CN104780915A

CN104780915A - Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk

Info

Publication number: CN104780915A
Application number: CN201380046376.XA
Authority: CN
Inventors: A.D.贝伦; M.S.法恩曼; N.R.A.比利
Original assignee: Elcelyx Therapeutics Inc
Current assignee: Elcelyx Therapeutics Inc
Priority date: 2012-07-11
Filing date: 2013-07-11
Publication date: 2015-07-15
Also published as: JP2018087214A; WO2014011926A1; AR091739A1; JP2015522080A; IL236647A0; AU2013290100A1; HK1210825A1; CA2878625A1; EP2872127A1

Abstract

Compositions and methods comprising at least one biguanide compound and at least one statin combined with at least one additional active agent in fixed dose combinations are provided for reducing cardiometabolic risk, and for the treatment of cardiovascular disease, wherein the biguanide compound is formulated for delayed release.

Description

Comprise statin, biguanide and the compositions for other medicament of reducing cardiac metabolism risk

Invention field

The present invention relates generally to and in patient in need, reduces cardiac metabolism risk in comprehensive and consistent mode by the combination treatment being applied in unit dosage forms the fixed dosage comprising the other activating agent of at least one biguanide, at least one statin and at least one.

Background of invention

Cardiovascular disease (CVD) comprises coronary artery disease, cerebrovascular disease and peripheral arterial disease substantially and is the main cause of M & M of the Western countries.(.Lipoprotein Management in Patients with Cardiometabolic Risk, the Diabetes Care 200831:811-822 such as Brunzell).Although have significant improvement in nearest decades in treatment option, the onset symptoms of coronary artery disease shows as the sudden death of patient up to 1/3rd especially.Ditto (Id.).Therefore, still need better and more effective intervention options come prevention of arterial atherosis and/or once lysis just reduce its development speed.

In order to more effectively solve the public health problem that this increases rapidly, ADA and ACC's foundation have been developed and have been proposed to treat the cardiac metabolism risk (CMR) being called the CVD of high Longevity Risk.(.Preventing Cardiovascular Diseaseand Diabetes, the Diabetes Care 200629:1697-1699 such as Eckel).It should be noted that the risk factor frequent of cardiovascular disease and type 2 diabetes mellitus, comprise obesity, insulin resistant, hyperglycemia, dyslipoproteinemia and hypertension.When patient have in these risk factor one or more and be on health inertia or smoke time, their cardiac metabolism risk increases even further.

Comprise high triglyceride, the lipoprotein abnormalities of LDL of low HDL cholesterol and increase is common discovery in the patient suffering from CMR.Like this, diabetics can be reduced for low LDL-C administering therapeutic agent such as Statins and there is the risk of CVD event of ND of other CVD risk factor.But, even when enough cholesterol reduce, with a lot of patients of Statins treatment, still there is significant CVD risk.(see Brunell, the same).Therefore, more effective therapy is still clearly needed to solve this changeable and range of conditions of complexity better.

Evaluate the impact that some blood sugar lowering is formed the atheromatous plaque in diabetics as pioglitazone and glimepiride.Pioglitazone and glimepiride are compared in periscope (PERISCOPE) research in diabetes; Measure atheromatous plaque volume and measure along with the time.Nissen etc., Comparison of pioglitazone vs glimepiride onprogression of coronary atherosclerosis in patients with type 2 diabetes " .JAMA 2,008 299 (13): 1561-73.The plaque volume that glimepiride therapy has the highly significant of 0.73% along with the time develops.In the comparison, pioglitazone has-0.16% plaque volume degeneration.But, it should be noted that up to the present, do not have gourmet's luck antidiabetic medicine to show the risk reducing cardiovascular complication.Ditto.

Metformin is common prescription drugs for carrying out glycemic control in the patient suffering from type ii diabetes and also shows to improve serum lipids, thus reduces triglyceride, free fatty and LDL-cholesterol and suitably increase HDL-cholesterol.(Bailey & TurnerMetformin.N Engl J Med.1996 Feb 29; 334 (9) but, unfortunately, metformin also produces significant gastrointestinal complication, and this limits its purposes to diabetics itself, and is taboo in addition in the patient suffering from the hypoxic conditions caused by such as respiratory failure or heart failure.In addition, conventional administration strategy needs to increase dosage gradually from 500mg bid to 1000mg bid, every day, maximal dose was 2000mg, wherein be increased to nearly 3000mg/ days further, to realize suitable glycemic control, thus itself and other active groups are combined in the ability in the combination treatment of fixed dosage by strict restriction fonnulator.Up to the present, proved to be difficult to effectively metformin and multiple actives are combined in identical single-dose preparations.

So it is clear that still need usually to reduce cardiac metabolism risk and be used in particular for treating and/or preventing the more comprehensive method of cardiovascular disease.

Summary of the invention

The invention provides cardiac metabolism risk for reducing patient in need and be used for the treatment of and/or the more comprehensive and effective combination treatment of activating agent that angiocardiopathy preventing, employing at least one biguanide, at least one statin and at least one are other.As herein prove, biguanide such as metformin can use delayed release (DR) preparation to use for significantly reducing gastrointestinal complication, thus with unit pharmaceutical composition, the combination of biguanide, statin and other activating agent safety also can be administered to PATIENT POPULATION widely effectively.In addition, and significantly, even can to obtain the biguanide administration carried out once a day with the dosage of described herein and required reduction and all treat effect.

Contain and comprise such as metformin, phenformin, buformin and similar compound as herein described for the applicable biguanide in the present invention.Such as lovastatin, atorvastatin, fluvastatin, rosuvastatin, simvastatin, pravastatin, Pitavastatin etc. are comprised for applicable statin of the present invention or HMG-CoA reductase inhibitor.The other activating agent contained for theme composition and method comprises such as antihypertensive and anti-platelet agents and diuretic, bile acid chelating agent, incretin reinforcing agent and analogies, oral antidiabetic, anti-obesity medicine and antiatherosclerotic.

Such as Beta receptor blockers (atenolol is comprised for applicable antihypertensive of the present invention, betaxolol, metoprolol, nadolol, nebivolol, oxprenolol, pindolol, Propranolol, timolol etc.), α-1 blocker (alfuzosin, arotinolol, doxazosin, indoramine, thymoxamine, phenoxybenzamine, phentolamine, prazosin, silodosin, tamsulosin, terazosin, tolazoline, trimazosin), α-2 agonist (apraclonidine, brimonidine, clonidine, guanabenz, guanfacine, lofexidine, first clonidine, α/β-blocker (the bucindolol of mixing, carvedilol, labetalol etc.), calcium channel blocker is as dihydropyridine (amlodipine, felodipine, isradipine, lercanidipine, nicardipine, nifedipine, nimodipine, nitrendipine etc.) and non-dihydropyridine (diltiazem, verapamil etc.), renin inhibitor (aliskiren), ACE inhibitor (captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, trandolapril, benazepril etc.), angiotensin ii receptor antagonist (Candesartan, Eprosartan, irbesartan, losartan, Olmesartan, telmisartan, valsartan etc.) etc.

Such as cyclooxygenase-2 inhibitors (aspirin (aspirin), aloxiprin, carbasalate calcium, indobufen, triflusal etc.), adp receptor inhibitor (clopidogrel, ticlopidine, ticagrelor etc.), phosphodiesterase inhibitor (cilostazol etc.), gland reuptake inhibitor (dipyridamole etc.), thromboxane synthetase or acceptor inhibitor (G-137, Leimaquban, terbogrel etc.), anagrelide, prasugrel, cloricromen etc. are comprised for applicable antiplatelet drug of the present invention.

Such as medullary loop diuretic (bumetanide, etacrynic acid, furosemide, torasemide etc.), thiazide diuretic (epitizide, hydrochlorothiazide, chlorothiazide, bendroflumethiazide etc.), thiazine sample diuretic (indapamide, chlortalidone, metolazone etc.), Potassium-sparing diuretic (amiloride, triamterene, spironolactone etc.) etc. are comprised for applicable diuretic of the present invention.

Such as colestyramine, colesevelam, colestipol etc. are comprised for applicable bile acid chelating agent of the present invention.

Comprise such as peptide class and non-peptide class GLP-1 analogies for applicable incretin analogies of the present invention and reinforcing agent (to comprise, such as, the allosteric activation agent of GLP-1 receptor), peptide and non-peptide PYY analogies, peptide and non-peptide class Leptin antagonist etc.

Applicable oral antidiabetic for using with combination with metformin in theme composition and method comprises such as sulfonylurea (glibenclamide, glimepiride, glipizide, gliclazide, glyclopyramide, gliquidone, tolbutamide, acetohexamide, tolazamide, chlorpropamide, carbutamide etc.), non-sulfonylurea (repaglinide, Nateglinide etc.), thiazolidinediones (rosiglitazone, pioglitazone, carry out lattice row ketone, troglitazone, ciglitazone, darglitazone, netoglitazone (netoglitazone), englitazone etc.), two PPAR agonist (such as, aleglitazar, farglitazar (farglitazar), Mo Geta azoles, for Ge Liezha, telmisartan etc.), dipeptidyl peptidase-4 inhibitors (vildagliptin, sitagliptin, BMS-477118, Li Gelieting, Egelieting (allogliptin), septagliptin, berberine etc.), sodium glucose co-transporter 2 white 1 or 2 (SGLT1 or 2) inhibitor (Kan Gelie piperazine, empagliflozin, dapagliflozin (dapagliflozin), LX4211 etc.), meglitinides (Nateglinide, repaglinide etc.), Alpha-glucosidase inhibitor (acarbose, miglitol, voglibose etc.), GPR40, GRP120, GPR119, GPR41, the agonist etc. of GPR43.

Such as orlistat (Zenical) is drawn together for applicable anti-obesity medicated bag of the present invention, chlorine Ka Selin (Belviq), sibutramine (Meridia, exit from most of market), Rimonabant (Acomplia), Exenatide (Byetta and Bydureon), Pramlintide (Symlin), Fen-Phen, Redux, ZGN-433, phentermine/topiramate (Qsymia), naltrexone/amfebutamone (Contrave), and alternative medicine option, these medical science options comprise such as puts together linoleic acid, green tea extract, khat, thioctic acid, ephedrine (ECA Stack) (EphedrineCaffeine Stack), raspberry ketone etc.

The atherosclerotic compound that can reduce and depend on other risk factor and change is comprised for applicable antiatherosclerotic of the present invention, the inhibitor of such as fish oil and proprotein convertase subtilisin/kexin 9 type (PCSK9) is (as AMG145 (Amgen), 1D05-IgG2 (Merck & Co.) and SAR236553/REGN727 (Aventis/Regeneron)), simulate in conjunction with the LDLR of PCSK9 peptide (such as, Shan etc. (2008) Biochem.Biophys.Res.Commun.375:69-73) and exonuclease treatment agent (such as Graham etc. (2007) the J.Lipid Res.48:763-7 of targeting PCSK9, Lindholm etc. (2012) Mol.Ther:20:376-81).

What also contain as other activating agent is the compound changing HDL/LDL ratio, comprises other regulator etc. of such as nicotinic acid, acipimox (acipomox), MK-0354, GPR81, GPR109A, GPR109B.

Therefore, on the one hand, be provided for the combination dosage forms of the fixed dosage of the cardiac metabolism risk reduced in patient in need herein, this dosage form comprises at least one biguanide, at least one statin and at least one and is selected from by the other activating agent of the following group formed: antihypertensive, antiplatelet drug, diuretic, bile acid chelating agent, oral antidiabetic, incretin analogies and reinforcing agent, anti-obesity medicine and antiatherosclerotic.Subject combination dosage form can comprise the other activating agent of at least one, more preferably at least two kinds of other activating agents, more preferably at least three kinds of other activating agents, more preferably at least four kinds or five kinds of other activating agents, wherein metformin or other biguanide compound are formulated for delayed release.Statin, antihypertensive and other activating agent can be prepared for instant-free routinely, extend release and/or delayed release according to the dosage regimen of the foundation of its correspondence.The capsule of three or more components during combination dosage forms can be multilayer tablet or has the tabloid being encapsulated in suitably preparation.

In multiple preferred embodiment, the combination dosage forms of fixed dosage comprises at least one biguanide, at least one statin, at least one antihypertensive and optional at least one antiplatelet drug.In a particularly preferred embodiment of combination dosage forms, this biguanide comprises metformin and antihypertensive comprises ACE inhibitor or angiotensin ii receptor antagonist, and antiplatelet drug comprises aspirin.In an exemplary embodiment, subject combination dosage form comprises about 600-800mg metformin, about 20-40mg simvastatin or atorvastatin, about 20-25mg benazepril, lisinopril or losartan and optional about 75-90mg aspirin.

Optionally, combination dosage forms comprises and is less than about 950 or 900mg metformin or other biguanide, more preferably less than about 875 or 850mg, and is most preferably less than about 825 or 800mg biguanide.In preferred embodiments, combination dosage forms comprises about 3 or 30 or 300 to about 9 or 90 or 900mg metformin or other biguanide, is more preferably about 4 or 40 or 400 to about 8 or 80 or 800mg biguanide, and most preferably from about 6 or 60 or 600 to about 8 or 80 or 800mg biguanide.Suitable biguanide compound for using in subject methods comprises such as metformin, phenformin, buformin or imeglimin, comprises the analog of this compounds, salt, solvate, polymorph, hydrate, N-oxide and prodrug.

Can use according to the pharmaceutical composition of the fixed dosage of this instruction to experimenter in need to reduce its cardiac metabolism risk.The clinical condition presenting the cardiac metabolism risk of the increase of using that can have benefited from theme therapy comprises type ii diabetes, familial combined hyperlipidemiam, familial hypoalphalipoproteinemia and polycystic ovary syndrome, and clinical front condition of illness, generally in such as obesity, prediabetes and hyperglycemia.Method and composition disclosed herein is particularly suitable for the patient of the contraindication suffering from biguanide compound (such as, metformin, phenformin or buformin).This type of contraindication can be anoxia condition of illness, phosphagen system is impaired and/or biguanide compound clearance rate is impaired, and such as metformin clearance rate is impaired.

On the other hand, the method of the cardiovascular disease for the treatment of patient in need is also provided herein, it comprises with the combination dosage forms of fixed dosage to the other activating agent of at least one biguanide compound of described patient therapeuticallv's effective dose, at least one statin and at least one, and the other activating agent of wherein said at least one is selected from by the following group formed: antihypertensive, antiplatelet drug, diuretic, bile acid chelating agent, oral antidiabetic, incretin analogies, anti-obesity medicine and antiatherosclerotic.In preferred embodiments, the other activating agent of this at least one is antihypertensive, such as ACE inhibitor or angiotensin ii receptor antagonist.In particularly preferred embodiments, the combination dosage forms of fixed dosage also comprises antiplatelet drug, such as aspirin.

Advantageously, metformin or other biguanide are formulated for delayed release to make biguanide compound systemic bioavailability in patients minimize.In a particular embodiment, using compared with using the same approach of IR or the XR preparation with equivalent biguanide compound of theme delayed release preparation, makes the average blood plasma AUC of the biguanide compound in described patient, average blood plasma C _maxand/or circulating plasma concentration minimizes.In preferred embodiments, described biguanide compound is metformin, and IR compositions is and XR compositions is xR.

The using of theme dosage form can be twice daily (b.i.d.) (in the morning and evening) or (once a day (omni in die), is abbreviated as " OD ") once a day.In some preferred embodiment, use and can be in the morning once a day, such as, before 1pm, preferably at noon before 12am or 11am, more preferably before 10am or 9am, or when breakfast.In other preferred embodiment, use and can be at night once a day, such as, after 5pm, more preferably after 6pm or 7pm, or when dinner.In a further preferred embodiment, use and can be at h.d. once a day.

One or more biguanide compounds of subject methods administering therapeutic effective dose.But it should be noted that inventive method provided in this article advantageously allows the therapeutic dose lower than prior art preparation, the two is all on per unit basis and/or on every daily dose basis.In some embodiment of method disclosed herein, use biguanide compound with peroral dosage form twice daily by the per unit dosage being less than 1000mg BID, such as 600mg, 700mg or 800mg BID.In some preferred embodiment of method disclosed herein, oral dose is twice daily less than 500mg BID, such as, is less than 400mg BID, such as, is less than 300mg BID, such as about 150mg BID, 200mg BID or 250mg BID.In the preferred embodiment substituted, use biguanide compound once a day with the per unit dosage of 75mg OD, 125mg OD, 250mg OD, 300mg OD, 500mgOD, 600mg OD, 650mg OD, 700mg OD, 750mg OD, 800mg OD or 900mg OD.In further embodiment, total every daily dose (TDD) of biguanide compound is less than 2000mg/ days, preferably be less than 1500mg/ days, be more preferably less than 1000mg/ days or 750mg/ days, be most preferably less than 500mg/ days, 400mg/ days, 300mg/ days or 200mg/ days.

In any method disclosed herein, the delayed release preparation of metformin or other biguanide can be enteric coating.In one embodiment, biguanide compound is targeted for delivery to small intestinal, and under described preparation is included in a pH, at pH 5.0, pH 5.5 or pH 6.0 or be greater than pH 5.0, pH 5.5 or pH 6.0 times enteric coatings, the peroral dosage form of such as pH 5.0 enteric coating, pH 5.5 enteric coating, pH 6.0 enteric coating, pH 6.5 enteric coating or pH 7.0 enteric coating or its combination.In another embodiment, peroral dosage form can comprise the delayed release component for biguanide compound further.In preferred embodiments, biguanide compound is targeted for delivery to distal small bowel, and described preparation be included in a pH under, at pH6.0 or pH 6.5 or the peroral dosage form being greater than pH 6.0 or pH 6.5 times enteric coatings.

In compositions disclosed herein and method, biguanide compound can be or can comprise metformin, melbine salt, metformin solvate, metformin polymorph, metformin hydrate, metformin N-oxide or metformin prodrug.In preferred embodiments, biguanide compound is be selected from the melbine salt by the following group formed: hydrochlorate, phosphate, sulfate, hydrobromate, Salicylate, maleate, benzoic acid salt, succinate, esilate, fumarate, oxyacetate, embonate, Orotate, acetate, isobutyrate, acetylsalicylate, nicotinate, Buddha's warrior attendant hydrochlorate, chlorophyll zinc salt, carboxylate, benzoate, dichloroacetate, theophylline-7-acetate, clofibrate (clofibrate), tartrate, oxalates, tannate and hydroxy-acid salt.In an especially preferred embodiment, biguanide compound is metformin hydrochloride.

Accompanying drawing explanation

Fig. 1 shows the design of the research described in embodiment 1.

Fig. 2 shows the event during the treatment phase of the research described in embodiment 1.

Fig. 3 to show after the picked-up of t=-240 and t=0min dining after as time (y-axle; Min) metformin of function discharges plasma concentration (the x-axle of (metformin IR) (●) and metformin delayed release (metformin DR) (■) immediately; Ng/mL).

Fig. 4 A show baseline place (, zero) or picked-up metformin IR (●) or metformin DR (■) after and after the dining of t=0min in experimenter as time (y-axle; Min) PYY plasma concentration (the x-axle of function; Pg/mL).Fig. 4 B show baseline place (, zero) or picked-up metformin IR (●) or metformin DR (■) after and after the dining of t=0min in experimenter as time (y-axle; Min) active GLP-1 plasma concentration (the x-axle of function; GLP-1A pmol/L).Fig. 4 C show baseline place (, zero) or picked-up metformin IR (●) or metformin DR (■) after and after the dining of t=0min in experimenter as time (y-axle; Min) total GLP-1 plasma concentration (x-axle of function; GLP-1Tpmol/L).The percentage ratio increased for Fig. 4 A to Fig. 4 C, Abs AUC is relative to baseline value.

Fig. 5 A show baseline place (, zero) or picked-up metformin IR (●) or metformin DR (■) after and after the dining of t=0min in experimenter as time (y-axle; Min) glucose plasma concentration (the x-axle of function; Mg/dL).Fig. 5 B show baseline place (, zero) or picked-up metformin IR (●) or metformin DR (■) after and after the dining of t=0min in experimenter as time (y-axle; Min) plasma concentration of insulin (the x-axle of function; Pmol/L).The percentage ratio reduced for Fig. 5 A to Fig. 5 B, Abs AUC is relative to baseline value.

Fig. 6 is for illustrating PYY area under curve (the x-axle as the function of metformin area under curve (ng/mL*min) after picked-up metformin IR (●) and metformin DR (■); Logarithm conversion) chart.

Fig. 7 A to show after the picked-up of t=-240 and t=0min dining after as time (y-axle; The metformin IR (●) of function min) and plasma concentration (the x-axle of metformin DR (■); Ng/mL).Fig. 7 B show baseline place (, zero) or picked-up metformin IR (●) or metformin DR (■) after and after the dining of t=0min in experimenter as time (y-axle; Min) PYY plasma concentration (the x-axle of function; Pg/mL).

Fig. 8 shows as time (y-axle; Min) average blood plasma Determination of metformin (the x-axle of the 5th day at 500mg (◆) and 1000mg (■) metformin DR, 1000mg metformin IR (zero) and 500mg metformin IR+1000mg metformin DR (▲) of function; Ng/mL).The application dosage when t=-1 minute.

Fig. 9 shows 11 hours blood plasma metformin AUC (y-axles based on the 5th day; %AUC _(0-11h)) the steady statue relative bioavailability of 500mg BID and 1000mgBID metformin DR in the subject suffering from type 2 diabetes mellitus compared with 1000mg BID metformin IR.These levels of 500mg BID and 1000mg BID metformin DR are compared with 1000mg BID metformin IR, and form total blood plasma metformin degree of exposure 45% and 57% reduces.

Figure 10 shows in the 5th day (●) subject of baseline (zero) or TA interior as time (y-axle; Min) average blood plasma PYY total concentration (the x-axle of function; Pg/mL).

Figure 11 shows in the 5th day (●) subject of baseline (zero) or TA interior as time (y-axle; Min) the active GLP-1 concentration of average blood plasma (the x-axle of function; Pmol/L).Use breakfast when t=0min, the application dosage when t=-1min, and use lunch when t=300min.

Figure 12 shows in the 5th day (●) subject of baseline (zero) or TA interior as time (y-axle; Min) mean blood glucose concentrations (the x-axle of function; Mg/dL).

Figure 13 is shown in the subject for the treatment of with 500mg (◆) and 1000mg (■) metformin DR, 1000mg metformin IR (●) and 500mg metformin IR+1000mg metformin DR (▲) interior (y-axle) as time (the y-axle from baseline to the 5th day by scatterplot; Min) individuality change (the x-axle of the fasting plasma glucose concentration of function; Mg/dL) wire tag in figure often plants the glucose LS mean change (mg/dL) for the treatment of.

Figure 14 shows as time (y-axle; Hour) 500mg (◆) of function and 1000mg (■) metformin DR, 1000mg metformin IR (zero) and 2000mg metformin extend average blood plasma Determination of metformin (the x-axle of release (metformin XR); Ng/mL).At the little application dosage constantly of t=0.At little the second dosage using BID scheme constantly of t=12.Littlely meals/snack is provided constantly t=-.42 hour, 2.08 hours, 11.5 hours, 18 hours and 24.

Figure 15 shows the C giving 1000mg BID metformin IR, 500mg BID and 1000mg BID metformin DR and 2000mg QD metformin XR for a day _max(left figure) and AUC _0-36(right figure).* statistically significantly reducing (whole p < 0.0001) of the exposure compared with both metformin XR with metformin IR is represented

Figure 16 shows the relative bioavailability (left figure) giving 500mg with 1000mg BID metformin DR for one day compared with 1000mg BID metformin IR and the relative bioavailability (right figure) giving 500mg and 1000mg BID metformin DR for one day compared with 2000mgQD metformin XR

Figure 17 illustrates the plasma A UC level (left figure) of 1000mg QD AM, 1000mg QD PM and 500mg BID metformin DR and the change (right figure) of fasting glucose.

Describe in detail

Contain herein for using the combination treatment of fixed dosage to reduce the cardiac metabolism risk in individuality in need and being used for the treatment of and/or preventing the method and composition of cardiovascular disease as described herein, described combination treatment comprises the other activating agent of at least one biguanide, at least one statin and at least one.The other activating agent of described at least one is advantageously selected from following: antihypertensive, antiplatelet drug, diuretic, bile acid chelating agent, incretin analogies and reinforcing agent, oral antidiabetic, anti-obesity medicine and antiatherosclerotic.Preferably, theme composition and method adopt at least one biguanide (such as, metformin), at least one statin and at least one antihypertensive (such as ACE inhibitor or angiotensin-ii antagonist), and optionally comprise at least one antiplatelet drug further.

Advantageously, as herein prove, use with comparatively low dosage once a day or twice ground and use delayed release preparation can obtain metformin all to treat effect, thus obtain metformin and the more comprehensive combination of other activating agent in unit dosage form.In addition, subject methods and compositions also significantly improve GI toleration and reduce the probability of side effect as lactic acidosis, thus can safely and effectively for patient categories widely, those patients under the risk comprising developing cardiovascular diseases or be in cardiovascular disease.

Therefore, be provided for herein reducing cardiac metabolism risk and treatment or angiocardiopathy preventing, preparation be used for the pharmaceutical composition of the fixed dosage that the other activating agent of the metformin of DR or other biguanide compound and at least one statin and at least one, more preferably at least two kinds of other activating agents, more preferably at least three kinds or four kinds of other activating agents combine, described compositions can be prepared according to the conventional administration regime of correspondence such as IR, XR or DR.In preferred embodiments, the pharmaceutical composition of fixed dosage also comprises at least one antihypertensive and optional at least one antiplatelet drug.

In an exemplary embodiment, pharmaceutical composition comprises multilayer tablet or has the capsule of three or more the components be encapsulated in the suitable tabloid prepared.Also provide the method for the hyperglycemic symptoms for the treatment of patient in need herein, it comprises uses theme composition to described patient once a day or twice ground.In preferred embodiments, biguanide compound is selected from the group be made up of metformin, buformin, phenformin and imeglimin, and still realizes required metabolism improving to use described biguanide compound than the lower dosage indicated at present and/or lower bioavailability simultaneously.

Definition

Term used herein " gastrointestinal tract " and " intestinal " refer to harmonization of the stomach intestinal." little " intestinal or " epimere " intestinal comprise duodenum, jejunum and ileum and " greatly " intestinal or " hypomere " intestinal comprise caecum, colon and rectum." far-end " small intestinal comprises jejunum and ileum.

In some embodiments, " to have treated " or " treatment " any condition of illness, disease or disease refer to and improve disease, disease or condition of illness (that is, making the development of disease, disease or condition of illness or its at least one clinical symptoms stop or alleviating).In other embodiments, " treatment " or " treatment " refers to the physical parameter improved at least one and can or cannot be distinguished by experimenter, comprises undesirable but unimportant clinically physical parameter.In other embodiments, " treatment " or " treatment " refers to and suppresses disease, disease or condition of illness, health (such as, makes to distinguish symptoms stabilize), on physiology, (such as, makes physical parameter stablize) or the two." to prevent (Preventing) " or " prevention (prevention) " any condition of illness, disease or symptom refers to if do not occurred, if prevention or postpone outbreak, the prevention of disease progression or postpone disease or disease and come across and have the tendency of described disease or disease in advance but not to be diagnosed as in the experimenter suffering from described disease or disease and/or, to prevent or postpone further disease progression.

" treatment effective dose " or " effective dose " mean compositions, compound, therapy or therapeutic process use to experimenter for be enough to when disease therapy, disease or condition of illness realize to disease, disease or condition of illness this type for the treatment of amount." treatment effective dose " changes according to the age, weight etc. of compositions, compound, therapy, therapeutic process, disease, disease or condition of illness and its order of severity and experimenter to be treated.

When biguanide compound as herein described comprises one or more chiral centre, the spatial chemistry of this type of chiral centre can be in R or S configuration or the mixture for the two independently.Chiral centre can be indicated as R or S or R, S further; Or d, D, l, L or d, l, D, L.Correspondingly, if biguanide compound of the present invention can exist by optical active forms, then they in fact can enantiomer racemic mixture form or using the form of one of the independent enantiomer in the form of abstraction and purification substantially or as the mixture existence of enantiomer comprising any relative scale.

When biguanide compound as herein described comprises two or more chiral centres, so diastereomer is possible.This type of diastereomer can be used as pure diastereomeric enantiomer, diastereomeric enantiomer pure racemic mixture or due to complex array in remaining mixture of the diastereomer of mapping and with itself can be racemic or optically active non-enantiomer mixture can being had and exist.

If biguanide compound of the present invention can exist round the geometric isomer form of (such as) guanidine key, so in fact they can comprise the geometric isomer form of mixtures of the isomer of any relative scale or exist with the form of one of the independent geometric isomer in abstraction and purification form substantially in some cases.

When biguanide compound as herein described comprise one or more separation or linearly put together double bond time, the geometry round this type of double bond can be cis/trans, E/Z mixture or itself E or Z geometric isomer independently.

" alkyl " means the saturated monovalent hydrocarbon of straight or branched.As an example, hydrocarbon chain can have one to 20 carbon, one to 16 carbon, one to 14 carbon, one to 12 carbon, one to ten carbon, one to eight carbon, one to six carbon, one to four carbon etc." low alkyl group " can refer to have such as one to six carbon, an alkyl to four carbon etc.In some instances, straight chained alkyl can have one such as, to six carbon atom and branched alkyl can have three to six carbon atom, methyl, ethyl, propyl group, 2-propyl group, butyl (comprising all isomeric forms), amyl group (comprising all isomeric forms) etc." Me " means methyl, and " Et " means ethyl, and " iPr " means isopropyl.

" aryl " means such as to have 6 to 20 or 6 monovalent monocyclic to 10 annular atomses or bicyclic aromatic hydrocarbon groups, such as phenyl or naphthyl.

" alkylaryl " means (alkylidene)-R group, and wherein R is aryl as defined above.

" cycloalkyl " means ring filling or fractional saturation monovalent hydrocarbon (or alcyl).As an example, cycloalkyl can have three to 20 carbon atoms, three to ten six carbon atoms, three to ten four carbon atoms, three to 12 carbon atoms, three to ten carbon atoms, three to eight carbon atoms, three to six carbon atom etc., wherein one or two carbon atom can be replaced by oxygen base, such as, adamantyl (admantanyl), cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclohexenyl group, indanyl etc.

" alkyl-cycloalkyl " means (alkylidene)-R base, and wherein R is cycloalkyl as defined above; Such as Cvclopropvlmethvl, cyclobutylmethyl, cyclopentyl ethyl or cyclohexyl methyl etc.

" heterocyclic radical " or " Heterocyclylalkyl " means saturated or unsaturated monovalent monocyclic base, and wherein one or two annular atoms is the hetero atom being selected from N, O or S, and all the other annular atomses are C.Heterocyclic ring is optionally fused to as herein defined on (one) aryl or heteroaryl ring.In this application, the heterocyclic ring be fused on monocyclic aryl or heteroaryl ring is called as " bicyclic heterocyclic radical " ring.In addition, one or two available ring carbon atom in heterocyclic ring is optionally replaced by-CO-base.More precisely, term heterocyclic radical includes but not limited to pyrrolidino, piperidino, high-piperidine sub-base, 2-oxo-pyrrolidine base, 2-oxo-piperidine base, morpholino, Piperazino, THP trtrahydropyranyl, thiomorpholine generation etc.When heterocyclic ring is undersaturated, it can comprise one or two ring double bond.When heterocyclic radical comprises at least one nitrogen-atoms, it is also referred to as heterocyclic amino group in this article and is the subset of heterocyclic radical.When heterocyclic radical is saturated rings and is not fused on aryl as described above or heteroaryl ring, it is also referred to as saturated monocyclic heterocycles base in this article.

" Alkyl cycloheteroalkyl " means-(alkylidene)-R base, and wherein R is heterocyclic ring, such as oxolane ylmethyl, piperizinylmethyl, morpholinyl ethyl etc. as defined above.

" heteroaryl " means monovalent monocyclic or bicyclic aromatic base, and wherein one or more, preferably one, two or three annular atomses are the hetero atom being selected from N, O or S, all the other annular atomses are carbon.Representative example includes but not limited to pyrrole radicals, thienyl, thiazolyl, imidazole radicals, furyl, indyl, isoindolyl, oxazolyl, isoxazolyl, di azoly, pyrazolyl, triazolyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, tetrazole radical etc.

" oxo " or " carboxyl " mean respectively=(O) base or C=O base.

Term " replacement " means to be replaced individually by one or more other group and independently selected from group as herein described with reference to group.In some embodiments, optional substituent group is selected from: oxo, halogen ,-CN ,-NH ₂,-OH ,-NH (CH ₃) ,-N (CH ₃) ₂, alkyl (comprising straight chain, side chain and/or unsaturated alkyl), substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl, fluoroalkyl, substituted or unsubstituted assorted alkyl, substituted or unsubstituted alkoxyl, Fluoroalkyloxy ,-S-alkyl ,-S (O) ₂-alkyl ,-CONH ((substituted or unsubstituted alkyl) or (substituted or unsubstituted phenyl)) ,-CON (H or alkyl) ₂,-OCON (substituted or unsubstituted alkyl) ₂,-NHCONH ((substituted or unsubstituted alkyl) or (substituted or unsubstituted phenyl)) ,-NHCO alkyl ,-N (substituted or unsubstituted alkyl) CO (substituted or unsubstituted alkyl) ,-NHCOO (substituted or unsubstituted alkyl) ,-C (OH) (substituted or unsubstituted alkyl) ₂and-C (NH ₂) (substituted or unsubstituted alkyl) ₂.In some embodiments, as an example, optional substituent group is selected from oxo, fluorine, chlorine, bromine, iodine ,-CN ,-NH ₂,-OH ,-NH (CH ₃) ,-N (CH ₃) ₂,-CH ₃,-CH ₂cH ₃,-CH (CH ₃) ₂,-CF ₃,-CH ₂cF ₃,-OCH ₃,-OCH ₂cH ₃,-OCH (CH ₃) ₂,-OCF ₃,-OCH ₂cF ₃,-S (O) ₂-CH ₃,-CONH ₂,-CONHCH ₃,-NHCONHCH ₃,-COCH ₃,-COOH etc.In some embodiments, replacement group by one, two or three aforementioned groups replace.In some embodiments, the group of replacement is replaced by one or two aforementioned group.In some embodiments, the group of replacement is replaced by an aforementioned group.In addition, unless stated to the contrary, otherwise the formula of chemical bond had only as solid line not as solid line or dotted line display covers the mixture (as raceme and non-racemic mixture) of often kind of possible isomer (such as often kind of enantiomer and diastereomer) and isomer.

In some embodiments, disclosed biguanide compound is present in compositions as salt.In some embodiments, by disclosed compound and acid reaction are obtained salt.At some in other embodiment, by disclosed compound and alkali reaction are obtained pharmaceutically acceptable salt.In other embodiments, using compound as free acid or free alkali form for the manufacture of compositions as herein described.The type of salt includes but not limited to: (1) acid-addition salts, and it is by being formed the free alkali form of compound and following pharmaceutically acceptable acid reaction: mineral acid, such as, and hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, Metaphosphoric acid etc., or organic acid, such as, acetic acid, propanoic acid, caproic acid, Pentamethylene. propanoic acid, hydroxyacetic acid, acetone acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-(2-hydroxybenzoyl)) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, 1, 2-ethionic acid, 2-ethylenehydrinsulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-LOMAR PWA EINECS 246-676-2, 4-methyl bicyclic-[2.2.2] oct-2-ene base-l-carboxylic acid, glucoheptonic acid, 4, 4 '-di-2-ethylhexylphosphine oxide-(3-hydroxyl-2-thiazolinyl-l-carboxylic acid), 3-phenylpropionic acid, trimethylace tonitric, butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butanoic acid, phenylacetic acid, phenylbutyric acid, valproic acid etc., (2) when being present in the acid proton in parent compound by the salt formed during metal ion such as alkali metal ion (such as, lithium, sodium, potassium), alkaline-earth metal ions (such as, magnesium or calcium) or aluminium ion displacement.In some cases, biguanide compound as herein described and organic base are reacted, described organic base is such as but not limited to ethanolamine, diethanolamine, triethanolamine, trometamol, N-METHYL-ALPHA-L-GLUCOSAMINE, hexanamine, three (hydroxymethyl) methylamine.In other cases, compound as herein described and aminoacid form salt, and described aminoacid is such as but not limited to arginine, lysine etc.Accepted inorganic base for forming (comprising acid proton) salt with compound includes but not limited to aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide etc.

Term " aminoacid " comprises any one or any one the naturally occurring amino acid whose D-form in 20 kinds of naturally occurring aminoacid.In addition, term " aminoacid " also comprises the aminoacid that other non-natural except D-aminoacid exists, and they are naturally occurring amino acid whose functional equivalent.The aminoacid that this type of non-natural exists comprises such as nor-leucine (" Nle "), norvaline (" Nva "), L-or D-naphthylamines, ornithine (" Orn "), other aminoacid of homoarginine (homoArg) and peptide known, as described below those: M.Bodanzsky, " Principles of Peptide Synthesis, " the 1st time and the 2nd revised edition, Springer-Verlag, New York, N.Y., 1984 and 1993 and Stewart and Young, " Solid Phase Peptide Synthesis, " the 2nd edition, Pierce Chemical Co., Rockford, Ill., 1984, the two is incorporated to herein all by reference.

Business can buy (Sigma Chemical Co.; Advanced Chemtech) or use methods known in the art synthesizing amino acid or amino acid analogue.

In the scope of embodiment, biguanide compound as herein described comprises the compound of other form, as pharmaceutically acceptable salt, solvate (comprising hydrate), amorphous phase, partially crystallizable and crystal form (comprising all polymorphs), prodrug, metabolite, N-oxide, isotope-labeled, epimer, pure epimer, epimeric mixture, enantiomer (including but not limited to the diastereomer of single enantiomer and enantiomer), meso compound, stereoisomer, racemic mixture and non-enantiomer mixture.The biguanide compound as herein described with one or more double bond comprises cis/trans isomer, E/Z isomer and stereoisomer.Biguanide compound as herein described can be prepared as pharmaceutically acceptable salt, is replaced by metal ion such as alkali metal ion, alkaline-earth metal ions or aluminium ion when being present in the acid proton in parent compound; Or form described salt with during organic base coordination.In addition, the salt of parent material or intermediate can be used to prepare the salt form of disclosed compound.

In some embodiments, biguanide compound as herein described comprises solvent addition form or its crystal form, particularly solvate or polymorph.Solvate comprises the solvent of stoichiometry or non-stoichiometric amount, and can be formed during the pharmaceutically acceptable solvent of use is as the crystallization process of water, ethanol etc.Form hydrate when solvent is water, or form alcoholates when solvent is alcohol.

As previously discussed, in some embodiments, biguanide compound as herein described has one or more Stereocenter and each center has an independent existence with R or S configuration.Biguanide compound provided herein comprises all diastereomer form, enantiomeric form and epimeric form and its suitable mixture.

In some embodiments, the site on biguanide compound disclosed herein is easy to the impact being subject to the reaction of various metabolic.Therefore, metabolic reaction position on be incorporated to suitable substituent group by minimizing, minimize or eliminate metabolic approach.In specific embodiments, only as an example, reducing or eliminating the suitable substituent group of aromatic ring to the sensitivity that metabolic reacts is halogen, deuterium or alkyl.

In some embodiments, biguanide compound as herein described is isotope-labeled, this is identical with those described in structure with various formula provided herein, but the fact is one or more atom had be different from atomic weight or the atomic weight of mass number that occurring in nature finds usually or the atom of mass number replace.In some embodiments, one or more hydrogen atom is by deuterium exchange.In some embodiments, the metabolism site on compound as herein described is deuterate.In some embodiments, the substituent group with deuterium provides by some the treatment advantages caused by greater metabolic stability, such as, and the minimizing that the increase of Half-life in vivo or dosage need.In entire description, group and substituent group thereof can be selected to provide steady component and compound by those skilled in the art.

Statin

Such as lovastatin, atorvastatin, fluvastatin, rosuvastatin, simvastatin, pravastatin, Pitavastatin, mevastatin etc. are comprised for applicable HMG-CoA reductase inhibitor of the present invention or statin.The surrogate-data technique that can reduce triglyceride and/or LDL level includes but not limited to ascorbic acid, asparaginase, clofibrate, colestipol, cholestyramine (cholestyrine), fenofibrate, gemfibrozil, nicotinic acid, lovastatin, probucol and omega-fatty acid.These medicaments are prepared usually for discharging immediately, although also can use prolongation and/or delayed release.

Biguanide

Compositions disclosed herein and method relate to metformin and other biguanides.Technology as a setting, metformin is one of the simplest structural variant of the compounds being called as biguanide.From structural perspective, metformin is similar to the pharmacophoric group or fragment that have compared with the chemical constitution of mcroorganism activity.

An embodiment, biguanide compound of the present invention comprises following:

Wherein:

R ₁, R ₂, R ₃, R ₄, R ₅, R ₆and R ₇independently selected from:

H、OH；

O-Rx, wherein Rx is alkyl, cycloalkyl, alkyl-cycloalkyl, acyl group, ester, sulfur ester;

The alkyl of optional replacement (such as, optionally replaced by oxygen, silicon, sulfur or optionally by OH, O-alkyl, SH, S-alkyl, NH ₂, NH-alkyl replace C ₁to C ₁₂straight or branched alkyl); Cycloalkyl (such as, C ₃to C ₇cycloalkyl); Alkyl-cycloalkyl (such as, C ₄to C ₁₂alkyl-cycloalkyl); (such as, wherein heterocycle comprises the hetero atom that one or two is selected from O, S or N to Heterocyclylalkyl, comprises C ₂to C ₆heterocyclylalkyl); (such as, wherein heterocycle comprises the hetero atom that one or two is selected from O, S or N to Alkyl cycloheteroalkyl, comprises C ₃to C ₁₁alkyl cycloheteroalkyl, and comprise wherein when N is present in heterocycle, nitrogen-atoms can be amide, carbamate or form of urea); The thiazolinyl of optional replacement (such as, optionally replaced by oxygen, silicon, sulfur or optionally by OH, O-alkyl, SH, S-alkyl, NH ₂, NH-alkyl replace C ₁to C ₁₂straight or branched thiazolinyl); The alkynyl of optional replacement (such as, optionally replaced by oxygen, silicon, sulfur or optionally by OH, O-alkyl, SH, S-alkyl, NH ₂, NH-alkyl replace C ₁to C ₁₂straight or branched alkynyl);

The aryl of optional replacement (such as, the naphthyl of the phenyl of phenyl, replacement, naphthyl, replacement); The alkylaryl of optional replacement (naphthyl that phenyl, alkyl naphthyl, alkyl that such as, alkyl phenyl, alkyl replace replace); The heteroaryl of optional replacement (such as, pyridine radicals, furyl, thiophenyl, pyrrole radicals, oxazolyl, isoxazolyl, thiazolyl, di azoly, pyrazolyl, triazolyl, all these is optional replacement); The miscellaneous alkyl aryl of optional replacement; And

Or R ₆and R ₇a key can be joined together to form, thus form the ring comprising the nitrogen-atoms that they connect together;

Or R ₁and R ₂3 yuan to the 8 yuan heterocycles comprising the nitrogen-atoms that they connect can be formed together;

Or R ₄and R ₅the ring of group under being selected from comprising the nitrogen-atoms that they connect can be formed together: aziridine, pyrrole radicals, imidazole radicals, pyrazolyl, indyl, indolinyl, pyrrolidinyl, piperazinyl and piperidyl.

In certain embodiments, O-Rx can be selected from: O-C ₁to C ₈straight or branched alkyl; O-C ₃to C ₇cycloalkyl; O-C ₄to C ₈alkyl-cycloalkyl; O-acyl group; O-ester; And O-thioesters.

In other embodiments, optional substituent group can comprise such as OH, O-alkyl, SH, S-alkyl, NH ₂, NH-alkyl.In addition, alkyl, thiazolinyl, alkynyl etc. can be replaced to form assorted alkyl, assorted thiazolinyl, assorted alkynyl etc. by oxygen, silicon, sulfur etc.

In certain embodiments, R ₃, R ₆and R ₇; Or R ₃, R ₄, R ₅and R ₇; Or R ₃, R ₄, R ₅and R ₇; Or R ₃, R ₄, R ₅, R ₆and R ₇; Or R ₂, R ₃, R ₄, R ₅, R ₆and R ₇in each independently selected from:

H, methyl, ethyl, propyl group or isopropyl;

And all the other substituent R ₁, R ₂, R ₄and R ₅; Or R ₁, R ₂and R ₆; Or R ₁, R ₂and R ₆; Or R ₁and R ₂; Or R ₁in each be separately selected from:

H; The alkyl of optional replacement (such as, optionally replaced by oxygen, silicon, thia or optionally by OH, O-alkyl, SH, S-alkyl, NH ₂, NH-alkyl replace C ₁to C ₁₂straight or branched alkyl); The thiazolinyl of optional replacement (such as, optionally replaced by oxygen, silicon, thia or optionally by OH, O-alkyl, SH, S-alkyl, NH ₂, NH--alkyl replace C ₁to C ₁₂straight or branched thiazolinyl); The alkynyl of optional replacement (such as, optionally replaced by oxygen, silicon, thia or optionally by OH, O-alkyl, SH, S-alkyl, NH ₂, NH-alkyl replace C ₁to C ₁₂straight or branched alkynyl); Cycloalkyl (such as, C ₃to C ₇cycloalkyl); Alkyl-cycloalkyl (such as, C ₄to C ₁₂alkyl-cycloalkyl); (such as, wherein heterocycle comprises the hetero atom that one or two is selected from O, S or N to Heterocyclylalkyl, comprises C ₂to C ₆heterocyclylalkyl); (such as, wherein heterocycle comprises the hetero atom that one or two is selected from O, S or N to Alkyl cycloheteroalkyl, comprises C ₃to C ₁₁alkyl cycloheteroalkyl, and comprise wherein when N is present in heterocycle, nitrogen-atoms can be amide, carbamate or form of urea); Aryl (such as, the naphthyl of the phenyl of phenyl, replacement, naphthyl, replacement); Alkylaryl (such as, alkyl phenyl, alkyl replace phenyl, alkyl naphthyl, alkyl replace naphthyl); Heteroaryl (such as, pyridine radicals, furyl, thiophenyl, pyrrole radicals, oxazolyl, isoxazolyl, thiazolyl, di azoly, pyrazolyl, triazolyl, all these is optional replacement); Miscellaneous alkyl aryl;

There is exemplary compounds and the substituent R of formula I ₁, R ₂, R ₃, R ₄, R ₅, R ₆and R ₇illustrate as follows.Substituent R can be predicted ₁, R ₂, R ₃, R ₄, R ₅, R ₆and R ₇other combination of selection, and it is disclosed in co-pending U.S. Patent Application Serial No.13/547, and in 022, the disclosure of described patent is clearly incorporated to herein by reference.

In certain embodiments, the biguanide compound with formula I can comprise one or more asymmetric center and can be the form of the compositions of the mixture of racemic mixture, non-enantiomer mixture, single enantiomer, the diastereomer of enantiomer, meso compound, pure epimer or its epimer etc.In addition, biguanide compound can have one or more double bond and can be the form of cis/trans, E/Z mixture or itself E or Z geometric isomer.

The biguanide compound with formula I also can be prepared to salt form, such as pharmaceutically acceptable salt, comprise appropriate acid form, such as be selected from following salt form: hydrochlorate, hydrobromate, acetate, propionate, butyrate, sulfate, disulfate, sulphite, carbonate, bicarbonate, phosphate, phosphinate, oxalates, half-oxalates, malonate, half-malonate, fumarate, half-fumarate, maleate, half-maleate, citrate, half-citrate, tartrate, half-tartrate, aspartate, glutamate, Glu etc.

The alternate embodiment containing the biguanide compound for using in the present invention is especially included in co-pending U.S. Patent Application Serial No.13/547, related heterocyclic compounds described in 022, the disclosure of described patent is clearly incorporated to herein by reference.Phrase used herein " biguanide compound " comprises these related heterocyclic compounds, and the exemplary of described heterocyclic compound comprises following:

Triazole:

Triazine:

Dihydrotriazine:

7-unit ring-type biguanide:

In one embodiment, disclosed compound can be prepared to the three kinds of component salt forms comprising component A, B and C, wherein:

A is protonated form that is natural or alpha-non-natural amino acid;

B is the dianion of acid; And

C is the protonated form of the compound with formula I.

In some aspects, A, B and C of stoichiometric amount can be comprised, wherein:

A is the protonated form being selected from following natural amino acid: alanine, aspartic acid, agedoite, arginine, glycine, glutamine, glutamic acid lysine, phenylalanine, tyrosine, serine, threonine, tryptophan, leucine, isoleucine, histidine, methionine, proline, cysteine or cystine;

B is the dianion being selected from following acid: oxalic acid, malonic acid, citric acid, maleic acid, fumaric acid, tartaric acid, aspartic acid and glutamic acid etc.; And

C is the protonated form of the compound with formula I.

Comprise the purposes of the expansion of the biguanide compound of metformin

Owing to reporting that the whole body biguanide comprising metformin is substantially by renal excretion, so the risk of biguanide compound accumulation and lactic acidosis increases along with renal function injury degree.The relevant contraindication of biguanide compound (as metformin) comprises the impaired and anoxia condition of illness caused by such as respiratory failure or heart failure of phosphagen system.Therefore, the patient suffering from these contraindications can not treat with conventional formulation at present.In addition, the diabetic patient population of the conventional metformin preparation for treating of current use stands the intractable of a scope and the gastrointestinal side effect of final dose restriction usually, comprise Nausea and vomiting and diarrhoea, and therefore avoid these compounds more widely using in PATIENT POPULATION widely up to now.

But, as herein prove, in fact the treatment effect of metformin and other biguanide compound do not require metformin systemic exposure, and described systemic exposure exists the lactic acidosis risk increased.In addition, the generation of GI side effect is also by adopting delayed release preparation significantly to reduce, and therefore method and composition provided in this article can safely and effectively for the cardiac metabolism condition of illness of the more broad range in PATIENT POPULATION widely in need, generally comprise and reduce cardiac metabolism risk, and comprise treatment or angiocardiopathy preventing particularly.

Cardiovascular disease

Term " cardiovascular disease " refers to any disease of heart or blood vessel (i.e. artery and vein) or disease or its any symptom or causes or facilitate any disease or the condition of illness of cardiovascular disease in this article.The limiting examples of cardiovascular disease comprises acute cardiac ischemia event, acute myocardial infarction, angina pectoris (angina), angina pectoris (angina pectoris), arrhythmia, atrial fibrillation, atherosclerosis, tremulous pulse Fibrillation, cardiac insufficiency, cardiovascular disease, chronic heart failure, chronic stable angina pectoris, congestive heart failure, coronary artery disease, coronary heart disease, venous thrombosis, diabetes (diabetes), diabetes (diabetes mellitus), diabetic neuropathy, suffers from the diastolic dysfunction in the experimenter of diabetes, edema, essential hypertension, final pulmonary infarction, Fatty Liver Disease, heart disease, heart failure, isozygoty familial hypercholesterolemia (HoFH), isozygoty familial sitosterolemia, hypercholesterolemia, hyperlipemia, hyperlipemia in HIV positive subjects, hypertension, hypertriglyceridemia, the ischemic complications of unstable angina pectoris and myocardial infarction, hypotension, metabolism syndrome, mixed dyslipidemia, moderate is to mild heart failure, myocardial infarction, fat management, Paroxysmal atrial/tremulous pulse fibrillation (fibrillation)/fibrillation (fibrulation)/flutter, paroxysmal supraventricular tachycardia (PSVT), the edema of especially severe or rapid onset, platelet aggregation, primary hypercholesterolemia, Primary hyperlipemia, pulmonary hypertension, pulmonary hypertension, unstable relapse into ventricular tachycardia (VT) of recurrent hematodinamics, the ventricular arrhythmia of recurrent, relapse into ventricular fibrillation (VF), the aneurysm of breaking, sitosterolemia, apoplexy, supraventricular tachycardia, Symptomatic atrial fibrillation/atrial flutter, tachycardia, type ii diabetes, angiopathy, venous thromboembolism, ventricular arrhythmia and other cardiovascular event.

Metabolic disorder

The compositions and methods of the invention are also advantageously used in and treat and/or prevent metabolic disorder, comprise overweight, fat, prediabetes, polycystic ovary syndrome, dyslipidemia or lipid metabolism sexually transmitted disease (STD) disease and hyperglycemia condition of illness (as insulin dependent diabetes mellitus (IDDM) (1 type) or non-insulin-dependent diabetes mellitus (2 type) diabetes) and physiology condition of illness or with hyperglycemia condition of illness about or the disease that caused by physiology condition of illness.Therefore, the hyperglycemia condition of illness for the treatment of by method of the present invention also comprises the changes in histopathology relevant with chronic or chronic hyperglycemia (such as, diabetes).Instantiation comprises the risk of islets of langerhans degeneration (beta cell destruction), renal tubules calcification, liver degeneration, eye infringement (diabetic renal papillary necrosis), diabetic foot, mucosa (as mouth and gingiva) ulcer, Excessive bleedings, the coronary heart disease of the hemopexis of delay or wound healing and increase, apoplexy, peripheral vascular disease, dyslipidemia, hypertension and obesity.

Term used herein " hyperglycemia " or " hyperglycemia ", when the condition of illness relating to patient is to use, mean the instantaneous or chronic abnormal high glucose level be present in blood samples of patients.Described condition of illness causes by the delay of glucose metabolism or absorption; show glucose intolerance or high glucose state to make described patient and usually can not see normal patient (such as, in the sub-diabetics being in the glucose intolerance under development diabetes risk or in diabetics).Normoglycemic fasting glucose (FPG) level is less than about 110mg/dl, and the FPG of impaired glucose metabolism is about between 110mg/dl and 126mg/dl, and the FPG of diabetes is greater than about 126mg/dl.

Metabolic disorder also comprises obesity or unwanted body quality.Leptin, cholecystokinin, PYY and GLP-1 alleviate hunger, increase energy expenditure, and induction loses weight or provides normal glucose homeostasis.Therefore, in each embodiment, a kind of method of the present invention being used for the treatment of obesity or unwanted body quality or hyperglycemia relates to local application metformin and produces cholecystokinin, gut hormone, GIP, GLP-2, PYY or GLP-1 with exciting enteroendocrine cell.Medicable disease also comprises those usually relevant with obesity diseases, such as, the hypertension/apoplexy, coronary heart disease risk etc. of abnormal high serum/plasma LDL, VLDL, triglyceride, cholesterol, the Plaque Formation causing narrowed blood vessels or retardance, increase.

The synthesis of compound

Standard synthetic techniques well known by persons skilled in the art can be used or use methods known in the art to combine method as herein described to synthesize compound as herein described.In addition, solvent provided herein, temperature and other reaction condition can change according to the practice of those skilled in the art and knowledge.

Parent material for the synthesis of compound as herein described can obtain from commercial source, as Aldrich Chemical Co. (Milwaukee, Wis.), Sigma Chemical Co. (St.Louis, Mo.), or can parent material be synthesized.Compound described herein can use technology well known by persons skilled in the art and material to synthesize with other related compound with different substituents, as described in below such as: March, ADVANCED ORGANIC CHEMISTRY the 4th edition, (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY the 4th edition, A volume and B volume (Plenum 2000,2001); And Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS the 3rd edition (Wiley 1999) (all these documents by reference entirety are incorporated to herein).Conventional method for the preparation of compound as disclosed herein can come from the known response in this area, and described reaction is revised by using suitable reagent and condition, as technical staff cognitive, for being incorporated herein the various piece occurred in provided formula.

U.S. Application Serial No.12/593 is seen, 479 (being published as U.S.2010/0130498) for other biguanide synthetic method of compound described herein and scheme; U.S. Application Serial No.12/593,398 (being published as U.S.2010/0184796); U.S. Patent No. 7,829,299; U.S. Application Serial No.11/578,013 (being published as U.S.2010/0056621); U.S. Patent No. 7,416,867; U.S. Application Serial No.11/455,693 (being published as U.S.2007/0037212); U.S. Application Serial No.13/059,730 (being published as U.S.2011/0143376); U.S. Application Serial No.12/996,670 (being published as U.S.2011/0311991); U.S. Patent No. 7,811,788; U.S. Application Serial No.11/182,942 (being published as U.S.2006/0019346); U.S. Application Serial No.12/993,542 (being published as U.S.2011/0086138); U.S. Application Serial No.12/373,235 (being published as U.S.2010/0055209); International application sequence No.PCT/IL2007/000454 (being published as WO 2007/116404); U.S. Application Serial No.10/472,056 (being published as U.S.2004/0138189); U.S. Patent No. 5,891,919; U.S. Patent No. 6,376,657; U.S. Application Serial No.11/554,982 (being published as U.S.2007/0104805); U.S. Application Serial No.11/926,745 (being published as U.S.2008/0108604); International application sequence No.PCT/CA2009/001688 (being published as WO 2010/060198); U.S. Application Serial No.12/735,557 (being published as U.S.2010/0330205); International application sequence No.PCT/CA2007/001066 (being published as WO2008/000063); U.S. Application Serial No.11/438,204 (being published as U.S.2006/0269617); U.S. Application Serial No.10/563,713 (being published as U.S.2006/0172020); U.S. Application Serial No.10/902,352 (being published as U.S.2006/0024335); U.S. Application Serial No.10/538,038 (being published as U.S.2006/0275765); U.S. Application Serial No.11/555,617 (being published as U.S.2008/0187936); U.S. Application Serial No.12/739,264 (being published as U.S.2010/0316736); U.S. Application Serial No.12/215,609 (being published as U.S.2009/0042813); U.S. Application Serial No.11/893,088 (being published as U.S.2008/0050499); U.S. Patent No. 7,807,204; U.S. Application Serial No.11/811,166 (being published as U.S.2008/0003268); U.S. Patent No. 6,376,657; International application sequence No.PCT/US2011/041183 (being published as WO 2011/163183); International application sequence No.PCT/EP2011/059814 (being published as WO 2011/157692); U.S. Application Serial No.12/790,292 (being published as U.S.2011/0293753); International application sequence No.PCT/JP2009/071700 (being published as WO 2010/076879); U.S. Application Serial No.13/032,530 (being published as U.S.2011/0217394); International application sequence No.PCT/EP2011/000110 (being published as WO 2011/085979); International application sequence No.PCT/US2010/058467 (being published as WO 2011/068814); U.S. Application Serial No.13/060,996 (being published as U.S.2011/0152361); U.S. Application Serial No.12/09,253 (being published as U.S.2011/0124609); U.S. Application Serial No.12/687,962 (being published as U.S.2011/0119499); And international application sequence No.PCT/EP2010/004623 (being published as WO 2011/012298); Every portion application in these all by reference entirety is incorporated to herein.

Use and method

Disclosed biguanide compound can be used to experimenter in need, comprise the analog of this compounds, salt, solvate, polymorph, hydrate, N-oxide and prodrug, to reduce cardiac metabolism risk substantially and to treat and/or prevent cardiovascular disease particularly.In view of sloughing of the systemic bioavailability realized herein and treatment effect contacts and the surprising reduction of relevant GI toxicity, successfully and safely can realize now this compounds and show one or more cardiac metabolism risk factor and/or developing cardiovascular diseases or be in the effective use in the more extensive PATIENT POPULATION in the risk of cardiovascular disease.

In preferred embodiments, described compound is metformin.The existing preparation of metformin be in the news have 30% to 60% mean bioavailability, and a lot of comparable micromolecule has the bioavailability being greater than 60%.See, such as, Tucker etc., " Metforminkinetics in healthy subjects and in patients with diabetes mellitus " Br.J.Clin.Pharmacol.1981,12 (2) 235-246.It should be noted that, metformin use add normal, diabetes with the rodent body of DPP-IV-defect in and the GLP-1 plasma concentration suffering from and do not suffer from the patient body of type ii diabetes, but it is reported this to increase to indirectly and independent of carrying out the direct impact of intestinal L cell.Mulherin etc., the same.

But, as herein prove and contrary with the convention that this area has been established, triggered by the inner chamber signal in the epithelium aspect of intestinal by the enteroendocrine cell activation of metformin, and therefore in fact metformin systemic bioavailability is unnecessary after orally ingestible, so that stimulating gastrointestinal road hormone is as the release of GLP-1.Therefore, the effective treatment suffering from the patient of other contraindication is applicable to the compositions of the minimized biguanide compound of the systemic bioavailability of described compound (comprising its analog, salt, solvate, polymorph, hydrate, N-oxide and prodrug) is carried out by using to comprise now.In preferred embodiments, theme composition and method are formulated into and make the initial release in stomach and/or proximal small bowel (having the region of absorption maximum) minimize and most preferably be to avoid described initial release, to reduce systemic bioavailability when Orally administered.

Be delivered to specific intestinal position

Embodiment as herein described provides a kind of Therapeutic Method, described method comprises the delayed release compositions being formulated the one or more positions being delivered to small intestinal and/or hypomere intestinal and preferred distal small bowel used and comprise biguanide compound (comprising its any analog, salt, solvate, polymorph, hydrate, N-oxide and prodrug), so that by avoiding the absorption of stomach and proximal small bowel and corresponding C _maxquick increase minimizes systemic bioavailability.

Described biguanide compound is targeted to be crossed stomach to one or more region of small intestinal and is preferably targeted duodenal downstream or far-end.In preferred embodiments, described compound is delivered to jejunum, ileum, caecum and colon or its combination.In preferred embodiments, described compound is delivered to jejunum, ileum and caecum or its combination.In preferred embodiments, described compound is preferably delivered to ileum.In further embodiment, described compound is delivered to downstream or the far-end of jejunum or is delivered to hypomere intestinal individually.

In other embodiments, biguanide compound (comprising its analog, salt, solvate, polymorph, hydrate, N-oxide and prodrug) is delivered to one or more region of epimere intestinal and one or more regions of hypomere intestinal.Such as, compound can be delivered to duodenum and colon.In another limiting examples, described compound can be delivered to duodenum, jejunum, ileum and colon.

Biguanide such as metformin realizes to the favored area of intestinal or using of position by any known method.In preferred embodiments, biguanide compound is formulated in the compositions of delayed release, for oral delivery, described oral delivery by described compound delivery to the target area of intestinal or position.When biguanide compound send be targeted two or more regions of gastrointestinal time, compound can any ratio and mode be sent.

Systemic exposure is minimized

As previously discussed, method disclosed herein makes the systemic bioavailability of biguanide compound minimize.In some embodiments, biguanide compound has the average systemic bioavailability of reduction.In some embodiments, and have the release immediately of equivalent biguanide compound or extend compared with delivery formulations, the average systemic bioavailability of reduction is lower average systemic bioavailability.In other embodiments, the average systemic bioavailability of reduction be with have equivalent biguanide compound immediately or extend the average systemic bioavailability that average systemic bioavailability compared with delivery formulations reduces more than 50%, reduce more than 40% or 45%, reduce more than 30% or 35%, reduce and reduce more than 10% or 15% more than 20% or 25%.

In some embodiments, subject methods makes the average blood plasma C of biguanide compound in the patient body suffering from contraindication _maxand/or average A UC level minimizes.In some embodiments, application process causes the minimum Plasma absorption of biguanide compound in patient body, average C _maxand/or average A UC level.In other embodiments, the average blood plasma C of biguanide compound _maxand/or average A UC level discharges immediately with the routine with equivalent metformin and extends the report C of delivery formulations _maxand/or AUC level compares the Asia treatment being regarded as described compositions.Such as, the metformin plasma C of insignificant or sub-treatment _maxand/or (such as, AUC level comprises known metformin preparation deng) 75%, 60%, 50%, 40% and 30% report C _maxand/or AUC level.

In specific embodiments, relate to the invention compositions of metformin and method to produce to be not more than after orally ingestible and isodosely discharge metformin preparation (such as, immediately ) 75% or 85%, be preferably not more than 50% or 60%, more preferably no more than the C of 25% or 30% or 40% _max.In other embodiments, inventive method provides after orally ingestible metformin the last time and is not more than 3x, more preferably no more than 2.5x or 2x, also more preferably no more than the C of the initial minimum plasma concentration of 1.8x or 1.5x for 10 to 12 hours _max.In other embodiments, invention compositions and method provide and are not more than isodose immediate release formulation (such as, after orally ingestible in dosing interval ) 75% or 80%, be preferably not more than 50% or 60%, more preferably no more than the average blood plasma AUC of 25%, 30% or 40%.

Therefore, in specific embodiments, compared with using the same approach of IR or the XR preparation with equivalent biguanide compound, theme delayed release preparation use the average blood plasma AUC, the average blood plasma C that make biguanide compound in the patient body suffering from contraindication _maxand/or circulating plasma concentration minimizes.In one embodiment, by using the biguanide compound average blood plasma AUC caused _0-∞be less than about 15,000ng*h/mL or 14,000ng*h/mL, be preferably less than about 12,000ng*h/mL, 11,000ng*h/mL or 10,000ng*h/mL, be more preferably less than about 9,000ng*h/mL, 8,000ng*h/mL or 7,000ng*h/mL.In one embodiment, the biguanide compound average blood plasma C of gained _maxbe less than about 1000ng/mL, be preferably less than about 900ng/mL or 800ng/mL, be more preferably less than about 700ng/mL, 600ng/mL or 500ng/mL.In one embodiment, in patient body, the biguanide compound circulating plasma concentration of gained is lower than about 5 μ g/ml or 4 μ g/ml, preferably lower than about 3 μ g/ml or 2.5 μ g/ml, more preferably less than about 2 μ g/ml, 1 μ g/ml, 0.5 μ g/ml or 0.25 μ g/ml.In preferred embodiments, described biguanide compound is metformin, and IR compositions is and XR compositions is

Other activating agent

As above, the oral dosage form of fixed dosage is contained in the present invention, the conventional formulation of the delayed release preparation of metformin or other biguanide compound and suitable at least one statin and the other activating agent of the other activating agent of at least one, more preferably at least two kinds, more preferably at least three kinds or four kinds of other activating agents combines by described dosage form, and described activating agent comprises such as antihypertensive, antiplatelet drug, diuretic, bile acid chelating agent, incretin analogies, oral antidiabetic, anti-obesity medicine and antiatherosclerotic.These combination dosage forms provide additional and/or collaborative effect, thus cause compared with the known treatment agent of low dosage, compositions as herein described or the needs of the two.The additional benefit of combination treatment comprises the reduction toxicity relevant with any known therapies.

Such as Beta receptor blockers (atenolol is comprised for applicable antihypertensive of the present invention, betaxolol, metoprolol, nadolol, nebivolol, oxprenolol, pindolol, Propranolol, timolol etc.), α-1 blocker (alfuzosin, arotinolol, doxazosin, indoramine, thymoxamine, phenoxybenzamine, phentolamine, prazosin, silodosin, tamsulosin, terazosin, tolazoline, trimazosin), α-2 agonist (apraclonidine, brimonidine, clonidine, guanabenz, guanfacine, lofexidine, first clonidine, α/β-blocker (the bucindolol of mixing, carvedilol, labetalol etc.), calcium channel blocker is as dihydropyridine (amlodipine, felodipine, isradipine, lercanidipine, nicardipine, nifedipine, nimodipine, nitrendipine etc.) and non-dihydropyridine (diltiazem, verapamil etc.), renin inhibitor (aliskiren), ACE inhibitor (captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, trandolapril, benazepril etc.), angiotensin ii receptor antagonist (Candesartan, Eprosartan, irbesartan, losartan, Olmesartan, telmisartan, valsartan etc.) etc.These medicaments are prepared usually for discharging immediately, although also can use prolongation and/or delayed release.

Such as cyclooxygenase-2 inhibitors (aspirin (aspirin), aloxiprin, carbasalate calcium, indobufen, triflusal etc.), adp receptor inhibitor (clopidogrel, ticlopidine, ticagrelor etc.), phosphodiesterase inhibitor (cilostazol etc.), gland reuptake inhibitor (dipyridamole etc.), thromboxane synthetase or acceptor inhibitor (G-137, Leimaquban, terbogrel etc.), anagrelide, prasugrel, cloricromen etc. are comprised for applicable antiplatelet drug of the present invention.These medicaments are prepared usually for discharging immediately, although also can use prolongation and/or delayed release.

Such as medullary loop diuretic (bumetanide, etacrynic acid, furosemide, torasemide etc.), thiazide diuretic (epitizide, hydrochlorothiazide, chlorothiazide, bendroflumethiazide etc.), thiazine sample diuretic (indapamide, chlortalidone, metolazone etc.), Potassium-sparing diuretic (amiloride, triamterene, spironolactone etc.) etc. are comprised for applicable diuretic of the present invention.These medicaments are prepared usually for discharging immediately, although also can use prolongation and/or delayed release.

Such as colestyramine, colesevelam, colestipol etc. are comprised for applicable cholic acid chelating agent of the present invention.These medicaments are prepared usually for discharging immediately, although also can use prolongation and/or delayed release.

Comprise such as peptide class and non-peptide class GLP-1 analogies for applicable incretin analogies of the present invention and reinforcing agent (to comprise, such as, the allosteric activation agent of GLP-1 receptor), peptide and non-peptide PYY analogies, peptide and non-peptide class Leptin antagonist etc.These medicaments are prepared usually for discharging immediately, although also can use prolongation and/or delayed release.

Applicable oral antidiabetic for using with combination with metformin in this compositions and method comprises such as sulfonylurea (glibenclamide, glimepiride, glipizide, gliclazide, glyclopyramide, gliquidone, tolbutamide, acetohexamide, tolazamide, chlorpropamide, carbutamide etc.), non-sulfonylurea (repaglinide, Nateglinide etc.), thiazolidinediones (rosiglitazone, pioglitazone, carry out lattice row ketone, troglitazone, ciglitazone, darglitazone, netoglitazone, englitazone etc.), two PPAR agonist (such as, aleglitazar, farglitazar, Mo Geta azoles, for Ge Liezha, telmisartan etc.), dipeptidyl peptidase-4 inhibitors (vildagliptin, sitagliptin, BMS-477118, Li Gelieting, Egelieting, septagliptin, berberine etc.), sodium glucose co-transporter 2 white 1 or 2 (SGLT1 or SGLT2) inhibitor (Kan Gelie piperazine, empagliflozin, dapagliflozin, LX4211 etc.), meglitinides (Nateglinide, repaglinide etc.), Alpha-glucosidase inhibitor (acarbose, miglitol, voglibose etc.), GPR119 agonist (cannabinoid, AR-231, 453, MBX-2982, Oleoyl monoethanolamide, PSN-365, 963, PSN-632, 408, Palmitylethanolamide etc.), GPR120 agonist (omega-fatty acid, include but not limited to, a-linolenic acid, clupanodonic acid, docosahexenoic acid, eicosatrienoic acid, eicosatetraenoic acid, eicosapentaenoic acid, 21 carbon 5 alkene acids, hiragonic acid, parinaric acid, nisioic acid, tetracosa carbon pentaene acid etc.), and GPR40, GPR41 and GPR43 agonist (such as free fatty, comprise short, in, saturated and the unsaturated fatty acid of long-chain).These medicaments are prepared usually for discharging immediately, although also can use prolongation and/or delayed release.

Applicable GPR40, GPR41 and GPR43 agonist is also described in following publication and patent application: Stoddart LA, Smith NJ, Milligan G.International Unionof Pharmacology.LXXI.Free fatty acid receptors FFA1,-2, and-3:pharmacology and pathophysiological functtons Pharmacol Rev. (2008) Dec; 60 (4): 405-417; Trond Ulven.Short-chain free fatty acid receptorsFFA2/GPR43 and FFA3/GPR41 as new potential therapeutic targetsFront Endocrinol (Lausanne) (2012); 3:111; WO/2012/147516-Cydic amide derivatives; The 3-hydroxyisothiazole 1-oxide derivative that WO/2012/147518-is new; The compound that ortho position-fluorine that WO/2012/136221-is used for the treatment of metabolic disease replaces; WO/2012/072691-indanyl oxo-dihydro benzofuranacetic acid; WO/2012/046869-Cydic amide derivatives; The hydroxy phenyl hexynic acid that WO/2012/010413-aryloxy-alkylidene replaces, for generation of its method and its purposes as medicine; The agonist of WO/2012/011125-GPR40; WO/2012/004269-(2-aryloxy-acetylamino)-phenyl-propionic derivant, for generation of its method and its purposes as medicine; WO/2011/161030-have the heterocyclic substituted of oxo base methoxyphenyl derivative, for generation of its method and its purposes as GPR40 receptor modulators; 3-hydroxyl-5-aryl the Isothizole derivatives that WO/2011/078371-is new; The fat substitute that WO/2011/069958-is low in calories; 3-hydroxyl-5-Fang isoxazole the derivant that WO/2011/052756-is new; WO/2011/044073-pyrrolidine GPR40 regulator; The new fused ring compounds of WO/2010/143733-with and uses thereof; WO/2010/123016-carboxylic acid compound; WO/2010/123017-tetrazole compound; WO/2010/091176-contains the antidiabetic compound of phthalazines; WO/2010/085522-contains the antidiabetic compound of five fluorine sulfolane; WO/2010/085528-bridging and the antidiabetic compound condensed; WO/2010/085525-bridging and the heterocycle antidiabetic compound condensed; WO/2010/045258-volution GPR40 regulator; WO/2010/012650-is used for the treatment of the compound of metabolic disease; WO/2009/058237-diabetes tricyclic compound; WO/2009/054423-oxadiazole dione compounds (Oxadiazolidinedionecompound); WO/2009/054423-oxadiazole dione compounds; WO/2009/054390-thiazolidinedione compound; The biphenyl GPR 40 modulators that WO/2009/048527-replaces; The long-chain fatty acid derivative compound that WO/2009/038204-is new and containing this compound as the receptor stimulating agent of the G-albumen-coupling of active component; The receptor stimulating agent of WO/2008/139987-G-Protein Conjugation; The biphenyl phenoxy group that WO/2008/130514-replaces-; Thiophenyl-and aminophenyl propanoic acid GPR40 regulator; WO/2008/066097-carboxylic acid derivates; WO/2008/054675-anti-diabetic dicyclic compound; WO/2008/054674-anti-diabetic dicyclic compound; WO/2008/030520-heterocycle GPR40 regulator; WO/2008/001931-fused ring compounds; WO/2007/136572-anti-diabetic dicyclic compound; WO/2007/136573-anti-diabetic dicyclic compound; WO/2007/123225-oxadiazole dione compounds; WO/2007/049050-is used for the treatment of the GPR40 regulator of diabetes; WO/2007/013689-cyclopropane carboxylic acid compound; WO/2007/013689-cyclopropane carboxylic acid compound; WO/2006/083781-anti-diabetic dicyclic compound; WO/2006/083612-anti-diabetic dicyclic compound; WO/2006/038738-receptor function modulator; WO/2006/011615-is used for the treatment of diabetes; WO/2005/095338-alkoxypropan acid derivative; WO/2005/087710-aminophenyl propanoic derivatives; WO/2005/063729-3-(4-benzyloxy-phenyl) propanoic derivatives; WO/2005/063725-benzyl propionate derivant; WO/2005/051890-is as the aminophenyl cyclopropyl-carboxylic acid of the agonist of GPR40 and derivant; WO/2004/106276-fused ring compound; WO/2004/072650-is used for diagnostics and the therapy of the disease relevant with g protein coupled receptor 40 (GPR40); WO/2004/041266-function of receptors controlling agent; WO/2006/102653-is used for the treatment of the method and composition of the disease of insulin resistance and fat induction; WO/2006/052566-is used for the treatment of GPR41 and its regulator of insulin-related disorders; WO/2004/038421-is used for diagnostics and the therapy of the disease relevant with human g-protein coupled receptor 41 (GPR41); The discriminating of the regulator of WO/2001/061359-GPR41 or GPR42 activity; WO/2011/151436-is as the nitrogen heterocyclic derivative (Azepin-derivatives as derivatives as G-protein coupled receptor (GPR43) agonists) of g protein coupled receptor (GPR43) agonist derivatives; The amino acid derivativges that WO/2011/092284-is new and its purposes as GPR43 receptor modulators; WO/2011/073376-is used in treatment metabolic disorder as the pyrrolidine of the agonist of g protein coupled receptor 43 (GPR43) or thiazolidine carboxylic acid's derivant, pharmaceutical composition and using method; WO/2006/102653-is used for the treatment of the method and composition of the disease of insulin resistance and fat induction; WO/2006/036688-is used for the treatment of GPR43 and its regulator of metabolic-related disorders; WO/2004/038405-is used for diagnostics and the therapy of the disease relevant with g protein coupled receptor 43 (GPR43); WO/2003/057730-be used for g G-protein linked receptor GPR43 part with and uses thereof; WO/2000/028083-mice 7-transmembrane receptor GPR43; Every a document by reference entirety is incorporated to herein.These medicaments are prepared usually for discharging immediately, although also can use prolongation and/or delayed release.

Applicable GPR119 agonist is described in following patent application: the regulator of WO/2013/055910-GPR119 receptor and the treatment of disease related to this; WO/2013/011402-GPR119 regulator; WO/2012/173174-aza spiro alkane hydrocarbon compound; WO/2012/173174-aza spiro alkane hydrocarbon compound; WO/2012/168315-is used for the treatment of the piperidines of the replacement of metabolic disorder as GPR119 regulator; The regulator of WO/2012/170702-GPR119 receptor and the treatment of disease related to this; WO/2012/154009-Thienopyrimidine derivative; Its pharmaceutically acceptable salt; For the preparation of the method for Thienopyrimidine derivative; And contain Thienopyrimidine derivative as active component for preventing or treat the pharmaceutical composition of diabetes related diseases; The regulator of WO/2012/145603-GPR119 receptor and the treatment of disease related to this; The regulator of WO/2012/145361-GPR119 receptor and the treatment of disease related to this; The regulator of WO/2012/145604-GPR119 receptor and the treatment of disease related to this; The regulator of WO/2012/135570-GPR119 receptor and the treatment of disease related to this; WO/2012/123449-is as the N-cyclopropyl-N-piperidyl Benzoylamide of GPR119 regulator; WO/2012/111995-is as the 9 oxime derivate of GPR119 agonist; WO/2012/103806-is as the bicyclic heteroaryl compounds of GPR119 receptor stimulating agent; What WO/2012/098217-was used for the treatment of diabetes, obesity and associated conditions as GPR119 regulator condenses dihydrofuran; WO/2012/093809-regulates g protein coupled receptor for regulating the new dicyclic compound of g protein coupled receptor; What WO/2012/080476-was used for the treatment of diabetes, obesity and relevant disease as GPR119 regulator condenses dihydropyran; WO/2012/077655-has the Spirocyclic derivatives of GPR119 agonist activity; WO/2012/069948-is as 4-(5-cyano-pyrazol-1-the base)-piperidine derivative of GPR119 regulator; WO/2012/069917-dicyclo GPR119 regulator; WO/2012/046792-GPR119 agonist; The GPR119 agonist that WO/2012/046249-is new; WO/2012/041158-tricyclic compound, its preparation method and medicinal usage; The regulator of WO/2012/040279-GPR119 receptor and the treatment of disease related to this; WO/2012/037393-is as the lactams of the piperidyl-replacement of GPR119 regulator; WO/2012/025811-is as the indyl pyrimidine of GPR119 regulator; The Pyridione derivatives that WO/2012/011707-replaces and for the preparation of its method; WO/2012/006955-is used for the treatment of the compound of metabolic disorder; WO/2011/159657-bicyclic heterocycle derivatives and its using method; The quinazoline compound that WO/2011/148922-is new; WO/2011/147951-is as the ring aminoderivative of GPR119 agonist; The lactams that WO/2011/146335-replaces as the piperidyl of GPR119 regulator; Pyrrolo-[2, the 3-d] pyrimidine compound that WO/2011/145718-is new; WO/2011/140160-is as the bicyclic heteroaryl compounds of GPR119 regulator; WO/2011/138427-is as the 2H-Pyridazin-3-one of GPR119 agonist; WO/2011/140161-is as the benzofuranyl analog of GPR119 regulator; 5-(pyrrolidine-1-carbonyl) pyrrolidine that the 3-that WO/2011/128394-is used for the treatment of metabolic disorder replaces and its derivant; Amino 4-(pyrrolidine-1-carbonyl) pyrrolidine of 3-that the N-that WO/2011/128395-is used for the treatment of metabolic disorder replaces and its derivant; The regulator of WO/2011/127051-GPR119 receptor and the treatment WO/2011/127106-of disease related to this are as the pyrimidine radicals piperidyl oxo pyridine keto analog of GPR119 regulator; WO/2011/113947-is used for the treatment of the GPR119 agonist of diabetes and related pathologies and the combination of dpp-iv inhibitor BI 1356; WO/2011/093501-GPR119 agonist; WO/2011/078306-GPR119 agonist; The biaryl derivatives that WO/2011/066137-replaces and its using method; WO/2011/061679-is as the imidazolopyrazole of GPR119 inhibitor; WO/2011/055770-condensed heterocyclic compouds; WO/2011/053688-bridging bicyclic piperidine derivatives and its using method; WO/2011/044001-is as the compound of GPR119 active regulator and compositions; WO/2011/036576-GPR119 regulator; WO/2011/030139-is as 4-(the pyrimidine-2-base)-piperazine of GPR119 regulator and 4-(pyrimidine-2-base)-piperidine derivative; WO/2011/025006-GPR119 agonist; WO/2011/014520-is as the compound of the regulator of GPR119 activity and compositions; WO/2011/008663-GPR119 agonist; WO/2011/005929-piperidine derivative and its be used for the treatment of the purposes of diabetes and obesity; WO/2010/140092-is as 1-(the piperidin-4-yl)-pyrazole derivatives of GPR119 regulator; WO/2010/128414-GPR119 regulator; WO/2010/128425-GPR119 regulator; WO/2010/123018-diaza spiro alkane derivatives; WO/2010/106457-3-oxo-7-azabicyclo [3.3.1] nonane; WO/2010/103334-is used for the treatment of the compound of metabolic disorder; WO/2010/103333-is used for the treatment of the compound of metabolic disorder; WO/2010/103335-is used for the treatment of the compound of metabolic disorder; WO/2010/095663-condensed heterocyclic compouds; WO/2010/088518-is used for the treatment of the GPR119 heterocyclic modulators of disease; Pyrrolo-[2, the 3-d] pyrimidine compound that WO/2010/084944-is new; WO/2010/074271-is used for the therapeutic agent of diabetes; WO/2010/048149-is used for the treatment of the GPR119 heterocyclic modulators of disease; WO/2010/029089-is used for the treatment of the combination treatment of diabetes and related pathologies; WO/2010/013849-GPR119 agonist; WO/2010/008739-aryl GPR 119 agonists with and uses thereof; WO/2010/009195-bicyclic heterocycle derivatives and its purposes as GPR119 regulator; WO/2010/009183-is as the pyridone of GPR119 regulator and pyridazone analog; WO/2010/006191-is as the 4-phenoxymethyl piperidine of GPR119 active regulator; WO/2010/004348-heterocyclic gpcr agonists; WO/2010/004347-heterocyclic gpcr agonists; WO/2010/001166-is as the triazole derivative of GPR119 regulator; The GPR119 regulator that WO/2009/150144-is new; WO/2009/141238-GPR119 receptor stimulating agent; WO/2009/143049-bicyclic heterocycle derivatives and its purposes as GPR119 regulator; WO/2009/126245-uses g protein coupled receptor to differentiate to be applicable to treat PYY (PYY) sercretogogue of condition of illness that regulated by PYY and the method for compound; WO/2009/126535-is as the compound of GPR119 active regulator and compositions; WO/2009/123992-formaldehyde aryl compound with and uses thereof; WO/2009/117421-is used for the treatment of the GPR119 heterocyclic modulators of disease; WO/2009/106561-is used for the treatment of the pyrazine compound of GPR119 associated conditions; WO/2009/106565-GPR119 agonist; WO/2009/105715-is as the compound of GPR119 active regulator and compositions; WO/2009/105722-is as the compound of GPR119 active regulator and compositions; WO/2009/105717-is as the compound of GPR119 active regulator and compositions; WO/2009/055331-bicyclic heterocycle derivatives and its purposes as GPR119 active regulator; WO/2009/050522-azetidinyl G-protein-coupled receptor agonists; WO/2009/050523-azetidinyl G-protein-coupled receptor agonists; WO/2009/038974-is as the compound of GPR119 active regulator and compositions; WO/2009/034388-is used for the treatment of the compound of metabolic disorder; WO/2009/014910-is used for the treatment of the cyclosubstituted pyrroles of N-azepine of diabetes and metabolic disorder, pyrazoles, imidazoles, triazole and terazole derivatives as RUP3 or GPR119 receptor stimulating agent; WO/2009/012277-is for regulating the method for GPR119G G-protein linked receptor and selected compound; WO/2009/012275-pyridone GPR 119 g protein-coupled receptor agonists; WO/2008/137436-[6,5]-bicyclic gpr 119 g protein coupled receptor agonists; WO/2008/137435-[6,6] and [6,7]-bicyclic gpr 119 g protein coupled receptor agonists; WO/2008/130584-pyrimidone derivatives and its using method; WO/2008/130581-pyrimidone derivatives and its using method; WO/2008/130615-tetrahydropyridine is [4,3-d] pyrimidone derivatives and its using method also; WO/2008/109702-is as the compound of GPR119 active regulator and compositions; WO/2008/097428-is as the compound of GPR119 active regulator and compositions; WO/2008/025799-is used for the treatment of the pyridazine compound of GPR119 associated conditions; WO/2008/025798-is used for the treatment of the pyridine compounds of GPR119 associated conditions; WO/2008/025800-is used for the treatment of the pyrimidine compound of GPR119 associated conditions; WO/2008/008887-is used for the treatment of the GPR119 agonist of metabolic disorder; WO/2008/008895-is used for the treatment of the GPR119 agonist of diabetes and associated conditions; WO/2007/120702-is for increasing bone amount and be used for the treatment of the purposes of the GPR119 receptor stimulating agent of osteoporosis; And relative combination treatment; WO/2007/120689-uses GPR119 receptor to differentiate the method for the compound being applicable to the bone amount increased in individuality; WO/2007/116229-heterocyclic gpcr agonists; WO/2007/116230-is as the heterocyclic butane derivant of g protein coupled receptor (GPR119) agonist; WO/2006/076231-is used for the treatment of diabetes and condition of illness related to this and is used for the treatment of the combination treatment by increasing the condition of illness that blood glp-1 level improves; Every a patent all by reference entirety is incorporated to herein.These medicaments are prepared usually for discharging immediately, although also can use prolongation and/or delayed release.

Applicable GPR120 agonist is described in following patent application: WO/2012/058649-is along the compositions of 3,4-dihydroxy-2-(3-methylbutyryl base)-5-(-3-methyl butyl)-4-(4-methylvaleryl) ring penta-2-alkene-1-ketone derivatives, substantially enantiomer-pure and method; WO/2011/159297-GPR120 receptor stimulating agent with and uses thereof; WO/2011/072132-treats the method for inflammatory conditions; WO/2010/080537-GPR120 receptor stimulating agent with and uses thereof; WO/2010/048207-aryl GPR120 receptor stimulating agent with and uses thereof; The new isoxazole derivatives of WO/2009/147990-; WO/2009/125804-screening method; The long-chain fatty acid derivative compound that WO/2009/038204-is new and containing this compound as the G-protein-coupled receptor agonists of active component; WO/2008/139987-G-Protein Conjugation receptor stimulating agent; WO/2008/103500-is as the thiazole of g protein coupled receptor regulator; The phenyl-isoxazol-3-ol derivant that WO/2008/066131-is new; The GPR120 Active Regulation of WO/2007/134613-in adipose cell/fatty tissue; WO/2007/026874-is for using GPR120 and the method for phospholipase screening to the effective material of disease; WO/2007/014824-fat taste receptors and its using method; Every a patent all by reference entirety is incorporated to herein.These medicaments are prepared usually for discharging immediately, although also can use prolongation and/or delayed release.

Such as orlistat (Zenical) is drawn together for applicable anti-obesity medicated bag of the present invention, chlorine Ka Selin (Belviq), sibutramine (Meridia), Rimonabant (Acomplia), Exenatide (Byetta and Bydureon), Pramlintide (Symlin), Fen-Phen, Redux, ZGN-433, phentermine/topiramate (Qsymia), naltrexone/amfebutamone (Contrave), and alternative medicine option, these medical science options comprise such as puts together linoleic acid, green tea extract, khat, thioctic acid, ephedrine (Ephedrine Caffeine Stack), raspberry ketone etc.These medicaments are prepared usually for discharging immediately, although also can use prolongation or delayed release.

The atherosclerotic compound that can reduce and depend on other risk factor and change is comprised for applicable antiatherosclerotic of the present invention, the inhibitor of such as fish oil and proprotein convertase subtilisin/kexin 9 type (PCSK9) is (as AMG145 (Amgen), 1D05-IgG2 (Merck & Co.) and SAR236553/REGN727 (Aventis/Regeneron)), simulate in conjunction with the LDLR of PCSK9 peptide (such as, Shan etc. (2008) Biochem.Biophys.Res.Commun.375:69-73) and exonuclease treatment agent (such as Graham etc. (2007) the J.Lipid Res.48:763-7 of targeting PCSK9, Lindholm etc. (2012) Mol.Ther.20:376-81).

What also contain as other activating agent is the compound changing HDL/LDL ratio, comprises other regulator etc. of such as nicotinic acid, acipimox, MK-0354, GPR81, GPR109A, GPR109B.The applicable regulator of GPR81, GPR109A and GPR109B is described in following paper and patent application: Offermanns S, Colletti SL, Lovenberg TW, Semple G, Wise A, IJzerman AP.International Union of Basic andClinical Pharmacology.LXXXII:Nomenclature and Classification ofHydroxy-carboxylic Acid Receptors (GPR81, GPR1094, and GPR109B) Pharmacol Rev. (2011) June; On March 31st, 63 (2): 269-90.doi:10.1124/pr.110.003301.Epub 2011; WO/2010/030360-is applicable to 3H-imidazo [4, the 5-b] pyridine-5-01 derivatives for the treatment of GPR81 receptor disease; WO/2008/063321-GPR81-ligand complex and its preparation and purposes; WO/2011/057110-is used for the treatment of the GPR109A agonist of cerebral ischemia; WO/2011/044136-fatty acid acipimox derivant with and uses thereof; WO/2011/044139-fatty acid acifran derivant with and uses thereof; WO/2011/028689-fatty acid niacin conjugate with and uses thereof; WO/2009/033078-is for controlling compositions and the method for cholesterol levels; WO/2008/144423-is used for the treatment of the compositions comprising GPR109 part of digestive pathologies and/or cancer; WO/2007/021744-is for determining the method with the probability of the unfavorable of nicotinic acid receptor agonists or favourable reaction; WO/2009/151542-niacin receptor part; The method of WO/2006/127595-5-amino-pyrazol carboxylic acid derivates and its treatment metabolic-related disorders; WO/2006/069242-fused pyrazole derivatives and its treatment metabolic-related disorders method in purposes; The method of WO/2005/051937-4-oxo-4,5-dihydro-furan-2-carboxylic acid derivates and its treatment metabolic-related disorders; The method of WO/2005/044816-terazole derivatives and its treatment metabolic-related disorders; WO/2005/028488-is for regulating heterocycle phosphinyl and the sulfo-phosphinyl compound of glucose, triglyceride and LDL/HDL level; 2h-pyrazoles-3-the carboxylic acid derivates that the 5-that WO/2005/011677-is used for the treatment of dyslipidemia and relevant disease as the agonist of niacin receptor RUP25 replaces; WO/2004/033431-is used for the hydroxypyrazoles for metabolic-related disorders; WO/2004/032928-is used for the treatment of as the agent of lipotropism solution 2H-pyrazoles (the pyrazone)-3-carboxylic acid derivates that metabolic-related disorders replaces as the 5-of dyslipidemia; Every a document all by reference entirety is incorporated to herein.These medicaments are prepared usually for discharging immediately, although also can use prolongation and/or delayed release.

In an alternate embodiment, theme composition and method and psychosis or there is inducing weight to increase and/or the antidepressants of tendency of prediabetes and diabetes are combined and use.Applicable psychosis for using with theme composition and methods combining comprises such as haloperidol (Haldol, Serenace), droperidol (Droleptan, Inapsine), chlorpromazine (Thorazine, Largactil), fluphenazine (Prolixin), perphenazine (Trilafon), prochlorperazine (Compazine), thioridazine (Mellaril), trifluoperazine (Stelazine), mesoridazine (Serentil), periciazine, promazine, triflupromazine (Vesprin), methotrimeprazine (Nozinan), promethazine (Phenergan), pimozide (Orap), cyamemazine (Tercian), chlorprothixene (Cloxan, Taractan, Truxal), clopenthixol (Sordinol), flupentixol (Depixol, Fluanxol), tiotixene (Navane), zuclopenthixol (Cisordinol, Clopixol, Acuphase), clozapine (Clozaril), olanzapine (Zyprexa), risperidone (Risperdal), Quetiapine (Seroquel), Ziprasidone (Geodon), amisulpride (Solian), asenapine (Saphris), Paliperidone (Invega), iloperidone (Fanapt, Fanapta, and be called Zomaril in the past), zotepine (Nipolept, Losizopilon, Lodopin, Setous), Sertindole (Serdolect and Serlect, Mexico), Lurasidone (Latuda), Aripiprazole (Abilify), the partial agonist of dopamine receptor, cannabidiol, tetrabenaine, mglur 2 agonist (such as, LY2140023), glycine transporter 1 inhibitor (such as RG1678), L-threonine etc.These medicaments are prepared usually for discharging immediately, although also can use prolongation and/or delayed release.

Have inducing weight increase and/or prediabetes and diabetes tendency for comprising such as citalopram (Celexa) with the applicable antidepressants of theme composition and methods combining, escitalopram (Lexapro, Cipralex), paroxetine (Paxil, Seroxat), fluoxetine (Prozac), fluvoxamine (Luvox), Sertraline (Zoloft, Lustral), atomoxetine (Strattera), reboxetine (Edronax), viloxazine (Vivalan), mianserin (Tolvon), mirtazapine (Remeron, Avanza, Zispin), desmethylvenlafaxine (Pristiq), duloxetine (Cymbalta), midalcipran (Ixel, Savella), venlafaxine (Effexor), etoperidone (Axiomin, Etonin), nefazodone (Serzone, Nefadar), trazodone (Desyrel), norepinephrine-dopamine reuptake inhibitor, BUP (Wellbutrin, Zyban), tianeptine (Stablon, Coaxil, Tatinol), peace miaow how fourth, agomelatine (Valdoxan, Melitor, Thymanax), amitriptyline (Elavil, Endep), Clomipramine (Anafranil), doxepin (Adapin, Sinequan), imipramine (Tofranil), trimeprimine (Surmontil), desipramine (Norpramin), nortriptyline (Pamelor, Aventyl, Noritren), protriptyline (Vivactil), isocarboxazid (Marplan), moclobemide (Aurorix, Manerix), phenelzine (Nardil), pirlindole (Pirazidol), selegiline (Eldepryl, Emsam), tranylcypromine (Parnate) etc.These medicaments are prepared usually for discharging immediately, although also can use prolongation and/or delayed release.

In certain embodiments, compositions provided herein can use together with the diet auxiliary agent of other commercially available acquisition or other weight saving and/or anti-obesity medicine, described auxiliary agent or medicament be (as an example) PYY and PYY agonist, GLP-1 and GLP-1 agonist, CCK and CCK agonist, insulin secretion accelerating peptide (exendin) and insulin secretion accelerating peptide peptide agonists, GIP and GIP agonist, amylin and amylin agonist, Leptin regulator (such as, inhibitor) and leptin and leptin agonist such as.In some cases, the compositions and amylin, amylin agonist or the analogies that comprise biguanide compound provided in this article combine to use.Exemplary amylin agonist or analogies comprise Pramlintide and related compound.In some cases, compound provided in this article and compositions and leptin, leptin agonist or analogies combine to use.Can use and be incorporated to U.S. Patent No. 7,247 herein by reference, the method described in 427 differentiates other leptin agonist or analogies.In other cases, compound provided herein and compositions increase leptin sensitivity and increase the effect of leptin, leptin agonist or analogies.

Those medicaments of exploitation at present drawn together by the other anti-obesity medicated bag being applicable to subject methods.Other anti-obesity medicated bag draws together phentermine, Fenfluramine, sibutramine, Rimonabant, topiramate, zonisamide, BUP, naltrexone, chlorine Ka Selin (lorcaserin) or relevant sympathomimetic alone or in combination and orlistat or other intestinal lipase inhibitor.Be applicable to treat weight saving, gluttony, food addiction and can use together with compositions as herein described addicted to the therapeutic agent eaten, medicine and compound.Such as, the known other medicines suppressing hunger or appetite control of at least one can be used further to patient.This type of medicine and compound include but not limited to phentolamine (phenteramine), as with other therapeutic agent, medicine and compound are known in the art and contain herein.

Like this, on the other hand, theme composition and method can be used as the part of combination treatment for control, prevention or treatment of obesity or overeating disorders or condition of illness.Compound as a part for the combined therapy for the treatment of of obesity or weight reduction includes but not limited to: the central nervous system agents of affect the nerves mediator or neural ion channel, comprises antidepressant (BUP), NRI (GW320659), selectivity 5HT 2c receptor stimulating agent, Anti-epileptics (topiramate, zonisamide), some dopamine antagonist and cannabinoid-1 receptor antagonist (CB-1 receptor antagonist) (Rimonabant), leptin/insulin/central nervous system path medicament, comprise leptin analog, leptin transhipment and/or leptin receptor promoter, ciliary neurotrophic factor (Axokine (Axokine)), neuropeptide tyrosine and agouti related peptides antagonist, what proopiomelanocortin and cocaine and amfetamine regulated and controled transcribes promoter, the hormone analogs of alpha-melanophore-stimulation, melanocoritin-4 receptor stimulating agent, and affect the medicament of insulin metabolism/activity, described medicament comprises protein-tyrosine phosphatase-1B inhibitor, the receptor-gamma receptor antagonist of peroxisome proliferation activation, the bromocriptine (ergoset) that action time is short, somatostatin agonists (octreotide), and adiponectin/Acrp30 (Famoxin or fatty acid metabolism oxidation inducer), GI nerves path medicament, comprises increase cholecystokinin activity (CCK), PYY is active, NPY is active and PP active, increases those medicaments of glucagon-like-peptide-1 activity (Super-insulinotropic Peptide 4 SIP-4, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], inhibitors of dipeptidyl IV) and reduce those medicaments and the amylin analogs (Pramlintide (pramlintide)) of Leptin activity, the medicament (selectivity 3-3 stimulant/agonist, the homologue of non-coupling protein matter and thryoid receptor agonist) of tranquillization metabolic rate can be increased, other more how different medicament, comprise the hormone antagonist of melanin concentrating, phytostanol analog, functional oil, P57, amylase inhibitor, growth hormone fragment, the synthetic analogues of dehydroepiandrosterone sulfate, the antagonist of adipose cell 11B-hydroxysteroid dehydrogenase 1 type activity, corticotropin releasing hormone agonist, the inhibitor (cerulenin and C75) of fatty acid synthesis, carboxyl peptide enzyme inhibitor, indone/indanol, aminosterol (curvature Kui Ming (trodusquemine)/trodulamine), and other gastrointestinal lipases inhibitor (ATL962), amphetamine, as dexamphetamine, other sympathomimetic epinephrine, comprises phentermine, Benzphetamine, phendimetrazine, Mazindol and diethylpropion.

Other interested activating agent comprises ecopipam (ecopipam); Gut hormone (OM); Pancreotropic hormone polypeptide (GIP) inhibitor of dependence on the glucose; Gastrin. release peptide; Neuromedin B; Enterostatin; Amfebutamone, SR-58611; CP-045598; AOD-0604; QC-BT16; RGLP-1; 1426 (HMR-1426); iSIS-113715; Suo Labeilong (solabegron); SR-147778; Org-34517; Melanotan (melanotan)-II; Cetilistat (cetilistat); C-2735; C-5093; aPD-356; Radar method pungent (radafaxine); Fluorine sterone (fluasterone); GP-389255; 856464; S-2367; AVE-1625; T-71; Oleoyl-estrone; Intranasal PYY [3-36]; Androgen receptor agonist; PYY 3-36; DOV-102677; Tagatose; SLV-319; 1954 (Aventis PharmaAG); Gut hormone, Thiakis; Bromocriptine, PLIVA; Diabetes/hyperlipidemia therapeutic agent, Yissum; CKD-502; Thryoid receptor beta-agonists; β-3 adrenoreceptor agonists; CDK-A agonist; Galanin antagonists; Dopamine D 1/D2 agonist; Melanocortin regulator; Verongamine; Neuropeptide y antagonists; Melanin concentrating hormone receptor antagonists; Two PPAR α/gamma agonist; CGEN-P-4; Inhibitors of kinases; People MCH receptor antagonist; GHS-R antagonist; Leptin receptor stimulating agent; DG70 inhibitor; Can ferrum peaceful (cotinine); CRF-BP inhibitor; Ucn agonist; UCL-2000; According to azamethonium bromide (impentamine); β-3 adrenoceptor; Pentapeptide MC4 agonist; Curvature Kui Ming (trodusquemine); GT-2016; C-75; CPOP; MCH-1 receptor antagonist; RED-103004; Aminosterol; Aricine element (orexin)-1 antagonist; Neuropeptide Y 5 receptor antagonists; DRF-4158; PT-15; PTP enzyme inhibitor; A37215; SA-0204; Glycolipid metabolite; MC-4 agonist; Produlestan; PTP-1B inhibitor; GT-2394; Neuropeptide Y 5 antagonist; Melanocortin-4 receptor modulators; MLN-4760; PPAR gamma/delta double agonists; NPY5RA-972; 5-HT2C receptor stimulating agent; Neuropeptide Y 5 receptor antagonists (phenylurea analog); AGRP/MC4 antagonist; Neuropeptide Y 5 antagonist (benzimidazole); Glucocorticoid resistance agent; MCHR1 antagonist; Acetyl-CoA carboxylase inhibitor; R-1496; HOB1 regulator; NOX-B11; PYY 3-36 (eligen); 5-HT 1 regulator; Pancreatic lipase inhibitor; GRC-1087; CB-1 antagonist; MCH-1 antagonist; LY-448100; Magainin BRS3 agonist; Leptin antagonist; MC4 antagonist; Stearoyl-CoA desaturase regulator; H3 histamine antagonist; The full agonist of PPAR; EP-01492; The lipase inhibitor of hormone-sensitive; FABP4 inhibitor; Thiolactone derivative; Inhibitors of Protein Tyrosine Phosphatase 1 B; MCH-1 antagonist; P-64; PPAR γ part; Melanin-concentrating hormone antagonist; Thiazoles urgees digestive tract power reinforcing medicine; PA-452; T-226296; A-331440; Immune drug vaccine; Diabetes/obesity Remedies (Bioagency, Biofrontera Discovery GmbH); P-7 (Genfit); DT-011M; PTP1B inhibitor; Anti-diabetic peptide conjugate; KATP agonist; Bariatrician agent (Lexicon); 5-HT2 agonist; MCH-1 receptor antagonist; GMAD-1/GMAD-2; STG-a-MD; Neuropeptide y antagonists; Angiogenesis inhibitor; G protein coupled receptor agonist; Nicotine therapeutic agent (ChemGenex); Anti-obesity medicine (Abbott); Neuropeptide tyrosine regulator; Melanin-concentrating hormone; GW-594884A; MC-4R agonist; Histamine H 3 antagonists; Lonely GPCR regulator; MITO-3108; NLC-002; HE-2300; IGF/IBP-2-13; 5-HT2C agonist; ML-22952; Neuropeptide Y receptor antagonist; AZ-40140; Anti-obesity therapeutic agent (Nisshin Flour); GNTI; Melanocortin-4 receptor modulators; Alpha-amylase inhibitor; Neuropeptide Y 1 antagonist; β-3 adrenoreceptor agonists; Ob gene outcome (Eli Lilly & Co.); SWR-0342-SA; β-3 adrenoreceptor agonists; SWR-0335; SP-18904; Oral insulin analogies; β 3 adrenoreceptor agonists; NPY-1 antagonist; β .-3 antagonist; Bariatrician agent (7TM Pharma); 11 beta-hydroxysteroid dehydrogenases (HSD) 1 inhibitor; QRX-431; E-6776; RI-450; Melanocortin-4 antagonist; Melanocortin-4 receptor agonists; Bariatrician agent (CuraGen); Leptin analogies; A-74498; Second filial generation leptin; NBI-103; CL-314698; CP-114271; β-3 adrenoreceptor agonists; NMI 8739; UCL-1283; BMS-192548; CP-94253; PD-160170; Nicotinic agonist; LG-100754; SB-226552; LY-355124; CKD-711; L-751250; PPAR inhibitor; The agent of G-protein for treatment; Bariatrician agent (Amylin Pharmaceuticals Inc.); BW-1229; Monoclonal antibody (ObeSys/CAT); L-742791; (S)-sibutramine; MBU-23; YM-268; BTS-78050; Tubbiness (tubby-like) protein gene; Genome (overeating disorders; Allelix/Lilly); MS-706; GI-264879A; GW-409890; FR-79620 analog; Bariatrician agent (HybrigenicsSA); ICI-198157; ESP-A; 5-HT2C agonist; PD-170292; AIT-202; LG-100641; GI-181771; Anti-obesity therapeutic agent (Genzyme); Leptin regulator; GHRH analogies; Bariatrician agent (Yamanouchi Pharmaceutical Co.Ltd.); SB-251023; CP-331684; BIBO-3304; Cholestene-3-ketone; LY-362884; BRL-48962; NPY-1 antagonist; A-71378; .RTM.-dinor-sibutramine; Amide derivatives; Bariatrician agent (Bristol-Myers Squibb Co.); Bariatrician agent (LigandPharmaceuticals Inc.); LY-226936; NPY antagonist; CCK-A agonist; FPL-14294; PD-145942; ZA-7114; CL-316243; SR-58878; R-1065; BIBP-3226; HP-228; Ta Libeilong (talibegron); FR-165914; AZM-008; AZM-016; AZM-120; AZM-090; Vomer pheromone (vomeropherin); BMS-187257; D-3800; AZM-131; Gene discovery thing (gene discovery) (Axys/Glaxo); sX-013; ERR regulator; Press down thirsty albumen (adipsin); AC-253; A-71623; A-68552; BMS-210285; TAK-677; MPV-1743; Bariatrician agent (Modex); GI-248573; AZM-134; AZM-127; AZM-083; AZM-132; AZM-115; Exopipam; SSR-125180; Bariatrician agent (Melacure Therapeutics AB); BRL-35135; SR-146131; P-57; AZM-140; CGP-71583A; RF-1051; BMS-196085; Manifaxine; Beta-3 agonist; DMNJ (Korea Research Institute of Bioscience and Biotechnology); BVT-5182; LY-255582; SNX-024; Galanin antagonists; Neurokinin-3 agonist; Dexfenfluramine; Mazindol; Diethylpropion; Phendimetrazine; Benzphetamine; Amfebutmone; Sertraline; Metformin; AOD-9604; ATL-062; gT389-255; SLV319; HE-2500; PEG-axokine; L-796568; And ABT-239.

Preparation

As above, the metformin component of combination dosage forms is adjusted for delayed release to make Plasma absorption minimize.Send and can be any known method, comprise such as oral, rectum, nasogastric tube, parental injection such as enteral in tube chamber and inject.In preferred embodiments, subject combination dosage form is Orally administered.The oral delivery of biguanide compound is described and described oral delivery comprises time release delivery system, enteric coating and pH dependence system etc. in delayed release preparation part.In preferred embodiments, when two or more other activating agents are formulated for immediately and/or extend release, after administration biguanide compound is delivered to the some positions of gastrointestinal as duodenum, jejunum, ileum, hypomere intestinal or its combination.Such as, the combination dosage forms comprising biguanide compound discharges component by timing or delay (enteric) and is delivered to hypomere intestinal, and simultaneously other activating agent discharges immediately when absorbing.In preferred embodiments, combination dosage forms of the present invention is that the unit dosage form of fixed dosage is if double-deck or three layers or multilayer tablet or many particle form are as encapsulated micro-tablet or granule.

In some embodiments, delayed release component discharges biguanide compound due to enteric coating after required pH starts.The pH contained comprises about pH 5.0 or about pH 5.5, more preferably from about pH 6.0, about pH 6.5 and about pH 7.0.After required pH starts, described compound starts release.Such composition can discharge biguanide compound and/or can have in the timing of (1 hour according to appointment, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours or about 8 hours) release biguanide compound in one section of long period section, prolongation or slow releasing after required pH starts in about 15 minutes, about 20 minutes, about 25 minutes or about 30 minutes.In some embodiments, exemplary two kinds of component delivery systems can be bilayer or tri-layer tablets.Three kinds, four kinds and additional component is contained in embodiment.

For the delayed release preparation comprising biguanide compound, the dosage range of compound can be and is about 1mg to about 1000mg, about 10mg to about 950mg, about 50mg to about 900mg or about 100mg or about 800mg from every day.In some cases, the dosage of described compound is be about 800mg, about 700mg, about 600mg, about 500mg, about 400mg, about 300mg, about 250mg, about 200mg, about 150mg, about 100mg, about 75mg, about 50mg, about 25mg, about 10mg or about 1mg every day.In some embodiments, the dosage of described compound is less than 400mg.In some embodiments, the dosage of described compound is 250mg.

The salt of biguanide compound includes but not limited to, hydrochlorate, phosphate, sulfate, hydrobromate, Salicylate, maleate, benzoic acid salt, succinate, esilate, fumarate, oxyacetate, embonate, Orotate, acetate, isobutyrate, acetylsalicylate, nicotinate, Buddha's warrior attendant hydrochlorate, chlorophyll zinc salt, carboxylate, benzoate, dichloroacetate, theophylline-7-acetate, clofibrate (clofibrate), tartrate, oxalates, tannate and hydroxy-acid salt.In preferred embodiments, described salt is metformin hydrochloride.

Preparation for compositions provided herein comprises those preparations being applicable to oral or rectal administration, although the most applicable path can be depending on condition of illness and the disease of such as receiver.Described compositions can preferably provide with unit fixed dosage form and prepared by any method known by art of pharmacy.All methods comprise by active component with form one or more must the step of carrier combinations of composition.

Be applicable to the discrete unit that Orally administered preparation can be used as the active component separately containing scheduled volume, described discrete unit is as capsule, cachet or tablet; As powder or granule; As the solution be in liquid, aqueous or anhydrous liquid or suspension; Or provide as oil-in-water liquid emulsion or water-in-oil liquid emulsion.

The composite preparation that can orally use comprises tablet, fit (push-fit) capsule and the soft seal capsule be made up of gelatin and plasticizer (as glycerol or sorbitol) be made up of gelatin.Tablet is by optionally carrying out suppressing with one or more auxiliary elements or prepared by molding.

The tablet of compacting is prepared by suppressing the active component of free-flowing form (as powder or granule) in the machine be applicable to, optional and the binding agent of described active component (such as, polyvidone, gelatin, hydroxypropyl methylcellulose), inert diluent, antiseptic, disintegrating agent (such as, sodium starch glycolate, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose) or lubricant, surfactant or dispersant.The tablet of molding by carrying out molding to prepare to the mixture of the powder compound with inert liquid diluent moistening in the machine be applicable to.That tablet can be optional coating or indentation and can be formulated to provide active component that is slow or controlled release wherein.Tablet optionally can be provided with enteric coating to provide release in the part of intestinal instead of gastric.The dosage being applicable to this type of and using all is should be for Orally administered all preparations.Described fit capsule can containing the active component mixed as Talcum or magnesium stearate and optional stabilizer as starch and/or lubricant as lactose, binding agent with filler.In soft capsule, reactive compound solubilized or be suspended in suitable liquid as in fatty oil, liquid paraffin or liquid macrogol.In addition, stabilizing agent can be added.Dragee core core provides suitable coating.For this purpose, can use the sugar juice concentrated, described sugar juice optionally can contain Radix Acaciae senegalis, Talcum, polyvinylpyrrolidone, carbopol gel, Polyethylene Glycol and/or titanium dioxide, paint solution and the organic solvent be applicable to or solvent mixture.Dyestuff or pigment can be added in tablet or dragee coatings for differentiating or characterize different active compound doses combinations.

Should be understood that compound as herein described and compositions can comprise other common medicament of this area relevant with discussed preparation type, and being such as applicable to those Orally administered compositionss can comprise flavoring agent except the composition mentioned especially above.

Compositions as herein described also can comprise the biguanide compound being in and being applicable to orally use form, described form such as tablet, lozenge, lozenge, aqueous or oil-based suspension, dispersibles powder or granule, emulsion, hard capsule or soft capsule or syrup or elixir.Be intended for the compositions orally used to prepare according to any method for the manufacture of pharmaceutical composition known in the art, and such composition can comprise one or more is selected from reagent as the sweetener of limiting examples, flavoring agent, coloring agent and antiseptic, to provide pharmaceutical elegant and good to eat preparation.

Delayed release preparation

Can seek a lot of strategy to obtain delayed release, the position wherein discharged is controlled to make systemic Absorption minimize.Such as, by suitably selecting formulation parameters and composition (such as, suitable Co ntrolled release compositions and coating) to obtain delayed release.Example comprises single or multiple unitary tablet or capsule composition, oil solution, suspension, emulsion, microcapsule, microsphere, nanoparticle and liposome.When the early release of another kind of combined therapy agent is better than another kind, releasing mechanism can be controlled to make with certain hour interval release biguanide compound or Co ntrolled release position, the release of combination medicament can be simultaneously, or the delayed release of biguanide compound in combination can be affected.Different delivery system as herein described also can with at multiple interval (such as, Orally administered after about 30 minutes, about 120 minutes, about 180 minutes and about 240 minutes) or diverse location (such as, hypomere intestinal, epimere intestinal, jejunum, ileum, caecum, colon and/or rectum place release) or its combination under start release combination.Such as, the system that pH relies on can with time release delivery system or other system in combination any as herein described to realize required release characteristics.

In preferred embodiments, biguanide compound be configured in activating agent other with two or more in unit dosage form immediately and/or extend the delayed release component discharging component in conjunction.By any known method preparation immediate-release component, as surrounded the layer of a part for delayed release component or analog.The exemplary ratios of the additional therapeutic agent discharged immediately and the biguanide compound of delayed release for about 10%IR than about 90%DR, about 15%IR than about 85%DR, about 20%IR than about 80%DR, about 25%IR than about 75%DR, about 30%IR than about 70%DR, about 35%IR than about 65%DR, about 40%IR than about 60%DR, about 45%IR than about 55%DR or about 50%IR than about 50%DR.In certain embodiments, the activating agent discharged immediately and the ratio of the activating agent of delayed release are that about 25%IR is than about 75%DR.In certain embodiments, the activating agent discharged immediately and the ratio of the activating agent of delayed release are that about 20%IR is than about 80%DR.The unit dosage form with IR and DR component comprises any known preparation, comprises bilayer tablet, coated pill etc.

Time release delivery system

In one embodiment, delayed release mechanism is " regularly " or temporary transient release (" TR ") system, described system some time point release bioactive agent, such as biguanide compound after administration.Time release delivery system is that time release delivery system that is that this area has been known and that be applicable to can comprise any known excipient and/or coating.Such as, the excipient in substrate, layer or coating by the activating agent that slows down to the diffusion in environment to postpone the release of activating agent.The time controlled released excipient be applicable to includes but not limited to arabic gum (Radix Acaciae senegalis), agar, aluminium-magnesium silicate, alginate (sodium alginate), sodium stearate, Fucus Vesiculosus, bentonite, carbomer, carrageenin, carbopol, cellulose, microcrystalline Cellulose, carob, carrageenin, dextrose, Furcellaran, gelatin, gum ghatti, guar gum, galactomannan, Strese Hofmann's hectorite., lactose, sucrose, maltodextrin, mannitol, sorbitol, Mel, corn starch, wheaten starch, rice starch, potato starch, gelatin, karaya, xanthan gum, Glyceryl Behenate (such as, Compritol 888 ato), distearin (such as, Precirol ato 5), Polyethylene Glycol (such as, PEG 200-4500), poly(ethylene oxide), adipic acid, Tragacanth, ethyl cellulose (such as, ethyl cellulose 100), ethylhydroxyethylcellulose, ethylmethylcellulose, methylcellulose, hydroxy methocel, hydroxyethylmethyl-cellulose (such as, KlOOLV, K4M, K15M), hydroxypropyl cellulose, poly-(hydroxyethyl meth acrylate), cellulose acetate (such as, cellulose acetate CA-398-10 NF), cellulose acetate phthalate, cellulose-acetate propionate, cellulose acetate-butyrate, acetate succinate hydroxypropyl methylcellulose, phthalic acid hydroxypropyl methylcellulose, cellulose butyrate, celluloid, oxypolygelatin, pectin, polygeline, polyvidone, Allyl carbonate, polyanhydride (polyandride), Copolymer of Methyl Vinyl Ether/Maleic Anhydride (PVM/MA), poly-(ihethoxyethyl methacrylate), poly-(methoxyethoxyethyl methacrylate), hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose (CMC), silicon dioxide, polyvinyl (such as, polyvinyl pyrrolidone (PVP: polyvidone)), polyvinyl acetate, or Opaseal and mixture, Kollidon SR, acryl derivatives (such as, polyacrylate, such as Acusol772 Acusol771, methacrylic acid copolymer), (dextrose, maltodextrin and sucralose) or its combination.Time controlled released excipient can be in be had in the substrate of activating agent, is in another compartment of preparation or layer, as a part or its any combination of coating.One or more not commensurability time controlled released excipient can be used to realize the release time of specifying.

A limiting examples comprises the preparation of system.The formulation system of this Co ntrolled release provide the temporary transient release (SyncroDoseTM) of change and two-phase release ( ).(see, such as, Staniforth and Baichwal, : novelpolysaccharide composites for controlled/programmed release of activeingredients in the gastrointestinal tract, Expert Opin.Drug Deliv., 2 (3): 587-89 (2005)).Use preparation, as of the invention described herein these preparations, targeting epimere gastrointestinal tract, hypomere gastrointestinal tract or the compositions of the two can be formed, except temporarily controlling the release of this compounds what these position in office.

In some embodiments, time release delivery system is formulated into about 5 minutes after administration, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 100 minutes, about 110 minutes, about 120 minutes, about 130 minutes, about 140 minutes, about 150 minutes, about 160 minutes, about 170 minutes, about 180 minutes, about 190 minutes, about 200 minutes, about 210 minutes, about 220 minutes, about 230 minutes, about 240 minutes, about 250 minutes, about 260 minutes, about 270 minutes, about 280 minutes, about 290 minutes, about 300 minutes, about 310 minutes, about 320 minutes, about 330 minutes, about 340 minutes, about 350 minutes, about 360 minutes, about 370 minutes, about 380 minutes, about 390 minutes, about 400, about 400, about 410 or about 420 minutes start to discharge compound.Have in the embodiment repeatedly discharged, time release delivery system is formulated into and discharges at more than one time point.In certain embodiments, time release delivery system is formulated into about 10 minutes after administration, about 30 minutes, about 120 minutes, about 180 minutes and about 240 minutes and starts release.In certain embodiments, time release delivery system to be formulated into after using to patient about 5 minutes to about 45 minutes, about 105 minutes to about 135 minutes, about 165 minutes to about 195 minutes, about 225 minutes to about 255 minutes or the combination of its time starts release.

The system that enteric coating and pH rely on

Also available enteric coating carries out coating to preparation, and this can prolection agent (such as biguanide compound) avoid degraded and allow delayed release to arrive in target area (such as, ileum) to absorb in sour environment is as stomach.

Enteric coating can be (as limiting examples) wax or ceroidlike material, as Brazil wax, fatty alcohol, hydrogenated vegetable oil, zein, Lac, sucrose, Radix Acaciae senegalis, gelatin, dextrin, lantago Psyllium powder, polymethacrylates, anionic polymethacrylates, poly-(methacrylic acid, methyl methacrylate) mixture, come from polymer or the copolymer of acrylic acid and/or methacrylate, cellulose acetate phthalate, acetic acid benzenetricarboxylic acid cellulose, phthalic acid hydroxypropyl methylcellulose (HPMCP), propanoic acid phthalate, cellulose, acetic acid maleic acid cellulose, phthalic acid polyvinyl alcohol, acetate succinate hydroxypropyl methylcellulose (HPMCAS), hexahydro-phthalic acid hydroxypropyl methylcellulose, Opaseal, poly-(methacrylic acid, ethylacrylic acid) mixture, ethyl cellulose, methylcellulose, propyl cellulose, chitosan succinate, chitosan succinate, Opaseal (PVAP), polyvinyl acetate polymer carboxymethylethylcellulose and its compatibility mixture.In addition, non-activity intermediate coat can be provided between biguanide compound and enteric coating to interact to prevent biguanide compound and enteric coating.

In another unrestricted example, the silicone microsphere body that the gastrointestinal drug for pH control is sent is by Carelli etc., Int.J.Pharmaceutics 179:73-83, and 1999 are described.Described microsphere be by being encapsulated into of different ratio poly-(methacrylic acid-altogether-methylmethacylate) in silicone microsphere body ( l100 or and the pH responsive type semi-interpenetrating polymer hydrogel made of cross-linked polyethylene glycol 8000 S100). the methacrylic acid copolymer of series can be purchased from the Evonik Industries company in Darmstadt, Germany city.

Enteric coating can use the combination of enteric polymer to be mixed with and discharge biguanide compound under required pH.It is well known that the diverse location of gastrointestinal system has specific pH.Such as, duodenum can be corresponding with pH 5.5 environment facies and jejunum can be corresponding with pH 6.0 environment facies.In preferred embodiments, enteric coating is formulated into and such as starts to discharge described compound at distal small bowel and hypomere enteral (i.e. about pH 6, about pH 6.5 or about pH 7) under required pH.Have in the embodiment repeatedly discharged, enteric coating is formulated into and starts to discharge under two or more pH value.In certain embodiments, enteric coating is formulated into and starts to discharge for 7.0 times at pH6.0, pH 6.5 and pH.In certain embodiments, enteric coating is formulated into and starts to discharge for 7.0 times at pH 6.5 and pH.In certain embodiments, enteric coating is formulated into and discharges at jejunum, ileum and hypomere enteral.In other embodiments, enteric coating and other delivery system such as time release delivery system combine to use.

In other embodiments, enteric coating with discharge/extend the unit dosage form discharged immediately and combine to use.Such as, the bilayer tablet of unit dosage form as having the biguanide compound of 20%IR/80%MR component can carry out coating with enteric coating, described enteric coating at such as pH5.5, pH 6.0, pH 6.5, pH carries out for 7.0 times discharging to make the described hangover until dosage form reaches such as pH 5.5, pH 6.0, pH 6.5, pH 7.0, thus discharges IR component immediately and according to its MR releasing properties release MR component.In some cases, enteric coating with discharge immediately/unit dosage form of time controlled released combines to use.

In U.S. Patent No. 6,022,562,5,846,566 and 5,603, the microcapsule gastric retention system described in 957 can be used in delayed release delivering method as herein described.The microgranule of activating agent or medicine carries out coating by the material spray formed with the mixture by film forming polymer derivant, hydrophobic plasticiser, functional reagent and polymer with nitrogen.The size of the microcapsule of gained is less than or equal to 1000 microns (gm) and this type of microcapsule is between 100 microns and 500 microns in some cases.These microcapsules remain to few 5 hours at little enteral.

The film forming polymer derivant used in this type of microcapsule includes but not limited to ethyl cellulose, cellulose acetate and water insoluble cellulosic derivant.Polymer with nitrogen includes but not limited to polyacrylamide, poly-N-vinyl amide, poly-N-vinyl-lactams and polyvinylpyrrolidone.The plasticiser used in this type of microcapsule includes but not limited to glyceride, phthalic acid ester, citrate, sebacate, cetyl alcohol ester, Oleum Ricini and cutin.The surfactant used in this type of microcapsule and/or lubricant include but not limited to anionic surfactant, the alkali metal of such as fatty acid, stearic acid and/or oleic acid or alkali salt; Nonionic surfactant, the polyoxyethylene deriv of the polyoxyethylene ester of such as sorbitan and/or the polyoxyethylene ester of sorbitan and/or Oleum Ricini; And/or lubricant, as stearate, such as calcium stearate, magnesium stearate, aluminium stearate, zinc stearate, stearoyl-fumarate salt, sodium stearyl fumarate and Glyceryl Behenate.

A limiting examples of hypomere GI delivery formulation comprises the tablet sent for hypomere GI.The inner composition of tablet comprises the applicable active component of about 0.01 % by weight to about 10.0 % by weight; The hydrocolloid natural gum of about 50 % by weight to about 98 % by weight, it can obtain from higher plant; And the pharmaceutically acceptable excipient of about 2 % by weight to about 50 % by weight, as binding agent.Other optional material can be there is, the pharmaceutical composition feature that described material will contribute to needed for foundation.These comprise can the absorption of enhanced activity composition in hypomere GI, can prolection composition make its from degraded, can prevent dissolve etc. material.Optionally round tablet inner composition be the coating being preferably enteric polymer material.

Preparation is designed to utilize: the protective features of the hydrocolloid that (1) can obtain from higher plant in epimere GI and the disintegrative feature of (2) hydrocolloid in hypomere GI.Therefore, the inner composition of tablet can be one of following some designs: (a) it can be the substrate of the active component of whole homodisperse treatment effective dose and other excipient composition of high percentage ratio hydrocolloid and usual small amount; (b) it can have core, wherein active component is concentrated, by not containing active component and the material layer with other excipient of high percentage ratio hydrocolloid and usual small amount surrounded; (c) it can have the active component of a Concentraton gradient, to make there is larger amount in the heart at tablet core, in the multiple layers surrounding core, there is less amount and have few in skin or there is no active component.No matter whether the design of tablet is the design of above (a), (b) or (c), for the specificity be delivered locally in hypomere GI by carrying out enteric coating to strengthen to tablet with suitable enteric-coating material.

The hydrocolloid be applicable to is that this area has been known.See, such as, " the The Chemistry of Plant Gums and Mucilages " of Smith and Montgomery, from A.C.S.Monograph sequence, #141,1959, Reinhold Publishing Co. and be the 18 edition of The Merck Index.Usually, the amount of spendable hydrocolloid is for allowing compositions significantly disintegrate and do not discharge the amount of a large amount of active component (that is, to provide delayed release characteristic) in epimere GI road through epimere GI road.Usually, the described amount of hydrocolloid will be greater than about 50% but be less than about 98%.According to individual variability (no matter patient is feed or on an empty stomach) and other factors, tablet will about 3 little in 6 hours through stomach and epimere intestinal.At this moment, period, discharges a small amount of active component (be less than 20%, be preferably less than 10%) from tablet of the present invention.Once tablet arrives hypomere GI, then carried out the release of Triggered Activity composition by enzymatic degradation galactomannan gum.

Improve delivery formulations

In other embodiments, relate to the method and composition that biguanide compound sends and can adopt controlled release, sustained release further or extend delivery formulations, these preparations are called as generally " improving release " preparation.Compositions is by improving delivery system or being used by delivery apparatus known to persons of ordinary skill in the art.Example includes but not limited in U.S. Patent No. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; And 5,733, in 566 describe those.This type of dosage form can be used for using the hydroxypropyl methylcellulose of such as different proportion, other polymeric matrix, gel, permeable membrane, osmosis system, multiple coatings, microgranule, liposome, microsphere or its combination to provide required release characteristics, discharges to provide the improvement of one or more active component.Applicable improvement delivery formulations known to persons of ordinary skill in the art (comprise as herein described those) can be easily selected to use together with active component of the present invention.Therefore the present invention is contained and is applicable to Orally administered individual unit dosage form, such as but not limited to being applicable to improve the tablet of release, capsule, capsule ingot (gelcap) and caplet (caplet) further.

In some embodiments, improve delivery system be formulated into start release after about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 100 minutes, about 110 minutes, about 120 minutes, about 130 minutes, about 140 minutes, about 150 minutes, about 160 minutes, about 170 minutes, about 180 minutes, about 190 minutes, about 200 minutes, about 210 minutes, about 220 minutes, about 230 minutes, about 240 minutes, about 250 minutes, about 260 minutes, about 270 minutes, about 280 minutes, about 290 minutes, about 300 minutes, about 310 minutes, about 320 minutes, about 330 minutes, about 340 minutes, about 350 minutes, about 360 minutes, about 370 minutes, about 380 minutes, about 390 minutes, about 400, about 400, release compound in the persistent period of about 410 or about 420 minutes.Have in the embodiment repeatedly discharged, improvement delivery system is formulated into and discharges within the more than one persistent period in different time points.

A limiting examples, the mixture of chitosan and chitosan and sodium carboxymethyl cellulose (CMC-Na) has been used as the vehicle of sustained release activity composition, as Inouye etc., Drug Design and Delivery 1:297-305, described in 1987.The mixture of these compounds and composite reagent of the present invention forms tablet when suppressing under 200kg/cm2, activating agent when being administered to patient from described tablet slow releasing.Ratio by changing chitosan, CMC-Na and one or more activating agents changes release characteristics.Tablet also can comprise other additive, comprises lactose, CaHPO4 dihydrate, sucrose, crystalline cellulose or cross-linking sodium carboxymethyl cellulose.

In another unrestricted example, Baichwal is in U.S. Patent No. 6,245, describe the oral dosage form of sustained release in 356, described solid dosage forms comprises the agglomerated particles of the medicine of unbodied therapeutic activity, gellant, ionizable gel strength enhancing agent and inert diluent.Gellant can be xanthan gum and the mixture of tracasol that can be cross-linked with xanthan gum when xanthan gum is exposed to environment liquid.Preferably, therefore ionizable gel enhancing agent also extends the release of the drug component of preparation for the cross-link intensity strengthened between xanthan gum and tracasol.Except xanthan gum and tracasol, also can use acceptable gellant, comprise those gellant that this area has been known.Example comprises the naturally occurring natural gum of natural existence or modification, as alginate esters, carrageenin, pectin, guar gum, modified starch, hydroxypropyl methylcellulose, methylcellulose and other cellulosic material or polymer, such as sodium carboxymethyl cellulose and hydroxypropyl cellulose and aforesaid mixture.

In the non-limiting preparation of the another kind being applicable to combination of the present invention, Baichwal and Staniforth is in U.S. Patent No. 5,135, free-pouring slow releasing granule is described in 757, described granule is as comprising following drug excipient: the hydrophobic material of about 20 % by weight to about 70 % by weight or more, described material comprises heteropolysaccharide (such as, xanthan gum or derivatives thereof) and can be crosslinked with heteropolysaccharide under aqueous solution exists polysaccharide material (such as, galactomannan and most preferably tracasol); And the inert pharmaceutical filler of about 30 % by weight to about 80 % by weight (such as, lactose, dextrose, sucrose, sorbitol, xylitol, fructose or its mixture).After being mixed with tricyclic compound/corticosteriods of the present invention or combination agent by excipient, mixture is directly compressed into solid dosage forms as tablet.Therefore the tablet formed can slow releasing medicine when absorbing and be exposed to gastric juice.By changing the amount of excipient relative to medicine, slow releasing characteristic can be realized.

Slow releasing preparation also can comprise be not easy water-soluble but slowly attacked by water and remove or water by the coating of its slow infiltration.Therefore, such as combination of the present invention can carry out spray coating with binder solution under continuous fluid condition, as Kitamori etc., and U.S. Patent No. 4,036, described in 948.The example of water-soluble binder comprises pregelatinized starch (such as, pregelatinised maize starch, pregelatinization white potato starch), pregelatinized modified starches, water-soluble cellulose (such as, hydroxypropyl cellulose, hydroxy methocel, hydroxypropyl methylcellulose, carboxymethyl cellulose), polyvinylpyrrolidone, polyvinyl alcohol, dextrin, Radix Acaciae senegalis and gelatin, dissolve in the binding agent of organic solvent (as cellulose derivative, such as, Cellacefate, phthalic acid hydroxypropyl methylcellulose, ethyl cellulose).

In another limiting examples, Villa etc. are in U.S. Patent No. 6,773, describe the improvement delivery system containing interior lipotropy substrate (being wherein surrounded by active component) and outer hydrophilic matrix (wherein having disperseed lipotropy substrate) in 720.First active component is wrapped in low melt lipophilic excipient or excipient mixture as biguanide or related heterocyclic compounds, heat excipient itself is softened and/or melting simultaneously, thus by simply disperseing to mix in active component.At room temperature after cooling, form inert base, the size of described substrate can be reduced to obtain the matrix granule containing active ingredients particles.Subsequently inert base granule and one or more hydrophilic are met the expandable excipient of water to be mixed together.In this regard, when compositions contacts with biofluid, form high viscosity expanding layer, described expanding layer penetrates into the barrier in new construction with solvent molecule coordination and as aqueous fluid itself.Initial " burst effect " of described barrier antagonism caused by the dissolving of the active component wrapped in inert base, described inert base and then be in hydrophilic matrix.The system of such a kind of commercially available acquisition is from CosmoTechnologies Limited (Italy), and its commodity are called technology.Enteric coating can be carried out to carry out pH specific delivery further to lipotropy/hydrophilic matrix.

Send for epimere intestinal, hypomere intestinal sends or the two preparation is known in the art.Such as following description active component is to the targeting of the zones of different of intestinal: The Encyclopedia ofPharmaceutical Technology, James Swarbrick and James Boylan, InformaHealth Care, 1999,287-308 page.For site-specific delivery and/or specificity temporary delivery (that is, delay, control, extend or the release that continues) any applicable preparation sent of gastrointestinal tract to can be used in the present invention and to be incorporated herein.

Any delivery system as herein described can use to realize repeatedly discharging and/or specific release characteristics with other system in combination.In some embodiments, biguanide compound is in and realizes after administration in the preparation repeatedly discharged of gastrointestinal location.In certain embodiments, biguanide compound be in about 10 minutes after administration, about 30 minutes, about 120 minutes, about 180 minutes, about 240 minutes or its combination start discharge repeatedly delivery formulations in.In certain embodiments, biguanide compound be in after administration about 5 minutes to about 45 minutes, about 105 minutes to about 135 minutes, about 165 minutes to about 195 minutes, about 225 minutes to about 255 minutes or its combination start discharge repeatedly delivery formulations in.

In certain embodiments, biguanide compound is in the repeatedly delivery formulations be discharged into after administration in duodenum, jejunum, ileum, hypomere intestinal or its combination.In other embodiments, biguanide compound is in and starts in the repeatedly delivery formulations discharged under about pH 5.5, about pH 6.0, about pH 6.5, about pH 7.0 or its combination after administration.In other embodiments, biguanide compound is in and carries out in the repeatedly delivery formulations discharged to about pH 8.0 or its scope combined to about pH 7.0, about pH 7.0 at about pH 5.0 to about pH 6.0, about pH 6.0 after administration.In other embodiments, biguanide compound be in discharge sub-fraction or a part of biguanide as release immediately and discharged by delayed mode as herein described all the other compounds repeatedly delivery formulations in.

Peroral dosage form

The peroral dosage form being applicable to theme composition and method comprises tablet, hard capsule, the fit capsule be made up of gelatin and soft seal capsule and lozenge, lozenge, aqueous or the oil-based suspension be made up of gelatin and plasticizer (as glycerol or sorbitol), dispersibles powder or granule, emulsion, syrup or elixir.The peroral dosage form be applicable to can be prepared according to any method for the manufacture of pharmaceutical composition known in the art, and such composition can comprise the reagent that one or more are selected from (as limiting examples) sweetener, flavoring agent, coloring agent and antiseptic, to provide pharmaceutical elegant and good to eat preparation.

Tablet comprises the active component with pharmaceutically acceptable mixed with excipients, and described excipient is applicable to manufacture tablet.These excipient can be such as inert diluent, as calcium carbonate, sodium carbonate, lactic acid, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent, as microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, corn starch or alginic acid; Binding agent, such as starch, gelatin, polyvinylpyrrolidone or arabic gum; And lubricant, such as magnesium stearate, stearic acid or Talcum.Tablet is by optionally carrying out suppressing with one or more auxiliary elements or prepared by molding.The tablet of compacting is prepared by suppressing the active component of free-flowing form (as powder or granule) in the machine be applicable to, optional and the binding agent of described active component (such as, polyvidone, gelatin, hydroxypropyl methylcellulose), inert diluent, antiseptic, disintegrating agent (such as, sodium starch glycolate, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose) or lubricant, surfactant or dispersant.The tablet of molding by carrying out molding to prepare to the mixture of the powder compound with inert liquid diluent moistening in the machine be applicable to.Tablet carries out coating to postpone its disintegrate in gastrointestinal tract and absorb and therefore make the systemic bioavailability as more fully described minimize herein by known technology.

Preparation for orally using also can be provided as hard gelatin capsule, and wherein active component mixes with inert solid diluent (such as calcium carbonate, calcium phosphate or Kaolin); Or be provided as Perle, wherein active component mixes with water-solubility carrier (as Polyethylene Glycol) or oily medium (such as, Oleum Arachidis hypogaeae semen, liquid paraffin or olive oil).Alternatively, described fit capsule can containing the active component mixed as Talcum or magnesium stearate and optional stabilizer as starch and/or lubricant as lactose, binding agent with filler.In soft capsule, reactive compound solubilized or be suspended in suitable liquid as in fatty oil, liquid paraffin or liquid macrogol.In addition, stabilizing agent can be added.Dragee core core provides suitable coating.For this purpose, can use the sugar juice concentrated, described sugar juice optionally can contain Radix Acaciae senegalis, Talcum, polyvinylpyrrolidone, carbopol gel, Polyethylene Glycol and/or titanium dioxide, paint solution and the organic solvent be applicable to or solvent mixture.Dyestuff or pigment can be added in tablet or dragee coatings for differentiating or characterize different active compound doses combinations.

In each embodiment, compositions provided in this article is liquid form.Liquid form comprises (as limiting examples) neat liquid, solution, suspension, dispersion liquid, colloid, foams etc.In some cases, liquid form also comprises nutrition composition or substrate (such as, coming from milk, Yoghourt, milk shake or fruit juice).In some respects, described compound is micronized or as the nanoparticle of liquid form.In some cases, coating is carried out to cover up gustatory properties to described compound.In other cases, coating is carried out to change sending to intestinal and colon to described compound.

Aqueous solution or suspension comprise one or more active component with the mixed with excipients being applicable to manufacture waterborne suspension.This type of excipient is suspending agent, such as sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, Tragacanth and Radix Acaciae senegalis; Dispersant or wetting agent can be naturally occurring phospholipid (such as, lecithin) or alkylene oxide and fatty acid condensation product (such as, Myrj 45) or the condensation product (such as seventeen-ring oxygen ethyl hexadecanol) of oxirane and long-chain fatty alcohol or oxirane and come from the condensation product (as polyoxyethylene 80 sorbitan monooleate) of part ester of fatty acid and hexitol or oxirane and come from the condensation product (such as, polyoxyethylene sorbitan monoleate) of part ester of fatty acid and hexitan.Aqueous solution or suspension also can comprise one or more antiseptic (such as, ethylparaben or P-hydroxybenzoic acid n-propyl), one or more coloring agent, one or more flavoring agents and one or more sweeteners (as sucrose, glucide or aspartame).In some cases, flavoring agent is described compound.

Prepare by making one or more active component be suspended in vegetable oil (such as Oleum Arachidis hypogaeae semen, olive oil, Oleum sesami or Oleum Cocois) or mineral oil (as liquid paraffin) containing oil suspension.Thickening agent can be comprised, such as Cera Flava, hard paraffin or hexadecanol containing oil suspension.Can add sweetener (as listed above those) and flavoring agent to provide good to eat oral formulations.These compositionss are anti-by adding oxidant such as anethole htpb or alpha-tocopherol are preserved.

Be applicable to by add water prepare aqueous solution or suspension dispersible powder and granule provides the active component mixed with dispersant or wetting agent, suspending agent and one or more antiseptic.The dispersant be applicable to or wetting agent and suspensoid are by carrying out illustration at those medicaments above-mentioned.Also can there is other excipient, such as sweetener, flavoring agent and coloring agent.These compositionss are preserved by adding antioxidant such as ascorbic acid.

Compositions can be also O/w emulsion form.Oil phase can be vegetable oil (such as, olive oil or Oleum Arachidis hypogaeae semen) or mineral oil (such as, liquid paraffin or these mixture).The emulsifying agent be applicable to can be naturally occurring phospholipid (such as, soybean lecithin) and come from the ester of fatty acid and hexitan or part ester (such as, sorbitan monooleates) and the condensation product (such as, Lsmesorb SMO 20) of described part ester and oxirane.Emulsion also can comprise sweetener, flavoring agent, antiseptic and antioxidant.

Available sweetener is glycerol, propylene glycol, sorbitol or the agent of sucrose syrup blend and elixir such as.This type of preparation also can comprise demulcent, antiseptic, flavoring agent and coloring agent and antioxidant.

Compositions also can be configured to (such as) containing the rectal compositions of conventional suppository bases as cocoa butter, Polyethylene Glycol or other glyceride, as suppository or retention enemas.These compositionss by prepared by inhibitor and the non-stimulated mixed with excipients be applicable to, described excipient be solid at normal temperatures but under rectal temperature for liquid also therefore in the rectum melting to discharge medicine.This type of material comprises cocoa butter, glycerin gelatine, hydrogenated vegetable oil, the mixture of Polyethylene Glycol of different molecular weight and the fatty acid ester of Polyethylene Glycol.

Therefore, be also provided in the pharmaceutical composition being applicable to comprise biguanide compound in Orally administered delayed release preparation, described delayed release preparation is tablet, capsule, cachet, pill, lozenge, powder or granule, solution, liquid or suspension such as.Described pharmaceutical composition is preferably applicable to the unit dosage forms of the required biguanide compound (particularly metformin, phenformin, buformin or imeglimin or its salt) of single administration of precise dosages (such as 100mg, 200mg, 250mg, 300mg, 400mg, 500mg, 600mg, 750mg, 800mg or 1000mg).Pharmaceutical composition can comprise Conventional pharmaceutical carriers or excipient and crop active component according to biguanide compound of the present invention.They can comprise other medicines or medicament, carrier, adjuvant etc. further.

The carrier be applicable to can comprise inert diluent or filler, water and different organic solvents.If needed, compositions can comprise other composition, as flavoring agent, binding agent, excipient etc.Therefore, for Orally administered, the various excipient that tablet contains such as citric acid can use together with various disintegrating agent (as starch or other fibrous material, alginic acid and some composition silicate) and binding agent (as sucrose, gelatin and arabic gum).In addition, lubricant such as magnesium stearate, sodium lauryl sulfate salt and Talcum is applicable to tabletting object usually.Also can add other reagent, as inhibitor, surfactant or solubilizing agent, plasticiser, stabilizing agent, thickening agent or film former.The solid composite of similar type can be used in soft filling and hard gelatine capsule of filling.Material comprises lactose or toffee and high molecular weight polyethylene glycol.When aqueous suspensions or elixirs are desired for oral administration, reactive compound wherein can with various sweetener or flavoring agent, coloring agent or dyestuff and (if needs) emulsifying agent or suspending agent, together with diluent (as water, ethanol, propylene glycol, glycerol or its combine) combine.

Excipient

Any compositions as herein described or preparation comprise any usual excipients in pharmacopedics, and select based on the compatibility of one or more activating agents and the release characteristics performance of required dosage form.Excipient includes but not limited to binding agent, filler, flow aid/fluidizer, disintegrating agent, lubricant, stabilizing agent, surfactant etc.Excipient general introduction as herein described is found in such as Remington:The Science and Practice of Pharmacy, the 19 edition (Easton, PA:Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, (Easton, PA:Mack Publishing Co1975); Liberman, H.A. and Lachman, L. edits, Pharmaceutical DosageForms (New York, NY:Marcel Decker 1980); And PharmaceuticalDosage Forms and Drug Delivery Systems, the 7th edition (Lippincott Williams & Wilkins 1999), these documents by reference entirety are incorporated to herein.

Binding agent is given bond property and is comprised alginic acid and salt thereof; Cellulose derivative, as carboxymethyl cellulose, methylcellulose (such as, ), hydroxypropyl methylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose (such as, ), ethyl cellulose (such as, ) and microcrystalline Cellulose (such as, ); Crystallite dextrose; Amylose; Aluminium-magnesium silicate; Polysaccharide acid; Bentonite; Gelatin; Polyvinylpyrrolidone//vinyl acetate copolymers; Polyvinylpolypyrrolidone; Polyvidone; Starch; Pregelatinized starch; Tragacanth, dextrin, sugar, as sucrose (such as, ), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (such as, ) and lactose; The natural gum of natural or synthesis, as the mucus of arabic gum, Tragacanth, gum ghatti, isapol skin, polyvinylpyrrolidone (such as, cL, cL, xL-10), larch arabogalactan, polyethylene Glycol, wax, sodium alginate etc.

Disintegrating agent contributes to decomposing after administration or disintegrate oral dosage form.The example of disintegrating agent comprises starch, such as native starch (as corn starch or potato starch), pregelatinized starch (as National 1551 or ) or sodium starch glycolate (as or ); Cellulose, as woodwork, methyl crystalline cellulose (such as, Avice10, pH101, pH102, pH105, p100, ming and ), methylcellulose, cross-linked carboxymethyl cellulose or cross-linked cellulose (as cross-linking sodium carboxymethyl cellulose (Ac-Di-Solt), cross-linked carboxymethyl cellulose or crosslinked cross-linked carboxymethyl cellulose); Crosslinked starch, as sodium starch glycolate; Crosslinked polymer, as polyvinylpolypyrrolidone; Crosslinked polyvinylpyrrolidone; Alginate, as alginic acid or alginate, as sodium alginate; Clay, as hV (aluminium-magnesium silicate); Natural gum, as agar, Guar beans, tracasol, karaya, pectin or Tragacanth; Sodium starch glycolate; Bentonite; Natural sponge; Resin, as cation exchange resin; Citrus pulp; Sodium lauryl sulfate; With the sodium lauryl sulfate of starch composition; Deng.

Lubricant is the compound preventing, reduce or suppress material adhesion or friction.Exemplary lubricants comprises such as stearic acid; Calcium hydroxide; Talcum; Sodium stearyl fumarate; Hydrocarbon, if mineral oil, castor oil hydrogenated or hydrogenated vegetable oil are (as oil with hydrogenated soybean ); Higher fatty acids and its alkali metal salt and alkali salt, as aluminum salt, calcium salt, magnesium salt, zinc salt; Stearic acid, sodium stearate, magnesium stearate, glycerol, Talcum, wax, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, Polyethylene Glycol or methoxy poly (ethylene glycol) (as CarbowaxTM), ethylene oxide polymer, enuatrol, Glyceryl Behenate (such as, Compritol 888 Ato), distearin (Precirol Ato 5), Polyethylene Glycol, lauryl magnesium sulfate or sodium sulfate, silica gel (as SyloidTM, Carb-O-Si10), DL-LEUCINE, starch (as corn starch), silicone oil, surfactant etc.

Flow aid or fluidizer improve the flow performance of pulverulent mixture.This compounds comprises such as silica sol, as tricalcium phosphate, Talcum, corn starch, DL-LEUCINE, sodium lauryl sulfate, magnesium stearate, calcium stearate, sodium stearate, Kaolin and micronize amorphous silica deng.

Plasticiser contributes to the coating of oral dosage form.Exemplary plasticiser includes but not limited to triethyl citrate, glyceryl triacetate (glyceryl triacetate), acetyl triethyl citrate, Polyethylene Glycol (PEG 4000, PEG 6000, PEG 8000), Carbowax 400 (PEG400), diethyl phthalate, ethyl sebacate, acetyl triethyl citrate, oleic acid, glyceryl monostearate, tributyl citrate, acetylated monoglyceride, glycerol, fatty acid ester, polypropylene glycol and dibutyl phthalate etc.

Above-mentioned excipient only provides as an example and is not intended to comprise all possible selection.Other excipient classification be applicable to is comprising toner, granulating agent, antiseptic, defoamer, solubilizing agent etc.In addition, a lot of excipient can have more than a kind of effect or function, or can be classified as more than one group; Classification is only descriptive and is not intended to limit any use of particular excipient.

For evaluating the method for the treatment of

The evaluation for the treatment of diabetes

The effect of method evaluation biguanide compound treatment of the present invention to diabetes aspect of the treatment diabetics generally can put into practice according to known in the art and doctor.

Mensuration known in the art and method can be used to assess and to use compositions as herein described and method to treat the effect of diabetes/Metabolic Syndrome and diabetes related pathologies.As an example, the qualitative assessment of renal function and the parameter of renal dysfunction are that this area has been known.For determining that the mensuration example of renal function/renal dysfunction comprises serum creatinine level; Creatinine clearance; Urine creatine acid anhydride removing in cystatin (cystatin) C clearance rate, 24-hour, the secretion of 24-hours urine protein matter; Glomerular filtration rate (GFR); Urinary albumin creatinine ratio (ACR); Albumin excretion rate (AER); And Renal biospy.

The qualitative assessment of pancreas function and the parameter of pancreas dysfunction or pancreatic insufficiency are that this area has been known.Example for the mensuration determining pancreatic function/pancreatic function obstacle comprises and uses biology and/or physiologic parameters to evaluate pancreatic function, as the assessment of the size of assessment Langerhans' islands (islets ofLangerhan), growth and/or secretion activity, beta cell size, growth and/or secretion activity, insulin secretion and blood circulation level, blood sugar level, pancreas imaging and pancreas biopsy, the glucose uptake research excited by oral glucose, cytokine characteristic, blood gas analysis, blood-perfusion of tissues scope and in-house angiogenesis.

Other being used for the treatment of the diabetes condition of illness relevant with diabetes is determined as known in the art and is incorporated herein.

The evaluation of the treatment of weight saving, obesity and overeating disorders

In bariatrician, it is desirable for that the weight of patient and/or fat reduce to some extent.Weight reduction means over the course for the treatment of, and (no matter therapeutic process is sky, week, the moon or year) patient alleviates the part of his/her TBW.Alternatively, the ratio that weight reduction can be defined as fat mass and thin quality reduces (in other words, patient alleviates fat mass, but maintains thin mass conservation or increase thin quality, and without the need to alleviating TBW accordingly).The effective dose of the biguanide compound treatment of using in this embodiment is be effective in the amount that alleviates weight in patients over the course for the treatment of or alternatively for being effective in the amount reducing patient's percentage of fat mass over the course for the treatment of.In certain embodiments, over the course for the treatment of, having lost weight at least about 1% of patient, at least about 5%, at least about 10%, at least about 15% or at least about 20%.Alternatively, over the course for the treatment of, the percentage of fat mass of patient decreases at least 1%, at least 5%, at least 10%, at least 15%, at least 20% or at least 25%.

TBW and fat content can be measured at the end of the meals time.In rats, the method for the frequent determination TBF used is removed retroperitoneal fat pads for performing the operation and weighs retroperitoneal fat pads, and described fat pad is the fat-body being positioned at retroperitoneum, and described retroperitoneum is the region between posterior abdominal wall and posterior peritoneum parietal layer.Pad weight is considered to directly related with the body fat percent of animal.Because the pass between the body weight in rat and body fat is linear, fat animal has corresponding higher body fat percent and retroperitoneal fat pads weight.

Treatment is provided wherein, alleviates or prevents in the embodiment of patient addicted to the method for food, by using known in the art or being measured addicted to food by the application form of research addicted to personnel's foundation of food.This application form preferably carries out rank to addicted to drinking water is flat on numerical scale, if wherein patient is not addicted to food, then rank is 0, and if patient suffers from serious in food, then rank is 10 (if scale is 1 to 10).Application form also preferably include as patient the problem such as the food type thirsted for.Determine by utility efficiency table and gluttony graduation apparatus (BES) or measure gluttony.The gluttony order of severity can be divided into three classes (slightly, moderate and severe) based on total BES mark (by calculating the mark summation of each single project).Therefore, be provided for the method reducing patient B ES mark, described method comprises being effective in the amount reducing patient B ES mark and treats to patient's administered compound in need.In some embodiments, compounds for treating use the BES classification changing patient, such as, from severe to moderate, from severe to slight or from moderate to slightly.

The pretreat evaluation of patient's hormonal profile

In some embodiments, the expression of the method as herein described metabolic hormone of evaluate patient is in advance used.Therefore, the therapeutic agent provided to individuality can the his or her specific needs of targeting.In embodiments, the hormonal profile of evaluate patient and the change realized desired by doctor in advance, uses compound/metabolite combination of certain determined amounts.Can evaluation procedure be repeated and therefore treatments period or treatment after any time in adjustment for the treatment of.

Hormone determination

In embodiments, combine according to the standard method detection described in document the hormonal readiness measured with the inventive method, described hormone includes but not limited to GLP-1, GLP-2, GIP, gut hormone, PYY, CCK, active enteroglucagon, insulin, glucagon, Leptin, amylin, uroguanylin, C-peptide and/or its combination.Such as, measure protein by immunologic assay and measure transcription product by nucleic acid amplification technologies.Also the functional assays described in this area can be used time suitable.In embodiments, the sample measured comprises cultured cells, Patient cells or tissue sample, patient body fluid (such as, blood or blood plasma) etc.Similarly, combine according to any known method detection analysis thing (such as, glucose, triglyceride, HDL, LDL, apoB etc.) level measured with the inventive method.

Such as, immunofluorescence can be used for measuring GLP-1.The coverslip that cell can cover at matrigel at 37 DEG C in 12 orifice plates grows to fusion monolayer, be fixed in the phosphate buffer (PBS) of 4% paraformaldehyde and use primary antiserum (such as at 4 DEG C, the anti-α gusducin of rabbit, 1:150; Santa Cruz Biotechnology, and rabbit anti-GLP-1, Phoenix) overnight incubation, thoroughly change process 10 minutes with the 0.4%Triton-X in PBS subsequently and at room temperature close 1 hour.Three washing steps are carried out subsequently, at room temperature by suitable second antibody application (the anti-rabbit immunoglobulin of AlexaFluor 488,1: 1000 with Block buffer; Molecular Probes) 1 hour.After three washing steps, cell can be fixed in Vectashield culture medium and can immunofluorescence to be seen.

RT-PCR can be used to measure the GLP-1 RNA be separated from cell.Standard method can be used to carry out RT-PCR RNA from the separation cell.Can at Peltier thermal cycler (PTC-225 DNA Engine Tetrad Cycler; MJ Research) in 50pl volume, use the primer sequence of announcement (Integrated DNA Technologies) to carry out RT-PCR reaction.The reverse transcription of 30 minutes can be carried out at 50 DEG C; Carry out the initial activity step of 15 minutes at 95 DEG C after.By 40 circulations 94 DEG C of degeneration 1 minute, 55 DEG C of annealing 1 minute and 72 DEG C of downward-extensions 1 minute, carry out 10 minutes last extension steps to carry out PCR at 72 DEG C subsequently.Negative control can be comprised, such as, by water consumption substitution elliptical reverse transcriptase or template time suitable.Contrast can be the RNA be separated from such as Rat Tongue epithelial cell.PCR primer can be separated and be visible under w light in 2% agarose gel with ethidium bromide.

In the art, can such as (e.g.) Laferrere etc., 2007, " Incretin Levels andEffect are Markedly Enhanced 1 Month after Roux-en-Y Gastric BypassSurgery in Obese Patients with Type 2 Diabetes; Diabetes Care30 (7): 1709-1716 (using from Phoenix Pharmaceuticai; the material of the commercially available acquisition that Belmont, CA obtain) carries out the radioimmunoassay (RIA) of the total GLP-1 in patient blood samples describedly.Author describes and measures the effect of GIP and GLP-1 to insulin secretion by the insulin secretion difference (area under curve or AUC) measured in response to Oral glucose tolerance test and different blood glucose vein blood sugar test.

By such as Toft-Nielsen etc., 2001, " Determinants of the ImpairedSecretion of Glucagon-Like Peptide-1 in Type 2 Diabetic Patients, " J.Clin.End.Met.86 (8): 3717-3723 describe GLP-1, GIP, glucagon, insulin, C peptide, pancreas peptide, unesterified fatty acid, glutamic acid decarboxylase antibody and Islet Antigen antibody plasma concentration measure.Author describes and uses radioimmunoassay to carry out to measure by antibody numbering 89390 plasma concentration of amidatioon GLP-1-(7-36) for GLP-1.This measures total amount and the metabolite GLP-1-(9-36) thereof of GLP-1-(7-36).The GIP that author describes the antibody numbering R65 (RIA) using C-end on orientation measures, and described antibody and people GIP 100% react and do not react with 8-kDA GIP 100%.

Directly GLP-1 and PYY can be measured in the supernatant from Venous flow effluent, as by (such as) Claustre etc. (1999, " described in Stimulatory effect of (3-adrenergic agonists onileal L cell secretion and modulation by a-adrenergic activation, J.Endocrin.162:271-8).(also see, Plaisancie ' etc., 1994, " Regulationof glucagon-iike peptide-1-(7-36) amide secretion by intestinalneurotransmitters and hormones in the isolated vascularly perfused ratcolon, " Endocrinology 135:2398-2403 and Plaisancie ' etc., 1995, " Releaseof peptide YY by neurotransmitters and gut hormones in the isolated, vascularly perfused rat colon, " Scandinavian Journal of Gastroenterology30:568-574.) in this method, be used in the anti-GLP-1 antibody of 199D in 1: 250 000 diluent.This antibody and GLP-1-(7-36) amide react 100%, react 84% with GLP-1-(1-36) amide, and react with GLP-1-(1-37), GLP-1-(7-37), GLP-2 and pancreas hyperglycemia and be less than 0.1%.The A4D anti-pig PYY antiserum in 1: 800 000 diluent is used to measure PYY.

Method for measuring GLP-1 and GIP is also described in elsewhere in the art, and such as, by Jong etc., PNAS, 2007 etc. are described.

Also can use the PYY in radioimmunoassay method blood, as passed through (such as) Weickert etc., 2006, " Soy isoflavones increase preprandial peptide YY (PYY); but have no effect on ghrelin and body weight in healthy postmenopausal women " Journal of Negative Results in BioMedicine, described in 5:11.By blood collecting in ice-cold EDTA pipe for analysis glucose, Leptin and PYY.Under 1600g, 10 minutes centrifugal actions are carried out subsequently, until measure at aliquot is chilled in-20 DEG C immediately at 4 DEG C.The all samples from few patients is measured in same measured.The immunoreactivity Leptin total amount of the measurement described in author is measured by the radioimmunoassay (Phoenix Pharmaceuticals, Mountain View, CA, USA) of commercially available acquisition.(also see, Weickert etc., 2006, " Cereal fiber improves whole-body insulin sensitivity in overweight and obese women, " Diabetes Care 29:775-780).(LINCO Research is measured by the radiation immunity of commercially available acquisition, Missouri, USA), be used as the 125I-labelling biological activity PYY of tracer and PYY antiserum to determine that via double antibody/PEG technology active PYY level is to measure immunoreactivity people PYY total amount.PYY antibody in Cavia porcellus raises and identifies the people PYY of PYY 1-36 and PYY 3-36 (activity) two kinds of forms.

SGLT-1 (enteral Na-dependent glucose running 1) relates to the protein providing glucose to health.What reported is, it expresses (Margolskee etc. by the sugar of path responses in enteric cavity relating to T1R3,2007 " T1R3 and gustducin in gut sense sugars toregulate expression of Na+-glucose cotransporter 1; " Proc Natl Acad SciUSA 104,15075-15080 ").Can such as (e.g.) described by Margolskee etc., such as, quantitative PCR known in the art and western blotting be used to detect the expression of SGLT-1.The measurement of glucose transport has been described in document, such as Dyer etc., 1997, Gut 41:56-9 and Dyer etc., 2003, Eur.J.Biochem 270:3377-88.Such as by adding BBMV (100 μ g protein) to start D-Glucose picked-up via the 100pl containing 100mM NaSCN (or KSCN), 100mM mannitol, 20mM Hepes/Tris (pH7.4), 0.1mM MgSO4,0.02% (wt/vol) NaN3 and 0.1mM D-[U14C] glucose being hatched culture medium, can measure to carry out glucose transport in brush border membrane vesicle.Following ice-cold stop buffer stopped reaction is after 3 seconds contained: 150mM KSCN, 20mM Hepes/Tris (pH 7.4), 0.1mM MgSO4,0.02% (wt/vol) NaN3 and 0.1mM phlorhizin by adding 1ml.Under vacuo by the 0.22-[acetic/nitric acid cellulose filter (GSTF02500 in tm hole; Millipore, Bedford, MA) remove and filter out 0.9-ml reactant mixture partly.With 1ml stop buffer by filter wash five times, and measured the radioactivity retained on the filter by liquid scintillation counting.

Embodiment

The enteroendocrine cell generation of embodiment 1:PYY, GLP-1 (activity) and GLP-1 (total amount) and the minimizing of glucose and insulin do not rely on the Plasma absorption of metformin

Embodiment 1.1 materials and methods

Colony: about 18 the qualified masculinity and femininity experimenters of random selecting in this research, its age was 18 to 65 one full year of life, and BMI is 25.0kg/m ²to 35.0kg/m ².In order to meet the requirements, every experimenter also needs to meet following standard: (a) non-breast feeding; B () has negative pregnancy test result (human chorionic gonadotropin, β subunit); If c () is performed the operation sterillization, postclimacteric or had fertility, then within the whole research persistent period, carry out suitable birth control; D () carries out physical examination to determine not having clinical remarkable exception, include but not limited to following condition of illness: (i) hepatopathy; (ii) nephropathy; (iii) gastrointestinal disease; (iv) endocrine disorder, comprises diabetes; (v) cardiovascular disease; (vi) epilepsy; (vii) organ transplantation; And (viii) chronic infection; And (e) understand and be ready to follow protocol requirement ability.

Preparation

Metformin DR preparation is the film-coated release tablet immediately containing 500mg metformin hydrochloride of the commercially available acquisition of U.S.'s supply, other coating (sealing coating and enteric coating) is applied to described tablet to postpone the release of medicine in GI road, until tablet arrives the pH6.5 region of distal small bowel.Described tablet is white, biconvex, circular coated tablet, and every sheet contains 500mg metformin hydrochloride.Non-active ingredient in the tablet of commercially available acquisition comprises polyvidone, magnesium stearate, hydroxypropyl methylcellulose and Polyethylene Glycol.Non-active ingredient in other coated systems comprise hydroxypropyl methylcellulose, glyceryl triacetate, Talcum, methacrylic acid copolymer ( l30 D-55), poly-(methacrylate-altogether-methylmethacylate-altogether-methacrylic acid) 7: 3: 1 ( fS 30 D), sodium lauryl sulfate, polysorbate80, glyceryl monostearate and triethyl citrate.

Metformin IR preparation is the film-coated release tablet immediately containing 500mg metformin hydrochloride of the commercially available acquisition of same U.S. supply, only other sealing coating is applied to described tablet.Non-application delay release (enteric) coating.Hydroxypropyl methylcellulose, glyceryl triacetate and Talcum is comprised at the other intrasystem non-active ingredient of sealing coating.

Metformin preparation is supplied to website as the tablet in bulk be contained in the screw cap containers being marked with container number and lot number.All drugs are all as being stored in cooling indicated on label and only using indicated in research worker under the condition of drying.The website pharmacists selected by non-blind when each treatment phase starts according to randoming scheme or research worker distribution drugs.

Dispenser

The website pharmacists selected by non-blind when the 2nd time and the 4th are gone to a doctor according to randoming scheme or research worker distribution drugs.At the end of the 2nd time and the 4th are medical, experimenter holds the drugs of distribution and leaves clinic for the description that oneself uses, until they return to study medical (the 3rd time or the 5th go to a doctor) next time.

Using drugs as intact tablet (full wafer is swallowed, and need not chew or crush) and water nozzle clothes use.Used the drugs of first dosage for each treatment phase and latter two dosage (when first dosage when the 2nd time and the 4th are gone to a doctor and the 3rd time and the 5th are gone to a doctor latter two dosage) to experimenter by qualified research website personnel.Experimenter uses the drugs of distribution according to description oneself, until they return to study medical (the 3rd time or the 5th go to a doctor) next time.Research website personnel the contacting by phone and experimenter, to assess compliance and adverse events by non-specific aim enquirement of administration of each treatment phase for second day.If experimenter experiences significant gastrointestinal symptom, under the judgement of researcher, instruction experimenter does not want progressively increased dosage amount.

The program of carrying out during studying is listed in following table 1 to table 3.

Table 1: project (scheme LCPOC6)

[1] call is to put question to assessment compliance and adverse events and to remind experimenter's increased dosage amount gradually by non-specific aim

[2] unless experimenter has hysterectomized or it is postclimacteric to be, otherwise all female subjects all need to carry out pregnancy tests.

[3] GLP-1, PYY, blood glucose, insulin and triglyceride when the 2nd time and the 4th are gone to a doctor; GLP-1, PYY, blood glucose, insulin, triglyceride and metformin when the 3rd time and the 5th are gone to a doctor.

After the meals that the 2nd time and the 4th are medical excite.When the 3rd time medical and the 5th is gone to a doctor, at dosage morning of the late dosage of the 4th day and the 5th day.

Table 2: standardization breakfast that the 2nd time medical goes to a doctor with the 4th and the calendar of blood sampling characteristic

[1] each sampling time point amounts to 6-mL blood volume, for assessment PYY, GLP-1, blood glucose, insulin and triglyceride.

[2] indicate experimenter at 20 minutes internal consumption standardization breakfast.

Table 3: the 5th day calendar of the administration that the 3rd time medical goes to a doctor with the 5th, standardization breakfast and blood sampling characteristic

Pharmacodynamics is assessed

According to provide in table 1, table 2 and table 3 and calendar as previously discussed collect blood sample.The concentration of intestinal hormones as the empty stomach of GLP-1 and PYY and Post-prandial plasma concentration and blood glucose, insulin and triglyceride is measured by analytical method.Process and store from each medical blood sample for the other hormone of exploratory analysis in future at-70 DEG C.

Pharmcokinetic evaluation

According to provide in table 1, table 2 and table 3 and calendar as previously discussed collect blood sample.Blood plasma Determination of metformin is measured by analytical method.Process and store from each medical blood sample for the other hormone of exploratory analysis in future at-70 DEG C.

Clinical laboratory evaluations

Calendar according to providing in table 1, table 2 and table 3 and preceding sections collects sample.

Chemistry

Chemistry assessment comprises following: blood urea nitrogen, kreatinin, gross protein, albumin, uric acid, total bilirubin, alkali phosphatase, alanine aminotransferase, aspartate transaminase, γ glutamyl transpeptidase, creatine phosphokinase, glucose, sodium, potassium, chlorine, bicarbonate, phosphorus, (or conventional chemical combination of other approval of lactic acid and calcium.

Hematology

Hematology's assessment comprises following: red blood cell count(RBC), hemoglobin, hematocrit, numeration of leukocyte, platelet, differential counting, mean corpuscular volume, mean corpuscular hemoglobin amount and mean corpuscular hemoglobin concentration (or routine hematology assessment of other approval).

Urinalysis

Urinalysis assessment comprises following: pH, proportion, glucose, blood, ketone and protein (or routine urinalysis of other approval).

Pregnancy tests

No matter whether all female subjects, be fertility status (unless experimenter is postclimacteric or has hysterectomized), be all provided for blood or the urine of pregnancy tests.Unless acquisition negative findings, otherwise not study drug-administration.

Vital sign and other observation relevant with safety

And if follow the trail of vital sign and other clinical remarkable abnormal needs of observing relevant with safety by researcher, other test is used to evaluate, until diagnose out basic reason or be resolved.

Vital sign

Life sign measurement comprises seat and shrinks and diastolic blood pressure, heart rate and body temperature.Vital sign is measured after about 5 minutes of experimenter's tranquillization when experimenter is on position of sitting quietly.Repeated blood pressure measurements after at least 30 seconds and record the meansigma methods of twice reading.

Embodiment 1.2: result

Research design and event time line have been shown in Fig. 1 to Fig. 2.Demographics and the baseline characteristic (table 5) of gained experimenter distribution and colony's (table 4) and 18 experimenters have been shown in following table 4 and table 5.

Table 4: experimenter's distribution and colony

Parameter	Result
		Random	18
Complete	17
		Exit (positive drug test)	1
The colony evaluated	16

2 experimenters get rid of from evaluating colony; 1 exit and 1 can not complete at the end of the 2nd treatment phase test meal

Table 5: demographics and baseline characteristic (n=18)

Parameter

Result

Sex (M/F)	9/9
		Appraisal age (yr) ± SD	44±10
Race	9 white men, 7 Spaniards, 2 Black people
		Average BMI (kg/m2) ± SD	29.3±2.8

Fig. 3 shows that the absorption that the picked-up of metformin DR compared with metformin IR makes metformin in blood plasma minimizes.Provide area under curve (AUC) and the cmax value of metformin DR and metformin IR in following table 6.

Table 6: metformin plasma pharmacokinetics

Fig. 4 A to Fig. 4 C show to treat with metformin IR compared with the increase of intestinal hormones that increases of meals after metformin DR treats in 16 subject, although use the treatment of metformin DR to make whole body metformin level minimize (Fig. 3) compared with metformin IR.In addition, Fig. 5 A to Fig. 5 B show to treat with metformin IR compared with the minimizing of the glucose that increases of meals after treating with metformin DR in 16 subject and insulin.Fig. 6 shows and causes the PYY similar to metformin IR to respond with metformin DR treatment, but has lower systemic exposure.It is separable that Fig. 7 A to Fig. 7 B metformin PK/PD shown at least one patient body closes.

Embodiment 2-assesses delayed release and discharges the steady statue PK of metformin in the subject suffering from type 2 diabetes mellitus and the random crossing research of PD immediately

This random crossing research assessment 500mg and 1000mg metformin delayed release (metformin DR), 1000mg metformin discharge steady statue pharmacokinetics in the subject suffering from type 2 diabetes mellitus of (metformin IR) and 500mg metformin IR+1000mg metformin DR and pharmacodynamics (glucose, insulin, glucagon-sample peptide-1 [GLP-1] and PYY [PYY] immediately.The experimenter managing its diabetes with oral antidiabetic treatment agent before immediately randomization at least fortnight must forbid those medicines.

Each treatment phase length is five days and is separated by the removing phase of seven days.Each treatment phase comprised the identical characteristics (medication evaluation) in standardization breakfast and lunch characteristic (baseline estimate) and the 5th day morning on the 1st day before study drug-administration.

Embodiment 2.1: materials and methods

Use standard method for treat at every turn in about 10 hours in response to standard twice meals (during at t=0min about 500 kilocalories of standardization breakfast and at t=300min time about 1000 kilocalories of standardization lunches) to cycle P YY, GLP-1, glucose and insulin concentration be used for evaluation experimenter.Also evaluate the metformin pharmacokinetics in about 11 hour sample time section.

Colony: most of randomized subjects is white man's (79.2%) and half is women's (50.0%).Appraisal age was 51.3 one full year of life, and average weight is 93.4kg, and average BMI is 33.3kg/m when baseline ².19 in 24 experimenters complete described research.

The main foreigner tourists of pharmacokinetics and pharmacodynamic analyses is valuable colony (N=19), and described colony has been defined as all experimenters of all treatment phases consistent with scheme processes.The main foreigner tourists of safety analysis is purpose treatment (ITT) colony (N=24), and described colony is defined as all experimenters of the drugs accepting at least one dosage.

Preparation

Metformin DR preparation is the film-coated release tablet immediately containing 500mg metformin hydrochloride of the commercially available acquisition of U.S.'s supply, other coating (sealing coating and enteric coating) is applied to described tablet to postpone the release of medicine in GI road, until tablet arrives pH 6.5 region of distal small bowel.Described tablet is white, biconvex, circular coated tablet, and every sheet contains 500mg metformin hydrochloride.Non-active ingredient in the tablet of commercially available acquisition comprises polyvidone, magnesium stearate, hydroxypropyl methylcellulose and Polyethylene Glycol.Non-active ingredient in other Elcelyx coated systems comprise hydroxypropyl methylcellulose, glyceryl triacetate, Talcum, methacrylic acid copolymer ( l30D-55), poly-(methacrylate-altogether-methylmethacylate-altogether-methacrylic acid) 7: 3: 1 ( fS 30D), sodium lauryl sulfate, polysorbate80, glyceryl monostearate and triethyl citrate.

+ metformin preparation is supplied to website as the tablet in bulk be contained in the screw cap containers being marked with container number and lot number.All drugs are all as being stored in cooling indicated on label and only using indicated in research worker under the condition of drying.The website pharmacists selected by non-blind when each treatment phase starts according to randoming scheme or research worker distribution drugs.

Dispenser

When breakfast and dinner start, water nozzle takes the drugs (full wafer is swallowed) used as intact tablet.According to the description that research website staff provided at the 1st day, experimenter is at the self-drugs using distribution in the 1st day evening to the 4th day morning.Used the drugs (the 4th day evening and the 5th day morning) of latter two dosage of each treatment phase to experimenter by quantitative study website personnel.In order to reduce gastrointestinal side effect, all therapeutic schemes start 3 initial dosage with 500mg/ dosage, increase the randomization dosage (500mg/ dosage, 1000mg or 1500mg/ dosage) of all the other research phases subsequently.Research website personnel being contacted by phone and experimenter for second day of administration of each treatment phase, and if to assess compliance by non-specific aim enquirement and adverse events properly reminds their increased dosage amount gradually.

Embodiment 2.2: result

Pharmacokinetic Evaluation

Pharmacokinetic properties

Fig. 8 represents the treatment average blood plasma Determination of metformin of the 5th day and time point.At the 5th day, when t=0, before the administration of metformin IR, (pre-dose) mean concentration is 350ng/mL, and this concentration is consistent with the steady statue least concentration announced in document.Use metformin IR when t=-1 minute after, Determination of metformin existence increases sharply, and described concentration after administration 90min, to peaking 1249ng/mL, stably declines in section in all the other sample times subsequently.

Before the administration of the metformin DR of two dosage concentration ratio metformin IR administration before concentration high about 2 times (1000mg DR be 716ng/mL and 500ng/mL DR is 602ng/mL to contrast 1000mg IR be 350ng/dL).After t=-1 minute uses the metformin DR of two dosage, in initial 240 minutes, Determination of metformin reduces to some extent, and after standardization lunch, Determination of metformin slightly rises subsequently, then reaches stable in all the other sample times in section.Whole 11-hour metformin curve to remain on before the administration that t=0 measures below concentration.The absorption curve of the metformin DR that adjoint dinner gives slows down to some extent relative to the dosage used with breakfast, and this is consistent with the intestinal transport slowed down in the length of one's sleep.The metformin DR concentration of 500-mg dosage at all time points all lower than 1000-mg dosage, although described minimizing is less than dose ratio.This observe to lack with the metformin IR of report and the ratio of dosage consistent and be attributable to the saturable absorption process of enteral.

Metformin DR+ metformin IR treatment group has concentration (761ng/mL) before administration the highest in four treatment groups.When t=-1 minute after study drug-administration, but Determination of metformin increases sharply in the mode similar to metformin IR and usually in initial 500 minutes, keeps below metformin IR concentration curve.For all the other of section sample time, concentration reach stable but wherein higher than by other treatment those concentration viewed.

Pharmacokinetic parameter

Table 7 and Fig. 9 represent the metformin relative bioavailability at the 5th day treatment contrast metformin IR.Compared with metformin IR preparation, from t=0 to the time of the final concentration after drugs is used, metformin exposes (AUC _0-t) (average ratio % is 54.8 statistically to significantly reduce 45.2% (using 1000mg metformin DR); P < 0.0001) and 56.6% (use 500mg metformin DR) (average ratio % is 43.4; P < 0.0001).Compared with metformin IR, C _maxalso (average ratio % is 65.1 statistically to significantly reduce 34.9% (using 1000mg metformin DR); P < 0.0001) and 47.7% (use 500mg metformin DR) (average ratio % is 52.3; P < 0.0001).

Metformin DR+IR treatment causes the exposure similar to the exposure of 1000mg metformin IR, and (average ratio % is 90.9; P=0.2271), although every daily dose increases by 50%.

Table 7. is in the metformin relative bioavailability-can evaluate colony of the 5th day treatment contrast metformin IR

Abbreviation: NA=is not used in conjunction; T=after dosage is used finally can be quantitative concentration.

Attention: in subject, CV% is for AUC _0-tbe 24.2 and for C _maxbe 26.3.

[1] (1000mg Met IR, 1000mg Met DR or 500mg Met DR)/1000mg Met IR.

Pharmacodynamics is evaluated

PYY total amount

Figure 10 and table 8 is illustrated respectively in baseline and treats the average blood plasma PYY total concentration curve of the 5th day and the correspondence analysis of time point and pharmacodynamic parameters.Baseline plasma PYY total concentration between the treatment of most of time point is similar.In addition, all Or Metformin In Treatings statistically significantly reduce PYY and always expose and peak concentration (the p < 0.01 of all values), wherein AUC _0-tbe 1.26 to 1.55 with percentage ratio (the 5th day/the 1st day) scope of Cmax.For each treatment, also statistically significantly increase (table 9, the p < 0.01 of all values) from baseline the 5th day fasting plasma PYY total concentration.These results show that the similar PYY overall response to standard twice meals is all drawn in all treatments studied.

The pharmacodynamic analyses of table 8. blood plasma PYY total amount (pg/mL)-within the treatment of sketch-based user interface is compared-can colony be evaluated

Abbreviation: BL=baseline (the 1st day); EOT=treatment terminates (the 5th day); Geo.=geometry; T=dosage use after finally can quantitative concentrations.

[1] EOT (the 5th day)/BL (the 1st day) of each treatment

The fasting plasma PYY total amount (pg/mL) of table 9. baseline and the 5th day-can colony be evaluated

Abbreviation: BL=baseline (the 1st day); EOT=treatment terminates (the 5th day).

Active GLP-1

Figure 11 and table 10 is illustrated respectively in the correspondence analysis of baseline and the active GLP-1 concentration curve of the treatment average blood plasma of the 5th day and time point and pharmacodynamic parameters.The active GLP-1 concentration of Baseline plasma between the treatment of most of time point is similar.In addition, all Or Metformin In Treatings statistically significantly reduce active GLP-1 and expose and peak concentration (the p < 0.01 of all values), and wherein percentage ratio (the 5th day/the 1st day) scope of AUC0-t and Cmax is 1.42 to 1.88.For each treatment, also statistically significantly increase (table 11, the p < 0.05 of all values) from baseline the 5th day fasting plasma GLP-1 total concentration.These results show that all treatments studied all are drawn and respond the shares activity GLP-1 of standard twice meals.

The pharmacodynamic analyses of table 10 plasma activities GLP-1 (pmol/L)-within the treatment of sketch-based user interface is compared-can colony be evaluated

Abbreviation: BL=baseline (the 1st day); EOT=treatment terminates (the 5th day); Geo=geometry; T=dosage use after finally can quantitative concentrations.

[1] EOT (the 5th day)/BL (the 1st day) of each treatment.

The active GLP-1 (pmol/L) of the fasting plasma of table 11. baseline and the 5th day-can colony be evaluated

Glucose

Figure 12 and table 12 is illustrated respectively in baseline and the treatment mean blood glucose concentrations curve of the 5th day and time point and the corresponding pharmacodynamic parameters via meals.

Between treatment, the baseline glucose concentration of most of time point is similar.In addition, the exposure of the glucose at two meals intervals and peak concentration are statistically significantly decreased to similarity degree (the p < 0.01 of all values) by all Or Metformin In Treatings.

The pharmacodynamic analyses of the blood glucose (mg/dL) at table 12 meals interval-within the treatment of sketch-based user interface is compared-can colony be evaluated

Abbreviation: BL=baseline (the 1st day); EOT=treatment terminates (the 5th day); T=dosage use after finally can quantitative concentrations.

[1] EOT (the 5th day)/BL (the 1st day) of each treatment.

Table 13 represent glucose use from t=0 to drugs after the pharmacodynamic parameters of time of final concentration.Consistent with the pharmacodynamic parameters at breakfast and lunch interval, all Or Metformin In Treatings statistically significantly reduce glucose and expose and peak concentration (the p < 0.001 of all values), wherein AUC _0-tbe 0.84 to 0.92 with percentage ratio (the 5th day/the 1st day) scope of Cmax.

The pharmacodynamic analyses of table 13 blood glucose (mg/dL) and insulin (pmol/L)-within the treatment of sketch-based user interface is compared-can colony be evaluated

[1] EOT (the 5th day)/BL (the 1st day) of each treatment.

Table 14 represents LS meansigma methods (SE) and Figure 13 represents that the individuality of the fasting plasma glucose concentration of the 5th day from baseline to treatment changes.Baseline fasting glucose concentration in treatment group is similar and scope is 196mg/dL to 200mg/dL.All treatment groups realize the statistically evident reduction (the p < 0.01 of all values) of fasting glucose after 5 days in treatment.As shown in figure 13, single response LSM and be distributed between treatment group as similar.

The fasting glucose (mg/dL) of table 14. baseline and the 5th day-can colony be evaluated

Insulin

Table 15 and table 16 represent the Fasting plasma insulin concentration of insulin pharmacodynamic parameters and baseline and the 5th day respectively.There is not statistically evident change (the p > 0.05 of all values) in the insulin exposure of any treatment, peak concentration or fasting concentrations.Although circulating glucose concentration is lower, the maintenance instruction incretin effect of insulin concentration.

The pharmacodynamic analyses of table 15 insulin (pmol/L)-within the treatment of sketch-based user interface is compared-can colony be evaluated

[1] EOT (the 5th day)/BL (the 1st day) of each treatment.

The fasting insulin (pmol/L) of table 16. baseline and the 5th day-can colony be evaluated

Safety evaluatio

The treatment burst adverse events of nearest treatment when table 17 summarizes by SOC, preference (preferred term) and shows effect.

Consistent with metformin prescription information, in fact adverse events is mainly gastrointestinal, wherein Nausea and vomiting and retch to occur over just and accept metformin IR and acceptance or do not accept in the treatment group of metformin DR.All treatment groups all report diarrhoea and diarrhoea seems to be dose-dependent, wherein maximum incidence rate is metformin IR+ metformin DR (7 experimenters, 33.3%) and minimum incidence rate is the metformin DR (2 experimenters, 10.0%) of lowest dose level.Note, the removing phase after all gastrointestinal event in 500mg metformin DR group all occur in the treatment of not use research medicine.

Neurological conditions is as dizziness and have a headache also frequently, and wherein metformin IR than DR dosage frequently.In a word, use metformin DR than using metformin IR and report less gastrointestinal and neurological conditions adverse events, this instruction improves toleration by walking around proximal small bowel to realize to the systemic exposure of the reduction of metformin.

Table 17 is by the summary-ITT colony of the treatment burst adverse events of SOC and preference and outbreak treatment

Embodiment 2.3: discuss

In this research, what give that (early before the meal with dinner before) 1000mg discharges that metformin (metformin IR), 500mg metformin DR and 1000mg metformin DR or 500mg metformin IR and 1000mg metformin DR combine immediately at BID measured metformin plasma concentration (Fig. 1) on the 5th day at steady state in 11 hours.All experimenters all suffer from type 2 diabetes mellitus and in randomization cross-over design, accept each treatment, wherein have one week removing phase between treatment.

The curve observed shows the lower circulation metformin amount when using metformin DR compared with metformin IR.The concentration before the metformin administration in the 5th day in the 5th day morning using metformin IR is 350ng/mL, and described concentration is consistent with the steady statue least concentration announced in document.After the 5th day morning used metformin IR, Determination of metformin existence increases sharply, and described concentration after administration 90min, to peaking, stably declines in section in all the other sample times subsequently.

When giving metformin DR, observe the maximum concentration of metformin at the 5th day before morning dose, described concentration is approximately high 2 times in the concentration of this time point than metformin IR.After the metformin DR using one of two dosage, the Determination of metformin of initial 240 minutes reduces to some extent, and then 360 minutes time, Determination of metformin slightly raises, and it reaches stable in all the other sample times in section.Whole 11-hour metformin DR PK curve to remain on before the administration that t=0 measures below concentration.These results show, the absorption curve of the metformin DR that adjoint dinner gives slows down to some extent relative to the dosage used with breakfast, and this is consistent with the intestinal transport slowed down in the length of one's sleep.Therefore, the concentration curve running through the 5th day initial 240 minutes is mainly the result from dosage absorption in the 4th day evening and was mainly the result of the early dosage absorption from the 5th day from 240 minutes to the concentration of 660min.

Embodiment 3: the analysis of the pharmacokinetic difference between administration in morning and administration in evening

In order to characterize the pharmacokinetic difference between administration in morning and administration in evening better, the research of embodiment 3 is designed to obtain the metformin DR 36-hour PK curve under breakfast and dinner give 500mg and 1000mg dosage in health volunteer's body.At independent treatments period, experimenter also accepts 1000mg metformin IR when breakfast and dinner and accepts 2000mg metformin when dinner to extend release (metformin XR).All experimenters all accept each treatment in randomization cross-over design, wherein have one week removing phase between treatment.

Metformin DR preparation is the film-coated release tablet immediately containing 500mg metformin hydrochloride of the commercially available acquisition of U.S.'s supply, other coating (sealing coating and enteric coating) is applied to described tablet to postpone the release of medicine in GI road, until tablet arrives pH 6.5 region of distal small bowel.Described tablet is white, biconvex, circular coated tablet, and every sheet contains 500mg metformin hydrochloride.Non-active ingredient in the tablet of commercially available acquisition comprises polyvidone, magnesium stearate, hydroxypropyl methylcellulose and Polyethylene Glycol.Non-active ingredient in other coated systems comprise hydroxypropyl methylcellulose, glyceryl triacetate, Talcum, methacrylic acid copolymer ( l30D-55), poly-(methacrylate-altogether-methylmethacylate-altogether-methacrylic acid) 7: 3: 1 ( fS 30D), sodium lauryl sulfate, polysorbate80, glyceryl monostearate and triethyl citrate.Metformin IR and metformin XR preparation are the preparation (being respectively Aurobindo Pharma Limited and Bristol-Myers Squibb) without any the commercially available acquisition of modifying.

As shown in figure 14, the metformin DR of two dosage all causes less whole body metformin more viewed than use metformin IR or metformin XR substantially.Note, total blood plasma metformin measured by the AUC by 1000mg metformin IR BID and 2000mg metformin XR QD (2000mg accumulated dose every day) exposes closely similar, and the bioequivalence previously set up between this with two kinds of preparations is consistent.Metformin DR curve display in initial 12 hours, there is delay in the systemic Absorption of metformin DR, wherein works the quantitative plasma concentration that begins and occur about 6 to 7 hours after administration.Within about 11 hours after late dosage, realize maximum concentration.After second dosage of metformin DR in the morning, metformin plasma concentration reduces, until the first dosage approximately 15h, slightly to rise subsequently, this with after the second dosage about 3 hours corresponding.

As previously discussed, the metformin DR of data instruction metformin IR and two dosage has the bioavailability larger a little than morning dosage after late dosage, may be because intestinal transhipment is slack-off during sleeping.

Table 18 shows average (CV%) the plasma pharmacokinetics parameter of metformin after Orally administered each treatment and Figure 15 compares C _max(left figure) and AUC _0-36haverage (SEM) value of (right figure).The metformin DR of two dosage causes a large amount of minimizing of exposure and the absorption delay of 6 to 7 hours.

Average (CV%) plasma pharmacokinetics parameter-can colony be evaluated of metformin after table 18 Orally administered treatment A, B, C and D

^aintermediate value (min, max)

^bn＝18

^cn＝17

Table 19 shows the C treating (500mg BID [treatment B] and 1000mg BID [treatment C]) ln-conversion relative to metformin IR (1000mg BID [treatment A]) from metformin DR _max, AUC _0-tand AUC _0-∞geometry LSM ratio and 90% confidence interval and marked and drawed relative bioavailability in the left figure of Figure 16.The instruction of these results is from the exposure ratio of 500mg BID metformin DR and degree (C _max, AUC _0-tand AUC _0-∞) respectively than from 1000mg BID metformin IR exposure ratio and degree low by about 55%, 68% and 67%.When 1000mg BID metformin DR (treatment C, every day 2000mg metformin accumulated dose), exposure ratio and degree (C _max, AUC _0-tand AUC _0-∞) respectively than from the exposure ratio of 1000mgBID metformin IR (treatment A, every day 2000mg metformin accumulated dose) and degree low by about 33%, 52% and 47%.When 500mg BID with 1000mg BID metformin DR compared with 2000mg QD metformin XR time observe the similar reduction (table 20 of exposure ratio and degree; Figure 16, right figure).

Metformin relative bioavailability after the Orally administered 500mg BID of table 19 treats with 1000mg BID metformin DR compared with 1000mg BID metformin IR-can colony be evaluated

SS: statistically evident (p-value < 0.0001)

Treatment A:1000mg metformin IR BID (agent of 2x 500mg metformin hydrochloride tablet [discharging immediately])

Treatment B:500mg metformin DR BID (agent of 1x 500mg metformin hydrochloride tablet [delayed release pH6.5 enteric coating])

Treatment C:1,000mg metformin DR BID (agent of 2x 500mg metformin hydrochloride tablet [delayed release pH6.5 enteric coating])

Metformin relative bioavailability after the Orally administered 500mg BID of table 20 treats with 1000mg BID metformin DR compared with 2000mg QD metformin XR-can colony be evaluated

SS: statistically evident (p-value < 0.0001)

Treatment D:2000mg metformin XR QD (agent of 4x 500mg metformin hydrochloride tablet [extending release])

Generally speaking, the pharmacokinetic results instruction of embodiment 2 and embodiment 3, relative to metformin IR and the metformin XR of identical every daily dose, send metformin by bioavailability reduction about 50% in 24 hours by using metformin DR to hypomere intestinal.Observe more big exposure to reduce when metformin DR dosage is reduced to 1000mg from every TDD 2000mg, and effect can not reduce.In addition, metformin DR administration time (with breakfast or dinner) meaningfully affect metformin at the time controlled released (contrasting 6 to 7 hours in after being respectively administration 3 hours) of enteral and provides the explanation observed the research from embodiment 2, and the metformin DR minimum namely observed before dosage in morning is higher than the minimum observed for 12 hours after dosage in morning.In research subsequently, prove the importance of QD am administration, described research makes to eat the breakfast the 1000mg metformin DR QD evaluated in 12 type ii diabetes patients with dinner compared with 500mg metformin DR bid.As shown in Figure 17 A and Figure 17 B, QD am administration display and QD pm compare the tendency of the maximum effect had for fasting glucose lowest sum total metformin with bid administration exposes.

In embodiment 2 is studied, although substantially reduce (to be 45% for 2000mg/ days and for 1000mg/ days for about 60% about the systemic exposure of metformin DR to metformin, metformin IR relative to 2000mg/ days), whole hypoglycemic activities of metformin IR (2000mg/ days) are kept.Consider and observe whole hypoglycemic activity under 2000mg and 1000mg metformin every day DR, be feasible compared with low dosage, to allow than usually available existing product (metformin IR and metformin XR (namely, tabloid, fully effective fixed dosage combination, daily once) better dosage form.In addition, different from metformin IR, the metformin DR of arbitrary dosage and any nausea and vomiting have nothing to do.

Embodiment 4: the assessment effect of metformin in the experimenter suffering from type 2 diabetes mellitus of delayed release, safety and toleration 12 weeks, at random, double blinding, placebo, parallel group, multicenter study

This research will compare delayed release metformin (Met DR) with placebo to the effect of glycemic control, as fasting plasma glucose during by using 4 weeks in the experimenter suffering from type 2 diabetes mellitus (T2DM) is assessed, and safety and the toleration of the Met DR of the dosage of the scope using 4 weeks in the experimenter suffering from T2DM will be assessed further.

Described research also will compare Met DR and placebo to the effect of glycemic control, as HbAlc during by using 12 weeks in the experimenter suffering from T2DM and fasting plasma glucose are assessed.The safety of the Met DR of the dosage of the scope of assessment when using 12 weeks in the experimenter suffering from T2DM and toleration.Also assessment Met DR when using 4 weeks and 12 weeks in the experimenter suffering from T2DM, to the dose-dependent effects of HbAlc and fasting plasma glucose, and is compared Met DR, the prolongation of in the experimenter suffering from T2DM, to use 4 weeks and 12 weeks and discharges metformin (Met XR) and placebo to following effect:

-fasting plasma glucose is along with the time is from the change of baseline

-HbAlc is along with the time is from the change of baseline

-body weight is along with the time is from the change of baseline

Research design

Scheme LCRM105 is stage 2, randomization, double blinding, multicenter, placebo, six groups of researchs.There is 8 research medical; Primary screening medical (going to a doctor for the 1st time) is 7 randomization treatment phases medical (go to a doctor for the 2nd time to the 8th time go to a doctor) afterwards.The experimenter taking metformin and/or dipeptidyl peptidase-4 (DPP-4) inhibitor stopped at least 14 days and was no more than 17 days using these medicines before the 2nd medical randomization.When the 2nd time is medical, by each in about 240 experimenters with 1: 1: 1: 1: 1: 1 ratio be randomized into one of 6 treatment groups.Will in the morning (AM) daily once (QD) treat A, B, C and D and this is by for blind choosing.Will at night (PM) QD administering therapeutic E and F, and this will not be blind choosing.By the 1st medical (screening) HbAlc (< 8% contrast >=8%), randomization is divided into groups.

With shown in following table 21 research treatment group:

Table 21: the treatment group of research LCRM105

Group	N	Treatment
			A	40	Placebo QD AM
B	40	Met DR 600mg QD AM
			C	40	Met DR 800mg QD AM
D	40	Met DR 1000mg QD AM
			E	40	Met XR 1000mg QD PM
F	40	Met XR 2000mg QD PM*

* Met XR 2000mg QD PM group will start with Met XR 1000mg QD, continue 1 week, then continue to be titrated to 1500mg QD in 1 week, be increased to 2000mg QD afterwards in residue research

When Randomized treatment phase medical (the 2nd time, the 3rd time, the 4th, the 5th, go to a doctor for the 6th time, the 7th time and the 8th time), instruction experimenter studies clinic arriving after at least 10 hours the whole night on an empty stomach.Instruction is assigned to experimenter in QD AM dosage regimen at random and to be stopped using in these days that research is medical the drugs of early dosage, until complete after fasting blood extracts.Early the these days in research medical (only going to a doctor for the 2nd time to the 7th time) use at research website place by dosage.At the 8th medical assessment physical examination and electrocardiogram (ECG).At the 2nd time to the 8th time medical measurement body weight and vital sign.The 2nd time, the 4th, the 6th time, the 7th time and the 8th time medical time collect the sample being used for clinical chemistry, hematology and urinalysis.The 2nd time, the 6th time, the 7th time and the 8th time medical time measure HbAlc.To collect when the 2nd time to the 8th time medical and be used for the fasting blood sample measuring plasma glucose, metformin pharmacokinetics (PK), insulin, PYY and GLP-1.Adverse events is assessed when the 2nd time to the 8th time medical.When the 3rd time to the 8th time medical, drugs is checked to drug compliance

And if if the potential diabetes of experimenter are subject to unsuitable control experimenter during studying experience the hyperglycemia be significantly deteriorated from base line condition, then based on researcher clinical judgment, by proper standard instruct make experimenter from research exit.Researcher can contact medical monitors, participates in the continuation of the experimenter that suitable clinical management and experience hyperglycemia are discussed.

The research persistent period

Interval natural law between medical according to research, the ultimate survey persistent period can be between 83 days to 107 days.

Research Group

Masculinity and femininity, be 18 years old to 65 years old when the 1st time medical (screening), body-mass index is 25.0 to 45.0kg/m2 (comprising end points).Suffer from about 240 experimenters of type 2 diabetes mellitus, use when the 1st time medical (screening) independent meals and motion, independent metformin, independent DPP-4 inhibitor or only metformin and DPP-4 inhibitor assembled scheme treat.The experimenter of DPP-4 inhibitor or Or Metformin In Treating is used to continue 14 to 17 days and ran through described research to stop using any DPP-4 inhibitor or prescription drugs metformin before registration.If use independent meals and exercise therapy, when the 1st time medical (screening), HbAlc was 7.0% to 9.5% (comprising end points), if or use independent metformin, the assembled scheme of independent DPP-4 inhibitor or metformin and DPP-4 inhibitor treats, when going to a doctor (screening) for the 1st time, HbAlc was 6.0% to 9.5% (comprising end points).Before randomization, serum creatinine < 1.5mg/dL (male) or < 1.4mg/dL (women) and assessment glomerular filtration rate (eGFR) >=60mL/min/1.73m2.

Drugs

Placebo (EFP0079)

Met DR (EFB0080): 500mg metformin hydrochloride delayed-release tablet (using pH6.5 enteric coating)

Met DR (EFB0081): 300mg metformin hydrochloride delayed-release tablet (using pH6.5 enteric coating)

Met XR:500mg metformin hydrochloride prolongation release tablet ( xR)

Research method

Before breakfast, QD uses Randomized treatment (treatment A, B, C and D) or QD administering therapeutic (treatment E and F) before dinner, continues 84 days.Fasting plasma glucose, HbAlc, body weight, metformin PK, insulin, PYY and GLP-1 is collected at the time point arranged

Capability assessment

Fasting plasma glucose

·HbAlc

Body weight

Pharmcokinetic evaluation

Blood plasma metformin

Pharmacodynamics is assessed

Insulin

·PYY

·GLP-1

Safety evaluation

Adverse events

Electrocardiogram

Physical examination

Vital sign

Clinical chemistry, hematology and urinalysis

Any patent herein and patent disclosure are incorporated to herein all by reference.

Those skilled in the art will make some changes and improvements after the aforementioned description of reading.Should be understood that for simplicity with readable, these type of changes and improvements all are deleted in this article, but they are suitably in the scope of following claims.

Claims

1., for reducing a combination dosage forms for the fixed dosage of the cardiac metabolism risk of patient in need, it comprises the other activating agent of at least one biguanide compound, at least one statin and at least one.

2. combination dosage forms according to claim 1, the other activating agent of wherein said at least one is selected from by the following group formed: antihypertensive, antiplatelet drug, diuretic, bile acid chelating agent, incretin analogies and reinforcing agent, anti-obesity medicine, oral antidiabetic and antiatherosclerotic.

3. combination dosage forms according to claim 1 and 2, it comprises at least two kinds, three kinds or four kinds of other activating agents.

4. combination dosage forms according to claim 1, it comprises the metformin or other biguanide that are less than 950,900 or 850mg

5. combination dosage forms according to claim 1, it comprises the metformin of about 300mg to about 900mg, more preferably from about the metformin of 400mg to about 800mg.

6. combination dosage forms according to claim 6, wherein said oral antidiabetic is selected from by the following group formed: the agonist of sulfonylurea, non-sulfonylurea, thiazolidinediones, dual PPAR agonist, dipeptidyl peptidase-4 inhibitors, SGLT1 or SGLT2 inhibitor, meglitinides, Alpha-glucosidase inhibitor, GPR40, GRP120, GPR119, GPR41 and GPR43

7. combination dosage forms according to claim 2, wherein said antihypertensive is selected from by the following group formed: Beta receptor blockers, alpha blocker, mixed type α/β blocker, calcium channel blocker are as dihydropyridine and non-dihydropyridine, renin inhibitor, ACE inhibitor and angiotensin ii receptor antagonist.

8. combination dosage forms according to claim 2, wherein said antiplatelet drug is selected from by the following group formed: cyclooxygenase-2 inhibitors, adp receptor inhibitor, phosphodiesterase inhibitor, gland reuptake inhibitor, thromboxane synthetase or acceptor inhibitor, anagrelide, prasugrel and cloricromen.

9. combination dosage forms according to claim 2, wherein said diuretic is selected from by the following group formed: loop diuretic, thiazide diuretic, thiazine sample diuretic and Potassium-sparing diuretic.

10. combination dosage forms according to claim 2, wherein said metformin or other biguanide compound are targeted and are delivered to small intestinal and described preparation is included in pH 5.0 or pH 5.5 or is greater than the peroral dosage form of pH 5.0 or pH 5.5 times enteric coatings.

11. combination dosage forms according to claim 1, wherein said biguanide compound is targeted and is delivered to distal small bowel and described preparation is included in pH 6.0 or pH 6.5 or is greater than the peroral dosage form of pH6.0 or pH 6.5 times enteric coatings.

12. combination dosage forms according to claim 1, wherein said combination dosage forms comprises metformin, at least one statin, at least one antihypertensive and optional at least one antiplatelet drug.

13. combination dosage forms according to claim 12, wherein said antihypertensive comprises ACE inhibitor or angiotensin ii receptor antagonist.

14. combination dosage forms according to claim 12, it comprises about 600-800mg metformin, about 20-40mg simvastatin or atorvastatin, about 20-25mg benazepril, lisinopril or losartan and about 75-90mg aspirin.

15. 1 kinds of methods reducing the cardiac metabolism risk in patients in need, it comprises uses combination dosage forms according to any one of claim 1-13 to described patient.

16. methods according to claim 15, wherein reduce the potential metabolic disorder that cardiac metabolism risk comprises the described patient for the treatment of.

17. methods according to claim 15, wherein reduce cardiac metabolism risk and comprise the cardiovascular disease for the treatment of described patient.

18. methods according to claim 15, wherein said combination dosage forms to described patient daily once.

19. methods according to claim 18, wherein said combination dosage forms in the morning to described patient daily once.