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.

Claims

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.

Description

EXAMPLES

[0480] Linagliptin/Metformin HCl extended-release fixed-dose-combination tablets are film-coated tablets manufactured using typical processes and equipment for wet-granulation, tableting and film-coating. The core tablet contains metformin HCl for extended-release and may be based on an expandable polymeric swelling formulation that increases gastric retention and extends drug release from the matrix. This metformin HCl core tablet may be film-coated (spray-coated) with up to four layers (e.g. barrier coat layer, immediate-release active coat layer, color coat layer, final coat layer), one of which (active coat layer) contains the active pharmaceutical ingredient linagliptin to add the immediate-release active component.

[0481] Tablet Coating—Barrier Coat

[0482] Purified water is charged into a stainless steel mixing vessel equipped with a suitable mixer. While mixing at a speed that ensures vortex formation, the Film Forming System is added and mixed for at least 20 minutes. Mixing of the coating solution is continued throughout the coating operation. An appropriate quantity of metformin HCl extended release cores are charged to the coating pan of the perforated coating system equipped with a peristaltic pump and two spray nozzles. After the cores are preheated, pan rotation and spraying of the coating suspension begin. A fixed amount of the barrier coating suspension, which incorporates approximately 15% excess to account for losses during spraying, is applied to the cores. For example, the cores are coated to obtain a weight gain of 6%; to account for losses during spraying, an amount of coating solution equivalent to approximately 6.9% weight gain is used for spraying. Upon completion of the application of the coating solution, the cores are dried (target pan speed 3 rpm, target inlet air temperature 55° C.) for 15 minutes. The barrier-coated cores are then allowed to cool (product temperature not more than 35° C.).

[0483] Tablet Coating—Linagliptin Active Coat

[0484] Purified water is charged into a stainless steel mixing vessel equipped with a suitable mixer. While mixing at a speed that ensures vortex formation, each component polyethylene glycol (PEG 6000), L-arginine, linagliptin, talc and the Film Forming System (HPMC 2910-3 and PEG 8000) is added. The coating suspension is mixed for at least 20 minutes or until the last component added is homogenized. An appropriate quantity of barrier-coated tablet cores are charged to the coating pan of the perforated coating system equipped with a peristaltic pump and two spray nozzles. After the cores are preheated, pan rotation and spraying of the coating suspension begin. A fixed amount of the active coating suspension, which incorporates approximately 10% excess to account for losses during spraying, is applied. For example, the cores are coated to obtain a weight gain of 4.7%; to account for losses during spraying, an amount of coating solution equivalent to approximately 5.4% weight gain is used for spraying. Upon completion of the application of the coating solution, the cores are dried (target pan speed 3 rpm, target inlet air temperature 55° C.) for 15 minutes. The active-coated cores are then allowed to cool (product temperature not more than 35° C.).

[0485] The following compositions can be obtained.

TABLE-US-00010 TABLE A Linagliptin/Metformin HCl extended release formulation, FDC 2.5 mg/750 mg Component mg/tablet Extended release core Metformin hydrochloride (Metformin HCl) 750 Polyethylene Oxide 355.2 (e.g. high molecular weight such as about 7,000,000, such as WSR-303) Hydroxypropyl methylcellulose (Hypromellose) 25.5 (e.g. viscosity about 5 mPas for a 2% solution in water at 20° C., such as HPMC 2910-5 (Methocel E5)) Magnesium Stearate 11.3 Barrier coat: Film Forming System: 68.2 Hydroxypropyl methylcellulose (e.g. HPMCs of 3 cP, 6 cP and 50 cP, such as HPMC 2910-3 (e.g. 19.46% w/w), HPMC 2910-6 (e.g. 16.68% w/w) and HPMC 2910-50 (e.g. 2.79% w/w)), Polydextrose (e.g. 25.94% w/w), Polyethylene glycol (e.g. PEG 8000, e.g. 2.70% w/w), Titanium dioxide (e.g. 32.43% w/w), Purified water * Active (API) coat: Linagliptin (as API) 2.5 Film Forming System: 40.0 Hydroxypropyl methylcellulose (e.g. HPMC of 3 cP, such as HPMC 2910-3, e.g. 95% w/w) Polyethylene glycol (e.g. PEG 8000, e.g. 5% w/w) L-Arginine 10.0 Polyethylene glycol (e.g. PEG 6000) 10.0 Talc 9.0 Purified water * * Processing agent water used in manufacturing and removed by drying

TABLE-US-00011 TABLE B Linagliptin/Metformin HCl extended release formulation, FDC 2.5 mg/1000 mg Component mg/tablet Extended release core Metformin hydrochloride (Metformin HCl) 1000 Polyethylene Oxide 370 (e.g. high molecular weight such as about 7,000,000, such as WSR-303) Hydroxypropyl methylcellulose (Hypromellose) 34.0 (e.g. viscosity about 5 mPas for a 2% solution in water at 20° C., such as HPMC 2910-5 (Methocel E5)) Magnesium Stearate 15.0 Barrier coat: Film Forming System: 85.0 Hydroxypropyl methylcellulose (e.g. HPMCs of 3 cP, 6 cP and 50 cP, such as HPMC 2910-3 (e.g. 19.46% w/w), HPMC 2910-6 (e.g. 16.68% w/w) and HPMC 2910-50 (e.g. 2.79% w/w)), Polydextrose (e.g. 25.94% w/w), Polyethylene glycol (e.g. PEG 8000, e.g. 2.70% w/w), Titanium dioxide (e.g. 32.43% w/w), Purified water * Active (API) coat: Linagliptin (as API) 2.5 Film Forming System: 40.0 Hydroxypropyl methylcellulose (e.g. HPMC of 3 cP, such as HPMC 2910-3, e.g. 95% w/w) Polyethylene glycol (e.g. PEG 8000, e.g. 5% w/w) L-Arginine 10.0 Polyethylene glycol (e.g. PEG 6000) 10.0 Talc 9.0 Purified water * * Processing agent water used in manufacturing and removed by drying

TABLE-US-00012 TABLE C Linagliptin/Metformin HCl extended release formulation, FDC 5 mg/1000 mg Component mg/tablet Extended release core Metformin hydrochloride (Metformin HCl) 1000 Polyethylene Oxide 370 (e.g. high molecular weight such as about 7,000,000, such as WSR-303) Hydroxypropyl methylcellulose (Hypromellose) 34.0 (e.g. viscosity about 5 mPas for a 2% solution in water at 20° C., such as HPMC 2910-5 (Methocel E5)) Magnesium Stearate 15.0 Barrier coat: Film Forming System: 85.0 Hydroxypropyl methylcellulose (e.g. HPMCs of 3 cP, 6 cP and 50 cP, such as HPMC 2910-3 (e.g. 19.46% w/w), HPMC 2910-6 (e.g. 16.68% w/w) and HPMC 2910-50 (e.g. 2.79% w/w)), Polydextrose (e.g. 25.94% w/w), Polyethylene glycol (e.g. PEG 8000, e.g. 2.70% w/w), Titanium dioxide (e.g. 32.43% w/w), Purified water * Active (API) coat: Linagliptin (as API) 5.0 Film Forming System: 40.0 Hydroxypropyl methylcellulose (e.g. HPMC of 3 cP, such as HPMC 2910-3, e.g. 95% w/w) Polyethylene glycol (e.g. PEG 8000, e.g. 5% w/w) L-Arginine 20.0 Polyethylene glycol (e.g. PEG 6000) 10.0 Talc 9.0 Purified water * * Processing agent water used in manufacturing and removed by drying

[0486] Optionally, the above compositions may be further coated by a color coat layer and/or a clear final coat. Typically, the color coat and the final coat may represent 1-4% w/w (preferably 1-2% w/w) of the total composition and each comprise one or more film-forming agents, one or more plasticizers, one or more optional glidants, and one or more optional pigments and/or colors. For example, a color coat may comprise hydroxypropyl methylcellulose (e.g. HPMC of 3 cP and/or HPMC of 6 cP), polyethylene glycol (e.g. PEG 8000), titanium dioxide and a color or lake. For example, a final coat may comprise hydroxypropyl methylcellulose (e.g. HPMC of 3 cP) and polyethylene glycol (e.g. PEG 8000) as well as a polishing wax (e.g. carnauba wax).