, is allowed drying at room temperature 16 hours, and once more by the screening of 20 sieve meshes.At last, sized granules and weight are accounted for 0.5% magnesium stearate and mix 5 minutes (seeing people such as Kuczynski, United States Patent (USP) the 6th, 361, No. 795).

Described diazoxide or derivatives thereof compositions and described hydrogel composition are pressed into bilayer tablet.At first add diazoxide or derivatives thereof compositions and tamping, then add hydrogel composition and a kind of contact layer of compacting this layer one-tenth under 2 tons head pressure.

With the described bilayer of semi-transparent wall (that is: thin film) coating.This compositions that forms wall comprises 93% cellulose acetate and 7% Polyethylene Glycol with 39.8% acetyl content.The composition spray of described formation wall is gone up and on every side to double-deck.

At last, get out exit passageway to connect the outside of diazoxide or derivatives thereof medicine layer and formulation system by semi-transparent wall.Remove residual solvent by drying under 50 ℃ and 50% humidity.Then, at 50 ℃ of these osmosis systems of drying to remove residual moisture (seeing people such as Kuczynski, United States Patent (USP) the 6th, 361, No. 795).

7. the preparation of the salt of diazoxide

By at 500ml Et ₂The hydrogen chlorate that one mole of diazoxide of dissolving (230.7g) prepares diazoxide among the O.In this solution, feed dry HCl and increase 36g until container weight.During adding HCl, the described HCl salt of diazoxide is as powder precipitation.Leach this salt and use dry Et ₂The O washing.

B. obesity test in the body

1. obesity animal model

Can be as (Endocrinology 141:3630-3637 (2000)) of people such as Surwit description, the usefulness of the diazoxide or derivatives thereof preparation that test prepares as described herein in the animal model of obesity.In brief, 4 all 5 big in every cages of B6 male mice are supported in temperature control (22 ℃) chamber, follow 12 hours lights, 12 hours dark cycle.Higher fatty acid (HF) and low fat (LF) experimental diet contain 58% and 11% the calorie from fat respectively.In initial 4 weeks of research, feed the HF diet for one group of mice; Feed the LF diet for remaining 15 mices.Make the mice of designated LF diet in whole research, keep the reference group of this diet as thin control mice.In the 4th week, the mice that whole HF are raised is further divided into 2 groups of mices.First group keeps the HF diet as fat matched group in whole research.Feed the HF diet for remaining 3 groups of mices, and carry out the single dose administration of the controlled release preparation of diazoxide or derivatives thereof with the activating agent of the about 150mg of every kg every day by the oral cavity gavage.Weigh to animal weekly, and every cage measures food consumption weekly for twice and change in the 4th week until this diet, determine body weight and food intake every day.On the basis of every cage, calculate charging efficient (consuming the body weight gram number that every Cal obtains).The 24th day afterwards (preceding 4 days of metatrophia), 32 days (changing back 4 days) and collection biweekly are used for the sample that insulin, glucose and leptin are analyzed.In all experimental grouies, removed food in preceding 8 hours at the collection sample.Analyze glucose by glucose oxidase method.Measure insulin and leptin concentration with double antibody RIA.Insulin assay is based on the rat standard, and leptin is measured the mice standard of using.At the terminal point of this research, collect after the meal plasma sample and analyze triglyceride and nonesterified fatty acid concentration.After 4 weeks, put to death subgroup in Drug therapy from 10 animals of each group.Remove, prune and the white adipose tissue (EWAT) of the epididymis of weighing, retroperitoneal (RP) fat, IBAT's (IBAT) fat pad and gastrocnemius.Percent from the weight estimated body fat of the fat pad of epididymis.Give glucose from the subgroup lumbar injection 0.5g/kg of five animals of each group.In injection back 30 minutes, collect plasma sample and analyze glucose content by glucose oxidase method.

2. the treatment of human obesity disease

Can in the mankind of obesity, test the usefulness of the diazoxide or derivatives thereof preparation of preparation as described herein.The carrying out that this research such as Alemzadeh describe people such as (, J Clin EndocrMetab 83:1911-1915 (1998)) Alemzadeh.The curee comprise have Body Mass Index (BMI) more than or equal to 30kg/m ²Moderate to MO adult.Carry out complete physical examination when each curee assesses in the early stage, on the electronic scale of standard, measure body weight and measure the health composition by DEXA.

Before the research beginning, all curees accept low caloric diet, as the introductory phase in 1 week.This is intended to get rid of the individuality that can not comply with and can not guarantee to stablize body weight before treatment.Reach 50 routine patients with each drug dose test.With every day dosage be made as 100,200 and 300mg/ days.With every day dosage be divided into 2 doses and be used for administration.Described dosage is carried out administration at each administration time as capsule or the tablet of one, two or three part of 50mg.Each patient's administration every day is continued to reach 12 months.Observe the patient weekly, weigh and any side effect of inquiry or concurrent disease.

Obtain 24 hours diet record of each patient.The computer software programs of use standard are analyzed this diet record.Make all patients accept low caloric diet and encourage it to participate in regular exercise.

Before this research beginning and after finishing, carrying out following laboratory detects: blood pressure fasting glucose, insulin, cholesterol, triglyceride, free fatty (FFA) and glycohemoglobin, and the measurement of the occurrence rate of blood plasma derived fatty acid and oxidation.In addition, obtain conventional chemical feature and fasting glucose weekly and have the curee of the unusual sign of glucose intolerance and/or electrolyte to determine those.By the glucose in the glucose oxidase method analysed for plasma.

Use double antibody kit measurement insulin concentration by RIA.Measure cholesterol and triglyceride concentration by enzyme method.Fixed by the true plasma F FA of enzymic colorimetric.Use the minimal model of improvement to determine SI by intravenous glucose tolerance test (IVGTT).After one night of fasting, intravenous injection glucose infusion liquid (300mg/kg), then (after 20 minutes), intravenous injection infusion of insulin liquid.From lateral vein was obtained being used for the blood of glucose and insulin assay at-30 ,-15,0,2,3,4,5,6,8,10,19,22,25,30,40,50,70,100,140 and 180 minutes.Before finishing this research and afterwards, use the minimal model computer program of BergmanShi improvement to calculate SI and glucose effect (SG).The acute insulin responses of determining glucose at initial 19 minutes of IVGTT, and from 8-19 minute definite glucose disappearance rate (Kg) of IVGTT.Before this research is finished and in, form by the bio-electrical impedance measuring health.Measured REE (REE) by indirect calorimetry at 12 hours after the overnight fasted, the curee lies on the back and lies 30 minutes.In corresponding 24 hours, collect urine, be used for before this research and measure total nitrogen afterwards and definite substrate purposes.

3. the drug treatment mankind's obesity in the time of by diazoxide and phentermine

Moderate to morbid state and Body Mass Index (BMI) more than or equal to 30kg/m ²Obese people's apoplexy due to endogenous wind, estimate the solid oral dosage form of diazoxide or derivatives thereof and the long-term co-administered of phentermine.Carry out complete physical examination when each curee assesses in the early stage, on the electronic scale of standard, measure body weight and measure the health composition by DEXA.

Before the research beginning, all curees accept low caloric diet, as the introductory phase in 1 week.This is intended to get rid of the individuality that can not comply with and can not guarantee to stablize body weight before treatment.Test reaches 100 routine patients.Dosage every day of diazoxide was made as 200mg/ days.With every day dosage be divided into 2 doses and be used for administration.Described dosage is carried out administration at each administration time as the capsule of 100mg or the tablet of 100mg.Each patient's administration every day is continued to reach 12 months.Phentermine is carried out administration as independent dosage every day of 15mg.Per two weeks observe the patient, weigh and any side effect of inquiry or concurrent disease.

Make all patients continue to accept low caloric diet and encourage it to participate in regular exercise.Before this research beginning and after finishing, obtain the laboratory test of describing among the as above embodiment.

4. prevent diabetes in the prediabetes mankind

Present embodiment has been described and used the generation of diazoxide with prevent diabetes in the prediabetes individuality.Individuality is included in this research the whole individualities by a kind of development diabetes risk with raising that records in two kinds of methods.In the fasting glucose analysis, they have 100 and 125mg/dl between the plasma glucose value, pointed out impaired fasting glucose; Or in oral glucose tolerance test, they after the glucose load 2 hours, have 140 and 199mg/dl between the plasma glucose value, point out them to suffer from glucose tolerance and reduce.Accept the 200mg diazoxide subject individual every day: every day twice 100mg capsule or tablet, or two parts of 100mg capsules or tablet once a day.A Cebo-Caps of individual every day of twice acceptance of placebo treatment or tablet are perhaps accepted two parts of Cebo-Capses or tablet once a day.

Continue treatment, measure OGTT annually or measured the fasting glucose in every month.

5. the coupling preparation that is used for the treatment of the lasting release of the hydrochloric acid diazoxide of diabetics and metformin hydrochloride

Produce the coupling preparation of the lasting release of hydrochloric acid diazoxide and metformin hydrochloride by forming compressed tablet substrate, it comprises the hydrochloric acid diazoxide of 750mg and the metformin hydrochloride of 100mg.(about 25% (w/w) and magnesium stearate (＜2% (w/w)) are mixed with sodium carboxymethyl cellulose (about 5% (w/w)), hypromellose with these active component.Further use the compositions of ethyl cellulose (80% (w/w)) and methylcellulose (20% (w/w)) described compressed tablet to be carried out coating with control hydration rate and drug release rate as thin film.

The type 2 diabetes mellitus patient by the administration of two or per 12 hours a slices once a day, is treated with peroral dosage form.Continuation uses described Drug therapy until reaching a kind of in the terminal points of two kinds of treatments to the patient, or as long as the patient obtains medical treatment from administration benefit.Two kinds of treatment terminal points as the basis that determines stopped treatment comprise that the patient reaches the Body Mass Index (BMI (kg/m between 18 and 25 ²)) or when not treating, rebuild NGT.Regularly to the following project of patient-monitoring: (a) use oral glucose tolerance test monitoring glucose tolerance; (b) use standard blood sugar detection monitoring glycemic control; (c) weight increase or alleviate; (d) progress of diabetic complication; And (e) with use these active component relevant untoward reaction.

6. in the patient of olanzapine treatment, prevent or the treatment weight increase

Set about schizoid pharmacotherapy for the patient who meets schizophrenia DSM III-R standard.Olanzapine (Zyprexa (Zyprexa), gift comes (the Lilly)) administration of carrying out 10mg once a day for the patient.The 250mg equivalent of valproic acid such as divalproex sodium (Depakote, Abbott Labs) comprise to(for) schizophrenic's complementary therapy.In the patient with this associating psychosis treatment, weight increase, dyslipidemia and glucose tolerance reduction and metabolism syndrome are common side reactions.K by the treatment effective dose _ATPThe co-administered of channel opener, treatment weight increase, dyslipidemia, glucose tolerance reduction or metabolism syndrome.With 200mg/ days diazoxide,, the patient is carried out drug treatment as tablet formulation once a day.Continue the administration of diazoxide, until elimination weight increase, dyslipidemia, glucose tolerance reduction or metabolism syndrome, or until the treatment of interruption with olanzapine.By measuring the circulation composition of T-CHOL, HDL cholesterol and LDL cholesterol, triglyceride and non-esterified fatty acid, detect dyslipidemia.By using oral or test glucose tolerance by intravenous infusion detects glucose tolerance and reduces.Detecting by measuring its crucial risk factor of metabolism syndrome comprises that central obesity, dyslipidemia, glucose tolerance reduce, and the circulation composition of crucial proinflammatory cytokine.

Whole patents of quoting in this manual and other lists of references have been pointed out one of ordinary skill in the art's of the present invention level, and all incorporate into by reference, comprise any form and accompanying drawing, incorporate into as each list of references is complete separately by reference.

The understandable the present invention of being of those skilled in the art is suitable for obtaining described result and advantage well, and those the present invention inherent result of institute and advantages.Method of the present invention, variation and compositions are the exemplary and non-restrictions that is intended to as scope as present representational embodiment preferred.Those skilled in the art will expect variation and other purposes wherein, and it is included in the purport of the present invention, is limited by the scope of described claim.

Except as otherwise noted, non-being intended to of definition provided by the invention limited from the implication of those skilled in the art's common sense.

Do not having in the present invention that this illustrative is described to be put into practice aptly under the situation of any key element not disclosed herein especially or a plurality of key element, restriction or a plurality of restrictions.Therefore, for example term " comprises ", " comprising ", " containing " etc. should be understood with being expanded but not have restricted.In addition, be used for term herein and express being used as description and nonrestrictive term, and non-ly be intended to get rid of the term of any shown and described equivalent features or its part and the use of expression, but think that various modifications may be in desired interest field of the present invention.Therefore, should understand, although disclose the present invention clearly by embodiment preferred and optional feature, those skilled in the art can modify and change embodiment of the present invention disclosed herein, and think that such modifications and variations within the scope of the invention.

Widely and describing the present invention generically at this.Each the narrow class and the subgenus classification that fall into this general disclosure have also formed a part of the present invention.This comprises genus class description of the present invention, removes any theme with the negatory restriction of conditioned disjunction from such, no matter whether isolated material is clearly quoted at this.

Other embodiments are in following claim.In addition, feature of the present invention or aspect are described by the mode with Ma Kushi grouping, those skilled in the art will recognize that therefore the present invention also is described in the mode of any discrete member of Ma Kushi grouping or member's subgroup.

Claims

1. the K of formula II or formula III _ATPThe controlled-release pharmaceutical formulation of channel opener.

2. preparation according to claim 1, it is formulated into and is used for oral administration.

3. preparation according to claim 1 and 2, it is used for single-dose, contains 10 to 100mg described K _ATPChannel opener.

4. preparation according to claim 1 and 2, it is used for single-dose, contains 100 to 200mg described K _ATPChannel opener.

5. preparation according to claim 1 and 2, it is used for single-dose, contains 200 to 300mg described K _ATPChannel opener.

6. preparation according to claim 1 and 2, it is used for single-dose, contains 300 to 500mg described K _ATPChannel opener.

7. preparation according to claim 1 and 2, it is used for single-dose, contains 500 to 2000mg described K _ATPChannel opener.

8. according to each described preparation among the claim 1-7, wherein said K _ATPChannel opener is a diazoxide.

9. according to each described preparation among the claim 1-7, wherein said K _ATPChannel opener is the salt of diazoxide, but non-sodium salt.

10. according to each described preparation among the claim 1-9, it is obtained by at least a following method: (a) granularity refinement comprises pulverizing, spray drying or other micronization technology; (b) pharmaceutical salts of the chemical compound of described formula II of use or formula III; (c) make spent ion exchange resin; (d) use inclusion complex; (e) chemical compound with described formula II or formula III carries out compacting with comprising the solubilizing agent of low viscosity hypromellose, low viscosity methylcellulose or adjuvant or its compositions of similar functions; (f) before formulated, the chemical compound and the salt of associate described formula II or formula III; (g) solid dispersion of the chemical compound of described formula II of use or formula III; (h) use self-emulsifying drug delivery systems; (i) in described preparation, add one or more surfactants; Or (j) use nanoparticle.

11. preparation according to claim 2, it comprises at least a described K that suppresses basically from described preparation _ATPThe composition that channel opener just discharges after the stomach transhipment.

12. preparation according to claim 11, wherein said composition is selected from: (a) pH sensitive polymer or copolymer, as the pressed coated on the tablet; (b) pH sensitive polymer or copolymer are as the thin film on the tablet; (c) pH sensitive polymer or copolymer are used for encapsulated system as thin film; (d) pH sensitive polymer or copolymer are used for the encapsulate microgranule; (e) non-soluble polymer or copolymer are as the pressed coated on the tablet; (f) non-soluble polymer or copolymer are as the thin film on the tablet; (g) non-soluble polymer is used for encapsulated system as thin film; (h) non-soluble polymer is used for microgranule; (i) in osmotic pump system, mix described preparation; Reach the system that (j) uses by ion exchange resin control; And (k) these methods of coupling, wherein said pH sensitive polymer or copolymer degradation resistant under acid condition.

13. according to each described preparation among the claim 1-7, it also comprises and impels described K _ATPChannel opener continued the composition of release during 2-4 after the administration hour.

14. according to each described preparation among the claim 1-7, it also comprises and impels described K _ATPChannel opener continued the composition of release during 4-8 after the administration hour.

15. according to each described preparation among the claim 1-7, it also comprises and impels described K _ATPChannel opener continued the composition of release during 8-24 after the administration hour.

16. according to the described preparation of claim 13-15, wherein said composition is: (a) pH sensitivity polymeric coatings; (b) hydrogel; (c) film coating, it controls the diffusion rate of described medicine from coated substrate; (d) can lose the substrate of separating, its control drug release rate; (e) described medicine piller, granule or the microgranule of polymer coating, its can be further by encapsulate or be pressed into tablet; (f) contain the osmotic pump system of described medicine; (g) the coated tablet form of the compacting of described medicine; Or (h) these compositions.

17. according to each described preparation among the claim 1-7, it also comprises the other drug activating agent.

18. preparation according to claim 17, wherein said other drug activating agent is to be used for the treatment of the medicament that is selected from following illness: obesity, prediabetes, diabetes, hypertension, depression, cholesterol increases, fluid retention, or other comorbiditieses relevant with obesity, ischemic and reperfusion injury, or epilepsy, schizophrenia, mania or other mental diseases.

19. the salt of the non-sodium salt of a diazoxide.

20., wherein cause at least a following result: (a) suppress the fasting insulin secretion to individual administration fat, overweight or that have obesity to be inclined to according to each described preparation among the claim 1-7; (b) suppress glucose zest insulin secretion; (c) increase energy expenditure; (d) increase fatty beta oxidation; Or (e) appetite-suppressing is crossed and was contained about 24 hours.

21., wherein cause at least a following result: (a) suppress the fasting insulin secretion to individual administration fat, overweight or that have obesity to be inclined to according to each described preparation among the claim 1-7; (b) suppress glucose zest insulin secretion; (c) increase energy expenditure; (d) increase fatty beta oxidation; Or (e) appetite-suppressing is crossed and was contained about 18 hours.

22. K according to formula II or formula III _ATPThe pharmaceutical preparation of channel opener, its to fat, overweight or the individual administration of obesity tendency is arranged after cause at least a following result: (a) suppress the fasting insulin secretion; (b) suppress glucose zest insulin secretion; (c) increase energy expenditure; (d) increase fatty beta oxidation; Or (e) appetite-suppressing is crossed and was contained about 24 hours.

23. K according to formula II or formula III _ATPThe pharmaceutical preparation of channel opener, its to fat, overweight or the individual administration of obesity tendency is arranged after cause at least a following result: (a) suppress the fasting insulin secretion; (b) suppress glucose zest insulin secretion; (c) increase energy expenditure; (d) increase fatty beta oxidation; Or (e) appetite-suppressing is crossed and was contained about 18 hours.

24. induce the method that loses weight for one kind in fat or overweight curee, described method comprises per administration that was no more than twice the described preparation of claim 2 in 24 hours.

25. induce the method that loses weight for one kind in fat or overweight curee, described method comprises per administration of carrying out a described preparation of claim 2 in 24 hours.

26. one kind fat, overweight or have and keep the method that loses weight among the curee of obesity tendency, described method comprises per administration that was no more than twice the described preparation of claim 2 in 24 hours.

27. one kind fat, overweight or have and keep the method that loses weight among the curee of obesity tendency, described method comprises per administration of carrying out a described preparation of claim 2 in 24 hours.

28. induce the method that loses weight for one kind in fat or overweight curee, described method comprises the K that carries out formula II or formula III _ATPThe described pharmaceutical preparation of channel opener every day dosage administration, wherein said K _ATPDescribed every day of the dosage of channel opener is 50 to 180mg.

29. one kind fat, overweight or have the method for the comorbidities that treatment of obesity is relevant in the individuality of obesity tendency, described method to comprise per 24 hours to be no more than twice and treat the formula II of effective dose or the K of formula III _ATPThe administration of the solid oral dosage form of channel opener.

30. method according to claim 29, wherein said administration be per 24 hours once.

31. a method that realizes losing weight in obese individuals, described method comprise per 24 hours to be no more than twice and to treat the formula II of effective dose or the K of formula III _ATPThe administration of the solid oral dosage form of channel opener.

32. method according to claim 31, wherein said administration be per 24 hours once.

33. one kind overweight, fat or have the method that increases energy expenditure in the individuality of obesity tendency, described method to comprise per 24 hours to be no more than twice and carry out the formula II of effective dose or the K of formula III _ATPThe administration of the solid oral dosage form of channel opener.

34. method according to claim 33, wherein said administration be per 24 hours once.

35. one kind overweight, fat or have the method that increases fatty beta oxidation in the individuality of obesity tendency, described method to comprise per 24 hours to be no more than twice and carry out the formula II of effective dose or the K of formula III _ATPThe administration of the solid oral dosage form of channel opener.

36. method according to claim 35, wherein said administration be per 24 hours once.

37. a method that stops the prediabetes individuality to be converted into diabetes, described method comprise per 24 hours to be no more than twice and to carry out the formula II of effective dose or the K of formula III _ATPThe administration of channel opener.

38. according to the described method of claim 37, wherein said administration be per 24 hours once.

39. a method of recovering the NGT of diabetic individual, described method comprise the formula II that carries out effective dose or the K of formula III _ATPThe administration of channel opener.

40. a method of recovering the NGT of prediabetes individuality, described method comprise the formula II that carries out effective dose or the K of formula III _ATPThe administration of channel opener.

41. a method that postpones or stop the diabetes progress, described method comprise per 24 hours to be no more than twice and to carry out the formula II of effective dose or the K of formula III _ATPThe administration of channel opener.

42. according to the described method of claim 41, wherein said administration be per 24 hours once.

43. one kind by carrying out effective dose formula II or the K of the solid oral dosage form of formula III _ATPThe co-administered of channel opener and a kind of medicine, the comorbidities that treatment of obesity or obesity are relevant or other and K _ATPThe method of passage diseases associated or illness, described medicine is selected from the medicine of sibutramine, orlistat, Rimonabant, non-thiazide diuretic, cholesterol reducing, the medicine of rising HDL cholesterol, the medicine that reduces the LDL cholesterol, the medicine that brings high blood pressure down, antidepressant medicine, the medicine that improves insulin sensitivity, the medicine that improves glucose utilization or picked-up, antiepileptic, anti-inflammatory drug, appetite inhibiting medicine, reduces the medicine of circulation triglyceride, and is used for inducing the medicine that loses weight in overweight or obese individuals.

44. one kind in the treatment of disease or illness, reduce because of carrying out K _ATPThe method of the adverse reaction rate that the administration of channel opener causes, described method obtains via following any-mode: (a) in the method that prevention reduces with the weight increase among the curee of antipsychotic drug treatment, dyslipidemia or glucose tolerance, use a kind of pharmaceutical preparation that postpones to discharge, it relates to and carries out K _ATPThe administration of the pharmaceutical preparation of channel opener is finished until the stomach transhipment; (b) use a kind of lasting release to surpass 2 hours pharmaceutical preparation; (c) predose is in inferior treatment level and increases every day dosage until reaching described therapeutic dose in progressively mode, and wherein said number of steps is 2 to 10; (d) use minimal effective dose to obtain required treatment effect; And the described administration of (e) optimizing dosage with relative each meal in 24 hours regularly.

45. one kind in curee with antipsychotic drug treatment, the method that prevention weight increase, dyslipidemia or glucose tolerance reduce, described method comprises carries out K _ATPThe administration of the pharmaceutical preparation of channel opener.

46. one kind in curee with antipsychotic drug treatment, the method that treatment weight increase, dyslipidemia or glucose tolerance reduce, described method comprises carries out K _ATPThe administration of the pharmaceutical preparation of channel opener.

47. a treatment is reduced to the method for the disease of feature with obesity, bulimia nerovsa, dyslipidemia or energy expenditure, described disease comprises: (a) the sharp syndrome of pula moral-become; (b) Froehlich syndrome; (c) Cohen syndrome; (d) Sa Mite syndrome; (e) alstrom syndrome; (f) the gloomy syndrome of Bauer wise man; (g) Ahmedabad-other Dare syndrome; Or (h) I, II, III and IV type hyperlipoproteinemia, described method comprises carries out K _ATPThe administration of the pharmaceutical preparation of channel opener.

48. the K of formula II or formula III _ATPThe pharmaceutical preparation of channel opener, it also comprises the K that removes described formula II or formula III _ATPPharmaceutically active agents outside the channel opener.

49. according to the described preparation of claim 48, wherein said other drug activating agent is the medicament useful to the treatment of illness, described illness is selected from: obesity, prediabetes, diabetes, hypertension, depression, cholesterol raises, fluid retention, or other relevant comorbiditieses of obesity, ischemic and reperfusion injury, epilepsy, schizophrenia, mania or other mental diseases.