Pharmaceutical composition and uses thereof

Abstract

The present invention relates to pharmaceutical compositions comprising fixed dose combinations of a DPP-4 inhibitor drug and/or a SGLT-2 inhibitor drug, and metformin XR, processes for the preparation thereof, and their use to treat certain diseases.

1 . A pharmaceutical composition comprising:
 a) an inner extended release tablet core consisting of metformin hydrochloride, poly(ethylene oxide) as swelling and/or extended release polymer, low molecular weight hydroxypropyl methylcellulose as binder, and magnesium stearate as lubricant, wherein the metformin hydrochloride is present in a unit dosage strength of 1000 mg;   b) an immediate release coating comprising 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene and one or more excipients, wherein the 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene is present in a unit dosage strength of 5, 10, 12.5 or 25 mg; and   c) a barrier coating present between said inner extended release tablet core and said immediate release coating,   
       wherein said pharmaceutical composition is a tablet for oral administration, 
       wherein the barrier coating is a film coat formulation consisting of:
 one or more film-coating agents selected from a mixture of hydroxypropyl methylcellulose (HPMC) and polydextrose, 
 polyethylene glycol and titanium dioxide. 
 
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein said polyethylene glycol is polyethylene glycol 8000. 
     
     
         3 . The pharmaceutical composition according to  claim 1 , wherein
 the barrier coating has a weight in the range from 50 to 100 mg, or   the barrier coating has a weight of 68 mg or 85 mg.   
     
     
         4 . The pharmaceutical composition according to  claim 1  further comprising a color and/or final coating. 
     
     
         5 . The pharmaceutical composition according to  claim 4 , wherein the color and/or final coating is each a film coat formulation independently comprising:
 one or more film-coating agents selected from hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), ethyl cellulose, hydroxypropyl cellulose, polydextrose, methacrylic and/or acrylic polymer, or a mixture thereof,   optionally one or more plasticizers selected from polyethylene glycol, propylene glycol, diethyl phthalate, tributyl sebacate and/or triacetin, or a mixture thereof,   optionally a glidant selected from talc, magnesium stearate and fumed silica, and   optionally one or more pigments and/or colorants.   
     
     
         6 . The pharmaceutical composition according to  claim 4 , wherein the color and/or final coating is each a film coat formulation independently comprising a film-coating agent, a plasticizer, and, optionally, a glidant, one or more pigments and/or colors. 
     
     
         7 . A method of treating and/or preventing (including slowing the progression and/or delaying the onset) of metabolic diseases, especially type 2 diabetes mellitus and conditions related thereto (e.g. diabetic complications) comprising administering a pharmaceutical composition according to  claim 1 :
 either in type 2 diabetes patients who have not been previously treated with an antihyperglycemic agent,   or in type 2 diabetes patients with insufficient glycemic control despite therapy with one or two conventional antihyperglycemic agents selected from metformin, sulphonylureas, thiazolidinediones, glinides, alpha-glucosidase blockers, GLP-1 or GLP-1 analogues, and insulin or insulin analogues.   
     
     
         8 . The pharmaceutical composition according to  claim 5 , wherein said pigment is titanium dioxide. 
     
     
         9 . The pharmaceutical composition according to  claim 1 , wherein the immediate release coating comprises a film coat formulation of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, said film coat formulation comprising 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a film-coating agent, a plasticizer, and, optionally, a glidant. 
     
     
         10 . The pharmaceutical composition according to  claim 1 , wherein the immediate release coating comprises a film coat formulation of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, said film coat formulation comprising 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, one or more film-coating agents, one or more plasticizers, and, optionally, a glidant. 
     
     
         11 . The pharmaceutical composition according to  claim 1 , wherein the immediate release coating comprises a film coat formulation of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, said film coat formulation comprising 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, hydroxypropyl methylcellulose as film-coating agent, polyethylene glycol as plasticizer, and, optionally, a glidant. 
     
     
         12 . The pharmaceutical composition according to  claim 1 , wherein the immediate release coating comprises:
 10-25% w/w of polyethylene glycol,   5-35% w/w of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,   40-70% w/w of hydroxypropyl methylcellulose,   5-20% w/w of talc,   wherein % w/w relate to the weight of the immediate release coating.   
     
     
         13 . The pharmaceutical composition according to  claim 1 , wherein the immediate release coating comprises:
 8-20% w/w of polyethylene glycol of molecular weight of about 6000,   5-35% w/w of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,   40-70% w/w of hydroxypropyl methylcellulose,   0-5% w/w of polyethylene glycol of molecular weight of about 8000,   5-20% w/w of talc,   wherein % w/w relate to the weight of the immediate release coating.   
     
     
         14 . The pharmaceutical composition according to  claim 1 , wherein the immediate release coating comprises:
 10-18% w/w of polyethylene glycol of molecular weight of about 6000,   5-35% w/w of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,   40-65% w/w of hydroxypropyl methylcellulose,   2-4% w/w of polyethylene glycol of molecular weight of about 8000,   8-16% w/w of talc,   wherein % w/w relate to the weight of the immediate release coating.   
     
     
         15 . The pharmaceutical composition according to  claim 1 , wherein
 a) the extended release tablet core comprises:   60-75% w/w of the metformin hydrochloride,   2-3% w/w of the hydroxypropyl methylcellulose,   23-35% w/w of the polyethylene oxide,   0.5-2% w/w magnesium stearate,   wherein % w/w relate to the weight of the extended release tablet core, and   wherein the content of metformin hydrochloride is 1000 mg,   b) the barrier coating consists of polydextrose, hydroxypropylmethylcelluloses, polyethylene glycol and titanium dioxide; and   c) the immediate release coating comprises   8-20% w/w of polyethylene glycol of molecular weight of about 6000,   5-35% w/w of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,   40-70% w/w of hydroxypropyl methylcellulose,   0-5% w/w of polyethylene glycol of molecular weight of about 8000,   5-20% w/w of talc,   wherein % w/w relate to the weight of the immediate release coating, and   wherein the content of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene is 5, 10, 12.5 or 25 mg.   
     
     
         16 . The pharmaceutical composition according to  claim 1 , wherein
 a) the extended release tablet core comprises   60-75% w/w of the metformin hydrochloride,   2-3% w/w of the hydroxypropyl methylcellulose of viscosity about 5 mPas for a 2% solution in water at 20° C.,   23-35% w/w of the polyethylene oxide of high molecular weight of about 7,000,000,   0.5-2% w/w magnesium stearate,   wherein % w/w relate to the weight of the extended release tablet core, and   wherein the content of metformin hydrochloride is 1000 mg,   b) the barrier coating consists of polydextrose, hydroxypropylmethylcelluloses of 3 to 50 cP, polyethylene glycol PEG 8000 and titanium dioxide, and wherein the barrier coating has a weight in the range from 50 to 100 mg; and   c) the immediate release coating comprises   10-18% w/w of polyethylene glycol of molecular weight of about 6000,   5-35% w/w of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,   40-65% w/w of hydroxypropyl methylcellulose,   2-4% w/w of polyethylene glycol of molecular weight of about 8000,   8-16% w/w of talc,   wherein % w/w relate to the weight of the immediate release coating, and   wherein the content of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene is 5, 10, 12.5 or 25 mg.