NZ613301B2

NZ613301B2 - Pharmaceutical compositions comprising metformin and a dpp-4 inhibitor or a sglt-2 inhibitor

Info

Publication number: NZ613301B2
Application number: NZ613301A
Authority: NZ
Inventors: Kenji Egusa; Masanori Ito; Roman Messerschmid; Peter Schneider
Original assignee: Boehringer Ingelheim International Gmbh
Priority date: 2011-03-07
Filing date: 2012-03-07
Publication date: 2016-03-30

Abstract

Provided are pharmaceutical compositions comprising metformin and a DPP-4 inhibitor and/or a SGLT-2 inhibitor. A preferred DPP-4 inhibitor is linagliptin. A preferred SGLT-2 inhibitor is 1-chloro-4-(beta-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene. The pharmaceutical composition may comprise the following: a)an inner extended release core comprising metformin (particularly metformin hydrochloride) and one or more excipients; b)an optional intermediate seal coating; and c)an outer immediate release coating comprising at least one active pharmaceutical ingredient selected from: a DPP-4 inhibitor, preferably linagliptin, and a SGLT-2 inhibitor, preferably 1-chloro-4-(beta-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, and one or more excipients. The pharmaceutical compositions may be useful in the treatment of metabolic disorders such as diabetes. osition may comprise the following: a)an inner extended release core comprising metformin (particularly metformin hydrochloride) and one or more excipients; b)an optional intermediate seal coating; and c)an outer immediate release coating comprising at least one active pharmaceutical ingredient selected from: a DPP-4 inhibitor, preferably linagliptin, and a SGLT-2 inhibitor, preferably 1-chloro-4-(beta-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, and one or more excipients. The pharmaceutical compositions may be useful in the treatment of metabolic disorders such as diabetes.

Description

Pharmaceutical compositions comprising metformin and a DPP-4 inhibitor or a SGLT-2 inhibitor ___________________________________________________________________ The present invention relates to pharmaceutical compositions containing a fixed dose combination (FDC) comprising a DPP-4 inhibitor drug (particularly 1-[(4-methyl-quinazolinyl)methyl]methyl(2-butyn- 1-yl)(3-(R)-amino-piperidinyl)-xanthine, also named linagliptin) and/or a SGLT-2 inhibitor drug (particularly 1-chloro(β-D-glucopyranosyl)[4-((S)- tetrahydrofuranyloxy)-benzyl]-benzene, also named Compound “A” herein), min (particularly metformin hydrochloride) in extended e form rmin XR); processes for the preparation thereof, and their use to treat certain es.

In particular, the present invention relates to a pharmaceutical composition comprising a fixed dose combination of an extended release form of metformin hydrochloride, optionally seal coated, which is further coated with an immediate e form of methyl-quinazolin yl)methyl]methyl(2-butynyl)(3-(R)-amino-piperidinyl)-xanthine (linagliptin) and/or 1-chloro(β-D-glucopyranosyl)[4-((S)-tetrahydrofuranyloxy)-benzyl]-benzene (Compound “A”).

Further, the present invention s to a pharmaceutical composition, particularly a solid preparation (e.g. an oral solid dosage form, such as e.g. a tablet), comprising or consisting essentially of a) an inner extended release core comprising metformin cularly metformin hydrochloride) and one or more ents; b) an optional intermediate seal coating; and c) an outer immediate release coating comprising at least one active pharmaceutical ingredient selected from a DPP-4 inhibitor, preferably linagliptin, and a SGLT-2 tor, preferably Compound “A”, and one or more excipients.

According to the first aspect there is provided a pharmaceutical ition comprising a) an inner extended release core comprising metformin including metformin hydrochloride, and one or more excipients; b) an intermediate seal coating comprising a mixture of hydroxypropyl cellulose and hydroxypropyl methylcellulose ; and AH26(10574887_1):RTK c) an outer immediate release coating comprising: at least one active pharmaceutical ingredient, namely a DPP-4 inhibitor which is linagliptin, a plasticizer, and one or more excipients; wherein the inner extended e core a) is a formulation comprising metformin hydrochloride, a swellable and/or extended release polymer, and one or more further excipients, in which the ble and/or extended release r is a combination of poly(ethylene oxide) optionally in combination with hydroxypropyl methylcellulose (HPMC).

According to the second aspect there is provided use of a pharmaceutical composition according to the first aspect above for the manufacture of a medicament for ng and/or preventing (including slowing the progression and/or delaying the onset) of metabolic diseases, especially type 2 diabetes us and conditions related thereto including diabetic cations, 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 ed from metformin, sulphonylureas, thiazolidinediones (e.g. pioglitazone), es, alpha-glucosidase blockers, GLP-1 or GLP-1 analogues, and insulin or insulin analogues.

In a more detailed aspect, the t invention relates to a pharmaceutical composition, particularly a solid preparation (e.g. an oral solid dosage form, such as a tablet) of a selected dipeptidyl peptidase-4 (DPP-4) tor (preferably linagliptin, particularly in immediate release form) and metformin (particularly metformin hydrochloride) in extended release form (metformin XR). In one embodiment of this aspect, the present invention relates to a AH26(10574887_1):RTK pharmaceutical composition, particularly a solid preparation (e.g. an oral solid dosage form, such as a tablet), comprising a fixed dose combination of an extended release form of metformin hydrochloride, ally seal coated, and further coated with an immediate release form of linagliptin.

In another more detailed aspect, the present invention relates to a pharmaceutical composition, particularly a solid preparation (e.g. an oral solid dosage form, such as a tablet) of a selected SGLT-2 inhibitor (preferably 1-chloro(B-D-glucopyranosy|)[4-((S)- tetrahydrofuranyloxy)-benzyl]—benzene, particularly in immediate release form) and metformin (particularly metformin hydrochloride) in extended release form (metformin XR). In one embodiment of this aspect, the present invention relates to a pharmaceutical composition, particularly a solid preparation (e.g. an oral solid dosage form, such as a tablet), comprising a fixed dose combination of an extended release form of metformin hydrochloride, ally seal coated, and further coated with an ate e form of 1-chloro(B-D-glucopyranosy|)[4-((S)-tetrahydrofuranyloxy)-benzyl]—benzene.

In a further more detailed aspect, the present invention relates to a pharmaceutical composition, particularly a solid preparation (e.g. an oral solid dosage form, such as e.g. a tablet), comprising a first component, part or composition comprising min (particularly metformin hydrochloride) in extended release form and one or more excipients, and a second component, part or composition comprising a selected dipeptidyl peptidase-4 (DPP-4) inhibitor rably linagliptin), particularly in immediate release form, and one or more excipients.

In particular, the present ion relates to a pharmaceutical composition, particularly a solid preparation (e.g. an oral solid dosage form, such as a tablet), sing an extended release form of min hloride, optionally seal coated, and further coated with an immediate release form of linagliptin.

In r further more detailed aspect, the present invention relates to a pharmaceutical composition, particularly a solid preparation (e.g. an oral solid dosage form, such as e.g. a tablet), comprising a first component, part or composition comprising metformin (particularly metformin hydrochloride) in extended release form and one or more excipients, and a second component, part or composition comprising a selected SGLT-2 inhibitor (preferably 1-chloro(B-D-glucopyranosy|)[4-((S)-tetrahydrofuranyloxy)-benzyl]-benzene), particularly in immediate release form, and one or more ents.

In particular, the t invention relates to a pharmaceutical composition, particularly a solid preparation (e.g. an oral solid dosage form, such as a tablet), comprising an extended release form of metformin hydrochloride, optionally seal coated, and further coated with an ate e form of 1-chloro(B-D-glucopyranosy|)[4-((S)-tetrahydrofuran yloxy)-benzyl]-benzene.

In a yet further more detailed aspect, the present invention relates to a ceutical composition, particularly a solid preparation (e.g. an oral solid dosage form, such as e.g. a tablet), comprising a) an inner extended release core comprising metformin (particularly metformin hydrochloride) and one or more excipients, b) an optional seal coating, and c) an outer immediate e coating comprising a selected dipeptidyl peptidase-4 (DPP-4) inhibitor (preferably linagliptin) and one or more excipients.

In another yet further more detailed aspect, the present invention relates to a pharmaceutical composition, particularly a solid preparation (e.g. an oral solid dosage form, such as e.g. a tablet), comprising a) an inner extended release core comprising metformin (particularly metformin hydrochloride) and one or more excipients, b) an optional seal coating, and c) an outer immediate release g comprising a selected SGLT-2 inhibitor (preferably 1-chloro(B-D-glucopyranosy|)[4-((S)-tetrahydrofuranyloxy)- benzyl]—benzene) and one or more excipients.

Particularly, the pharmaceutical compositions of this invention comprise an inner core formulation of metformin hydrochloride comprising a swellable and/or ed e material.

In an embodiment, the pharmaceutical compositions of this invention comprise an inner ed e core which is a formulation (e.g. matrix fomulation) comprising metformin hloride, a swellable and/or extended release material, and one or more further excipients.

Particularly, the pharmaceutical itions of this invention comprise an outer coat of active pharmaceutical ingredient (API) (linagliptin and/or 1-chloro(B-D-glucopyranosy|)- 2-[4-((S)-tetrahydrofuranyloxy)-benzyl]—benzene) in an immediate release polymer film.

Further, the present ion relates to a coating process (e.g. coating logy and processing conditions) and immediate e coating formulations of active ceutical ingredients (API) in low doses (typically in doses of 0.5 to 25 mg) on top of tablet cores comprising active pharmaceutical ingredients (API) in high doses (typically in doses of 500 — 1500 mg) preferably, but not exclusively on extended release tablets. Anyhow, essential parts of the formulation and the process of this invention may be also applicable to any other fixed dose combination with the described setting.

An aim of the t invention is to provide a pharmaceutical composition comprising a combination of a selected DPP-4 inhibitor (preferably linagliptin, particularly in immediate e form), and metformin (particularly metformin hydrochloride) in extended release form.

Another aim of the present invention is to provide a pharmaceutical composition comprising a combination of a selected SGLT-2 inhibitor (preferably 1-ch|oro(B-D-glucopyranosy|) [4-((S)-tetrahydrofuranyloxy)-benzyl]-benzene, particularly in immediate release form), and metformin (particularly metformin hydrochloride) in extended release form.

The objectives of are to identify suitable formulations and processing ions, such as e.g. of a coat of iptin or of 1-chloro(B-D-glucopyranosy|)[4-((S)-tetrahydrofuran yloxy)-benzyl]-benzene on top metformin XR cores, providing adequate: - Chemical stability of the API (particularly linagliptin) in the API film coat, - Assay of linagliptin or 1-chloro(B-D-glucopyranosy|)[4-((S)-tetrahydrofuran yloxy)-benzyl]-benzene in the API film-coat (e.g. 95-105%), - t uniformity of iptin or 1-chloro(B-D-glucopyranosy|)[4-((S)- tetrahydrofuranyloxy)-benzyl]-benzene (e.g. RSD < 3%) in the API film-coat, - Low defect rate of the API-film during film coating process, - Fast dissolution of the API from the API film-coat and no changes of XR Metformin HCI ution, due to the API coating with immediate release of linagliptin or 1-chloro(B-D- glucopyranosy|)[4-((S)-tetrahydrofuranyloxy)-benzyl]—benzene, - Processing aspects of coating process/technology, sing conditions and immediate release API (linagliptin or Compound “A”) coating formulations (API film coat), - Processing aspects of coating s/technology, processing conditions and immediate release API (linagliptin or Compound “A”) coating formulations on top of metformin extended release tablets.

A particular objective of the present invention is to e a pharmaceutical composition and suitable coating process with very broad range of drug substance (linagliptin or Compound “A”)/drug substance (metformin) ratio: 1:400 - 1:40. And the ratio of very low dosed API, e.g. 1O linagliptin with 1 mg or 2.5 mg to very high dosed metformin with 1000 mg and more. And the suitable immediate release dissolution of the low dosed API with high dosed extended e min.

The unit dosage strength of the metformin hydrochloride for incorporation into the fixed-dose combination of the present invention is 500, 750, 850 or 1000 milligrams, or even more (e.g. 1500 mg).

These unit dosage strengths of metformin hydrochloride represent the dosage strengths approved in the US. for marketing to treat Type 2 diabetes.

The unit dosage strength of linagliptin for incorporation into the fixed-dose combination of the present ion is 2.5 or 5 milligrams, or even less (e.g. 0.5 mg or 1 mg).

The unit dosage strength of 1-chloro(B-D-glucopyranosyl)[4-((S)-tetrahydrofuran yloxy)-benzyl]-benzene for incorporation into the fixed-dose ation of the present invention is 5, 10, 12.5 or 25 milligrams.

Specific embodiments of dosage strengths for linagliptin and metformin hydrochloride in the fixed-dose combinations of the present invention are the following: (1) 5 milligrams of linagliptin and 1000 milligrams metformin hydrochloride; (2) 2.5 milligrams of linagliptin and 1000 rams min hydrochloride; (3) 2.5 milligrams of linagliptin and 750 milligrams metformin hloride.

Specific embodiments of dosage strengths for ro(B-D-glucopyranosyl)[4-((S)- tetrahydrofuranyloxy)-benzyl]-benzene and metformin hydrochloride in the fixed-dose ations of the present invention are the following: (1) 25 rams of 1-chloro(B-D-glucopyranosy|)[4-((S)-tetrahydrofuranyloxy)- benzyl]-benzene and 1000 milligrams metformin hydrochloride; (2) 12.5 milligrams of 1-chloro(B-D-glucopyranosy|)[4-((S)-tetrahydrofuranyloxy)— benzyl]-benzene and 1000 milligrams metformin hydrochloride; (3) 12.5 milligrams of 1-chloro(B-D-glucopyranosy|)[4-((S)-tetrahydrofuranyloxy)— benzyl]-benzene and 750 milligrams metformin hydrochloride; (4) 10 rams of 1-chloro(B-D-glucopyranosy|)[4-((S)-tetrahydrofuranyloxy)- benzyl]-benzene and 1000 milligrams metformin hydrochloride; (5) 10 milligrams of 1-chloro(B-D-glucopyranosy|)[4-((S)-tetrahydrofuranyloxy)- 1O benzyl]-benzene and 750 milligrams metformin hydrochloride; (6) 5 milligrams of 1-chloro(B-D-glucopyranosy|)[4-((S)-tetrahydrofuranyloxy)— benzyl]-benzene and 1000 milligrams metformin hydrochloride; (7) 5 milligrams of 1-chloro(B-D-glucopyranosy|)[4-((S)-tetrahydrofuranyloxy)— ]-benzene and 750 milligrams metformin hydrochloride. (a) Metformin part: The first part in the present ion is a part (composition, particularly solid composition, e.g. a solid pharmaceutical composition for oral administration, e.g. tablet) comprising metformin cularly metformin hydrochloride) in extended release form, particularly an extended release formulation of metformin.

Exemplary extended e formulations of metformin are disclosed in US 6,340,475; US 6,488,962; US 6,635,280; US 6,723,340; US 7780987; US 6,866,866; US 6,495,162; US 6,790,459; US 6,866,866; US 521; and US 6,660,300; the disclosures of which are incorporated herein in their entireties.

A particular ed release formulation of metformin is described in US 6,723,340, the disclosure of which is incorporated herein in its entirety.

In an embodiment, the fixed-dose combination products of the present invention se - as first part - an inner core matrix formulation with min hydrochloride dispersed n, said matrix formulation containing an extended release material. The matrix formulation is compressed into a tablet form.

In ular, the fixed-dose combination products of the present invention comprise - as first part - an inner core extended release formulation comprising metformin hydrochloride, hydroxypropyl methylcellulose (hypromellose), polyethylene oxide, microcrystalline cellulose, and magnesium stearate.

A particular extended release ation of metformin is described in US 6,723,340 as follows: In an embodiment, the extended release material of the matrix comprises poly(ethylene 1O oxide) and/or ypropyl methylcellulose (H PMC), preferably a combination of poly(ethylene oxide) and hydroxypropyl methylcellulose (HPMC), preferably at a weight ratio that causes the matrix to swell upon contact with gastric fluid to a size large enough to provide gastric retention.

The poly(ethylene oxide) ent of the matrix may limit initial release of the drug and may impart gastric retention through swelling. The hydroxypropyl cellulose (HPMC) component may lower the amount of poly(ethylene oxide) required while still allowing the swelling to occur.

Preferably, the poly(ethylene oxide) has a viscosity average molecular weight of from about 2,000,000 to about 10,000,000 daltons, more preferably from about 4,000,000 to about 7,000,000 daltons.

Preferably, the ypropyl methylcellulose (HPMC) has a viscosity of from about 4,000 oise to about 0 centipoise, more ably from about 50,000 to about 200,000 centipoise, even more preferably 80,000 centipoise to about 120,000 centipoise, measured as a 2% solution in water.

More preferably, the poly(ethylene oxide) has a viscosity average molecular weight of from about 4,000,000 to about 7,000,000 daltons, and the hydroxypropyl methylcellulose (HPMC) has a viscosity of from about 80,000 centipoise to about 120,000 centipoise, measured as a 2% solution in water.

In an embodiment, the weight ratio of the poly(ethylene oxide) to hydroxypropyl methylcellulose (HPMC) is within the range from about 1:3 to 3:1, preferably 1:2 to 2:1.

In a further embodiment, the weight ratio of the poly(ethylene oxide) and hydroxypropyl methylcellulose (HPMC) in combination constitutes from about 15% to about 90%, or from about 30% to about 65%, or from about 40% to about 50%, by weight of the metformin part.

Tablet cores in accordance with this ion can be prepared by common tab|etting methods that involve mixing, comminution, and fabrication steps commonly practiced by and well known to those skilled in the art of manufacturing drug formulations. Examples of such techniques are: 1O (1) Direct compression using appropriate punches and dies, lly fitted to a suitable rotary tab|etting press; (2) Injection or compression molding; (3) Granulation by fluid bed, by low or high shear granulation, or by roller tion, ed by compression; and (4) Extrusion of a paste into a mold or to an extrudate to be cut into lengths.

When tablets are made by direct ssion, the addition of lubricants may be helpful and is sometimes important to e powder flow and to prevent breaking of the tablet when the pressure is relieved. Examples of typical lubricants are magnesium stearate (in a concentration of from 0.25% to 3% by weight, preferably about 1% or less by weight, in the powder mix), stearic acid (0.5% to 3% by weight), and hydrogenated vegetable oil rably enated and refined triglycerides of stearic and palmitic acids at about 1% to 5% by weight, most preferably about 2% by weight).

Additional excipients may be added, such as e.g. granulating aids (e.g. low molecular weight HPMC at 2—5% by weight), s (e.g. microcrystalline cellulose), and additives to enhance powder flowability, tablet hardness, and tablet friability and to reduce adherence to the die wall.

An exemplary extended release metformin tablet core comprises min hydrochloride, a combination of poly(ethylene oxide) and hydroxypropyl methylcellulose (e.g. Methocel K100M) as a matrix for a ble extended release tablet, microcrystalline cellulose as binder, low molecular weight hydroxypropyl methylcellulose (e.g. Methocel E5) as granulating aid, and magnesium stearate as lubricant.

The composition of a representative metformin core tablet is provided as follows: metformin hydrochloride, e.g. 49.97% by weight of the first part, poly(ethylene oxide), e.g. 26.50% by weight of the first part, hydroxypropyl methylcellulose (e.g. Methocel K100M), e.g. 16.08% by weight of the first part, microcrystalline cellulose, e.g. 4.99% by weight of the first part, low molecular weight hydroxypropyl methylcellulose (e.g. Methocel E5), e.g. 1.70% by weight of the first part, and magnesium stearate, e.g. 0.75% by weight of the first part.

Tablets may be formulated by dry blending a granulation sing metformin hydrochloride and low molecular weight HPMC (e.g. Methocel E5) and the remaining excipients listed above, followed by pressing on a tablet press.

Such an extended release matrix ation of metformin is disclosed in US 6,723,340 (e.g.

Example 3), the disclosure of which is incorporatd herein in its entirety.

As further example of a lubricant sodium stearyl fumarate may be mentioned (e.g. at about 0.25-3 %by weight).

In a further embodiment, the metformin extended release formulation allows for targeted, controlled delivery of metformin to the upper gastrointestinal (GI) tract. In a further embodiment, the metformin extended release formulation is a el matrix system and contains a swelling hydrophilic polymer and further excipients, which may allow the metformin tablet core to be retained in the stomach (‘gastric ion’) for approximately eight to nine hours. During this time, the tablet core’s metformin is steadily delivered to the upper GI tract at the d rate and time, t potentially irritating ‘burst’ of drug. This l, extended release typically allows for more of the metformin drug to be ed in the upper GI tract and minimizes the amount of drug that passes through to the lower GI tract. (b1) Linagliptin part: In one variant, the second part in the present ion is a part (composition, particularly film coat) comprising iptin in immediate release form.

In a particular embodiment, the fixed-dose combination products of the present ion comprise - as second part - a film coat formulation of |inag|iptin, said film coat formulation comprising |inag|iptin, a izer for stabilizing |inag|iptin (e.g. a basic and/or nucleophilic excipient, preferably nine as stabilizer), a film-coating agent (such as e.g. hydroxypropyl methylcellulose, e.g. Hypromellose 2910, Methocel E5, or Methocel E15), a plasticizer (such as e.g. polyethylene glycol, e.g. Macrogol 400, 6000 or 8000, or propylene glycol), and, optionally, a glidant (such as e.g. talc).

In an embodiment, the weight ratio of the L-arginine to |inag|iptin is within the range from 1O about 2:1 to about 1:1, up to about 02:1.

The composition of a entative |inag|iptin containing film coat is provided as follows: - iptin, e.g. 2.5 mg or 5 mg; - L-arginine, e.g. depending from need of stabilizer amount, e.g. in the range from about 0.5 mg to about 10 mg (e.g. 5 mg); - hydroxypropyl methylcellulose (e.g. Methocel E5, Methocel E15, or Pharmacoat 603 or 606), e.g. from about 25 mg to about 40 mg (especially from 34.5 mg to 38 mg, or 34.5 mg); - polyethylene glycol (e.g. Macrogol 400, 6000 or 8000), e.g. from about 0 to about 12 mg; - propylene glycol, e.g. from about 0 mg to about 15 mg ially 9 mg); and - talc, e.g. from about 0 mg to about 15 mg (especially 9 mg).

Depending from need of stabilizer the amount of L-arginine may be in the range from 0.5 mg to 10 mg. With ent dose and different arginine amount, the arginine amount may be tued by hydroxypropyl methylcellulose (HPMC).

In an ment, polyethylene glycol and propylene glycol are mutually exclusive in above composition, i.e. if polyethylene glycol is present then propylene glycol is absent, or if propylene glycol is present then polyethylene glycol is absent.

The composition of a entative |inag|iptin containing film coat suspension further comprises water, e.g. from about 240 mg to about 1440 mg, especially in the range from 904 mg to 1440 mg. The total solids concentration of the suspension is from about 4% to about 12.5% w/w, especially from 4% to 6% w/w. Viscosity may be from about 10 mPas to 110 mPas (e.g. 46-56 mPas).

The sum solids of the iptin coating suspension is from about 50 mg to about 120 mg.

For example, the sum solids is 60 mg of solid amount of the film coating suspension for 2.5 mg iptin, and 120 mg sum solid amount of the film coating suspension for 5 mg Iinagliptin. ore with the same formulation of Iinagliptin and double coating time (i.e. double amount of coating suspension) it is le to prepare the higher dose range of iptin. Hence different dosage strengths can be achieved by altering coating (spraying) times. (b2) 1-Chloro(B-D-glucopyranosy|)[4-((S)-tetrahydrofuranyloxy)-benzyl]-benzene 1O part: In another variant, the second part in the present invention is a part (composition, ularly film coat) comprising 1-chloro(B-D-glucopyranosy|)[4-((S)-tetrahydrofuranyloxy)— benzyl]-benzene in immediate release form.

In another particular embodiment, the fixed-dose combination products of the present invention comprise - as second part - a film coat formulation of 1-chloro(B-D- glucopyranosy|)[4-((S)-tetrahydrofuranyloxy)-benzyl]—benzene, said film coat ation comprising 1-chloro(B-D-glucopyranosy|)[4-((S)-tetrahydrofuranyloxy)— benzyl]—benzene, a film-coating agent (such as e.g. hydroxypropyl methylcellulose, e.g. ellose 2910, Methocel E5, or Methocel E15), a plasticizer (such as e.g. polyethylene glycol, e.g. Macrogol 400, 6000 or 8000, or propylene glycol), and, optionally, a glidant (such as e.g. talc).

The composition of a representative 1-chloro(B-D-glucopyranosy|)[4-((S)- tetrahydrofuranyloxy)-benzyl]-benzene containing film coat is provided as follows: - 1-chloro(B-D-glucopyranosy|)[4-((S)-tetrahydrofuranyloxy)—benzyl]—benzene, e.g. mg, 10 mg, 12.5 mg or 25 mg; - optionally, L-arginine, e.g. from about 5 mg to about 25 mg; - hydroxypropyl methylcellulose (e.g. Methocel E5, Methocel E15, or Pharmacoat 603 or 606), e.g. from about 25 mg to about 40 mg (especially from 34.5 mg to 38 mg, or 34.5 mg); - polyethylene glycol (e.g. Macrogol 400, 6000 or 8000), e.g. from about 0 to about 12 mg; - propylene glycol, e.g. from about 0 mg to about 15 mg (especially 9 mg); and - talc, e.g. from about 0 mg to about 15 mg (especially 9 mg).

With different dose and different arginine amount, the arginine amount may be substitued by hydroxypropyl methylcellulose (HPMC).

In an ment, polyethylene glycol and propylene glycol are mutually exclusive in above composition, i.e. if polyethylene glycol is present then propylene glycol is , or if propylene glycol is t then polyethylene glycol is absent.

The composition of a entative 1-chloro(B-D-glucopyranosyl)[4-((S)- tetrahydrofuranyloxy)-benzyl]-benzene containing film coat suspension further comprises water, e.g. from about 240 mg to about 1440 mg, especially in the range from 904 mg to 1440 mg. The total solids concentration of the suspension is from about 4% to about 12.5% w/w, especially from 4% to 6% w/w.

The sum solids of the 1-chloro(B-D-glucopyranosyl)[4-((S)-tetrahydrofuranyloxy)- benzyl]-benzene coating suspension is from about 50 mg to about 120 mg. For example, the sum solids is 60 mg of solid amount of the film coating suspension for 12.5 mg 1-chloro(B- D-glucopyranosyl)[4-((S)-tetrahydrofuranyloxy)-benzyl]-benzene, and 120 mg sum solid amount of the film coating suspension for 25 mg 1-chloro(B-D-glucopyranosyl) [4-((S)-tetrahydrofuranyloxy)-benzyl]-benzene. Therefore with the same formulation of 1- chloro(B-D-glucopyranosyl)[4-((S)-tetrahydrofuranyloxy)-benzyl]-benzene and double coating time (i.e. double amount of g suspension) it is possible to prepare the higher dose range of ro(B-D-glucopyranosyl)[4-((S)-tetrahydrofuranyloxy)- benzyl]—benzene. Hence different dosage strengths can be achieved by altering coating ing) times.

L-Arginine is preferably necessary for the stabilization of linagliptin. Alternatively, a seal coat may be used between the metformin XR core and the linagliptin-containing film coat.

In one embodiment, a seal coat is present n the min XR core and the linagliptin-containing film coat (optionally further containing L-arginine). In another ment, the seal coat is absent between the metformin XR core and the linagliptin- containing film coat (preferably further containing L-arginine).

For Compound “A” preferably no arginine is necessary. For Compound “A” the seal coating of min XR cores is optional. In one embodiment, a seal coat is present between the metformin XR core and the Compound “A” containing film coat. In another embodiment, the seal coat is absent between the metformin XR core and the Compound “A” ning film coat.

Alternatively, for the API (linagliptin or Compound “A”) containing film coat, a film coat comprising a mixture of hydroxypropylcellulose and hydroxypropyl methylcellulose, or a e of polyvinyl alcohol (PVA) and polyethylene glycol (PEG); or a commercial film-coat such as Opadry®, Opadry ll® or other Opardy IR film coat, which are formulated powder blends provided by Colorcon, may be used. With Opadry II or PVA based API coating higher solid concentrations and shorter coating time ons are possible, therefore it works in a 1O range of 10-30%, ally 20% solid concentration. This higher solid concentration, e.g. %, typically results in a shorter coating time, e.g. 2-5 hours.

For example, further versions of API-containing film coat compositions comprising one or more of the following ingredients of Tables 1 or 2 may be provided, e.g. as follows from Tables 1 or 2: Table 1: Example formulations for API-coating of linagliptin on top of metformin XR cores PEG- PG- PG- PEG- containing_ _ Further r containing_ _ containing_ _ containing_ _ _ _ _ version version version Composition (%_ _ _ _ n verSIon verSIon (reduced _ (e.g. (e.g. w/w) (low DL) (high DL) (e.g. 2.5 arginine)_ _ 2.5 mg 5 mg (e.g. 2.5 (e.g. 2.5 mg API) (e.g. 5 mg API) API) mg API) mg API) API) HPMC (e.g Pharmacoat 67.23 70.18 72.73 70.55 615)* HPMC (e.g 57.5 57.5 Methocel E5) Polyethylene glycol (e.g. PEG 20.17 21.05 15 15 6000) —————-- ———--—— Solid content of .95 5.70 5.50 5.67 4.0 4.0 suspension (%) *Alternative Methocel E15 ** Solvent is a volatile component, which does not remain in the final product In one ment of the API coatings of this invention, the film-coating agent used is highly viscous.

In another embodiment of the API coatings of this invention, the film-coating agent used is low s.

Table 2: Further Example formulations for API-coating of linagliptin on top of min XR 1O COFGSI PEG- PEG- containing PG-containing PG-containing containing version version version Composition (% w/w) version (reduced (low DL) (high DL) (e.g. 2.5 mg arginine) (e.g. 2.5 mg (e.g. 2.5 mg API) (e.g. 5 mg API) API) API) Linagliptin 4.20 4.55 5.29 HPMC (e.g. 57.23 70.18 72.73 70.55 Pharmacoat 615) Polyethylene glycol '” 21'05 (e.g. PEG 5000) L-Arginine 8.40 4.39 m— ** Solvent is a le component, which does not remain in the final product Film coating suspensions/solutions of API (linagliptin or Compound “A”) according to this invention can be prepared by common methods, such as follows: The film-coating agent hydroxypropyl cellulose (HPMC), the plasticizer polyethylene glycol (PEG) (e.g. Macrogol 400, 6000 or 8000) or, as alternative plasticizer, propylene glycol (PG) and water are ved and mixed by a suitable mixer (e.g. by propeller mixer) to produce the API-free coating solution. Optionally, the glidant talc suspended in water is added and the obtained suspension is homogenized. Talc may be used optionally.

The API (linagliptin or Compound “A”) and - preferably in case of iptin - the stabilizer L- arginine are ved or suspended in water and added to the aqueous solution of HPMC, PEG or PG, and, optional talc, and dispersed by a suitable mixer (e.g. by propeller mixer) to provide the API coating suspension.

Alternatively, the oating agent hydroxypropyl methylcellulose (H PMC) and water are dissolved and mixed by a suitable mixer (e.g. by Ultraturrax).

The stabilizer L-arginine (which is present in case of linagliptin, and may be absent in case of Compound “A”), the plasticizer polyethylene glycol (PEG) (e.g. Macrogol 400, 6000 or 8000) or propylene glycol (PG), al talc, and water are dispersed, e.g. by homogenization using e.g. ultra turrax.

After degassing of the HPMC solution (or directly after manufacturing of the HPMC solution), the aqueous suspension of PEG or PG, optional nine and al talc are added to the aqueous HPMC solution and mixed/homogenized.

The API (linagliptin or nd “A”) is ved or ded in water and added to the aqueous solution of HPMC, PEG or PG, optional L-arginine and optional talc to provide the API coating suspension.

The film-coating operation is carried out in a conventional film coater. The API (linagliptin or Compound “A”) coating suspension/solution are coated at metformin XR cores via coating process.

Preliminary preheating of the cores may be necessary, due to need of equilibrium of water amount of the cores.

The spray rate and air flow through the coating pan is adjusted to produce a uniform coating and coverage of the entire width of the tablet bed. The amount of the coating suspension applied can be controlled by percent weight gain of tablet cores and typically ranges from about 4 to about 12.5%.

WO 20040 In one aspect, this range s in Iinagliptin drug assay close to the desired 2.5 mg or 5 mg with a standard deviation of about 2-4% for content uniformity assay of Iinagliptin. The duration of the coating step is about 4-10 hours. The duration of the coating step depends on batch size, process parameters like spray rate and solid concentrations of the coating suspension.

In another aspect, this range s in Compound “A” drug assay close to the desired 5 mg, 12.5 mg, 10 mg or 25 mg with a standard deviation of about 2-4% for content uniformity assay of Compound A’ The duration of the coating step is about 4-10 hours. The duration of the coating step depends on batch size, process parameters like spray rate and solid concentrations of the coating suspension.

The API g suspension is applied to the tablet cores containing the metformin XR formulation and the amount of solids deposited in the API film layer is controlled to achieve the desired APl doses.

The weight of the cores and film coated tablets may be controlled by t weight gain during the coating s. Instead of or in addition to weight gain method a PAT method, e.g. online NIR or Raman method for end point detection of assay ofAPl may be used.

An optional seal coat may separate the metformin XR core from the APl-containing film coat.

Typically, for the preparation of film-coated tablets a coating suspension is prepared and the tablet cores may be coated with the seal coating suspension using standard film .

The film coating t is a volatile component, which does not remain in the final product. A typical seal film-coat comprises a film coating agent, a plasticizer, and, optionally, a glidant, one or more pigments and/or colors.

The metformin XR core may be seal coated using a seal coating agent (and a plasticizer), such as with a mixture of hydroxypropylcellulose and hydroxypropyl methylcellulose, a mixture of polyvinyl alcohol (PVA) and hylene glycol (PEG), a mixture of hydroxypropyl cellulose and either polyethylene glycol (PEG) or propylene glycol (PG), or any other suitable immediate-release film-coating agent(s). A commercial film-coat is Opadry®, Opadry ll® or other Opardy IR film coat, which are formulated powder blend provided by Colorcon.

Optionally the seal coat may further comprise a glidant.

The final pharmaceutical compositions of the present invention are tablets. Such tablets may be further film-coated with a final film over-coat, such as with a mixture of hydroxypropylcellulose and ypropyl methylcellulose containing titanium dioxide and/or other coloring agents, such as iron , dyes, and lakes; a mixture of polyvinyl alcohol (PVA) and hylene glycol (PEG) containing titanium dioxide and/or other coloring agents, such as iron oxides, dyes, and lakes; a mixture of hydroxypropyl methylcellulose and either polyethylene glycol (PEG) or propylene glycol (PG) containing titanium dioxide and/or other coloring agents, such as iron oxides, dyes, and lakes; or any other suitable immediate- release film-coating s). The coat may provide taste masking and additional stability to the final . A commercial film-coat is Opadry®, Opadry ll® or other Opardy IR film coat, which are formulated powder blend provided by Colorcon.

Preferably, for the preparation of film-coated tablets a coating suspension is prepared and the tablet cores are coated with the coating suspension, typically for the APl-free film over- coat to a weight gain of about 2—4%, preferably about 3%, using standard film coater.

The film coating solvent is a volatile ent, which does not remain in the final product. A typical film-coat comprise a film coating agent, a plasticizer, and, optionally, a glidant, one or more pigments and/or colors. For e, the film coat may comprise hydroxypropylmethylcellulose (HPMC), propylene glycol or polyethylene glycol, talc and, optionally, titanium dioxide and/or iron oxide (e.g. iron oxide yellow and/or red).

The pharmaceutical tablet compositions of the present invention may also contain one or more additional formulation ingredients ed from a wide variety of excipients known in the pharmaceutical formulation art. According to the desired properties of the pharmaceutical composition, any number of ingredients may be selected, alone or in ation, based upon their known uses in preparing tablet itions. Such ingredients include, but are not limited to, diluents, compression aids, ts, disintegrants, lubricants, flavors, flavor enhancers, sweeteners, and preservatives.

The term t" as used herein is intended to encompass compressed ceutical dosage formulations of all shapes and sizes.

The present invention also provides s particularly for treating Type 2 diabetes by orally administering to a host in need of such treatment a therapeutically effective amount of one of the fixed-dose combination pharmaceutical compositions of the present invention. In one ment the host in need of such treatment is a human. In another embodiment the pharmaceutical composition is in the dosage form of a tablet. The pharmaceutical compositions comprising the fixed-dose combination may be administered once-daily (QD), twice-daily (BID), thrice-daily (TID), or four-times daily.

Manufacture and Polymorph The term |iptin" as ed herein refers to iptin, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a polymorphic form f. Crystalline forms are described in . Preferred crystalline forms are the polymorphs A and B described n. In particular, |inag|iptin is the free base 1-[(4-methyl-quinazolin hyl]methyl(2-butynyl)(3-(R)-amino-piperidinyl)-xanthine. As |inag|iptin or a 1O pharmaceutically acceptable salt thereof, |inag|iptin is preferred. Methods for the manufacture of |inag|iptin are described in the patent applications and WO 2006/048427 for example. 1-[(4-Methyl-quinazolinyl)methyl]methyl(2-butynyl)(3-(R)-amino-piperidinyl)- xanthine (|inag|iptin): @rﬁmN According to this invention, it is to be understood that the definition of the SGLT2 inhibitor, in particular 1-chloro(B-D-glucopyranosyl)[4-((S)-tetrahydrofuranyloxy)-benzyl]- benzene (Compound “A”), also comprises its hydrates, solvates and rphic forms thereof, and prodrugs thereof. Vlﬁth regard to the preferred 1-chloro(B-D-glucopyranos yl)[4-((S)-tetrahydrofuranyloxy)-benzyl]—benzene an advantageous crystalline form is described in the international patent applciation which hereby is incorporated herein in its entirety. This crystalline form possesses good solubility ties which enable a good bioavailability of the SGLT2 inhibitor. Furthermore, the crystalline form is physico-chemically stable and thus provides a good shelf-life stability of the pharmaceutical composition. 1-Chloro(B-D-glucopyranosyl)[4-((S)-tetrahydrofuranyloxy)-benzyl]-benzene (Compound “A”): Methods for the manufacture of SGLT2 inhibitors according to this invention and of prodrugs thereof are known to the one skilled in the art. Advantageously, the nds according to this invention can be prepared using synthetic methods as described in the literature, including patent applications as cited hereinbefore. Preferred methods of manufacture, in particular of 1-chloro(B-D-glucopyranosyl)[4-((S)-tetrahydrofuranyloxy)-benzyl]- benzene, are described in the .

For avoidance of any doubt, the disclosure of each of the foregoing documents cited above in connection with the specified SGLT2 or DPP-4 inhibitors is specifically incorporated herein by reference in its entirety. tions As described herein by the administration of the pharmaceutical composition ing to this invention, therapeutic effects can be achieved, which make it useful for treating and/or preventing n diseases, disorders or conditions, such as e.g. those described herein. ore, a treatment or prophylaxis according to this invention is advantageously suitable in those patients in need of such treatment or prophylaxis who are diagnosed of one or more of the ions selected from the group consisting of ovenNeight and obesity, in particular class I obesity, class II obesity, class III y, visceral obesity and abdominal obesity. In addition a treatment or prophylaxis according to this invention is advantageously le in those patients in which a weight increase is contraindicated. The pharmaceutical composition as well as the methods according to the present ion allow a reduction of the HbA1c value to a desired target range, for example < 7 % and preferably < 6.5 %, for a higher number of patients and for a longer time of therapeutic treatment ed with a corresponding monotherapy.

The pharmaceutical ition according to this invention and in particular the active ingredients therein exhibits a very good efficacy with regard to glycemic control, in particular in view of a reduction of fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin (HbA1c). By administering a pharmaceutical ition according to this invention, a reduction of HbA1c equal to or greater than preferably 0.5 %, even more preferably equal to or greater than 1.0 % can be achieved and the reduction is particularly in the range from 1.0 % to 2.0 %.

Furthermore, the method and/or use according to this invention is advantageously applicable 1O in those patients who show one, two or more of the following conditions: (a) a fasting blood e or serum glucose concentration greater than 110 mg/dL, in particular r than 125 mg/dL; (b) a postprandial plasma glucose equal to or greater than 140 mg/dL; (c) an HbA1c value equal to or r than 6.5 %, in ular equal to or greater than 7.0 %, especially equal to or greater than 7.5 %, even more particularly equal to or greater than 8.0 %.

The present invention also discloses the use of the pharmaceutical composition for improving glycemic control in patients having type 2 diabetes or showing first signs of pre- diabetes. Thus, the invention also includes diabetes prevention. lf therefore a pharmaceutical composition according to this invention is used to e the glycemic control as soon as one of the above-mentioned signs of pre-diabetes is present, the onset of manifest type 2 diabetes mellitus can be delayed or prevented. rmore, the pharmaceutical composition according to this invention is particularly suitable in the treatment of patients with insulin dependency, i.e. in ts who are d or othenNise would be treated or need treatment with an insulin or a tive of insulin or a tute of insulin or a formulation comprising an insulin or a derivative or substitute f. These patients include patients with diabetes type 2 and patients with diabetes type 1.

Therefore, according to a preferred embodiment of the present ion, there is provided a method for improving glycemic control and/or for reducing of fasting plasma glucose, of postprandial plasma glucose and/or of ylated hemoglobin HbA1c in a patient in need thereof who is diagnosed with impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG) with insulin resistance, with metabolic syndrome and/or with type 2 or type 1 diabetes mellitus characterized in that a pharmaceutical ition as defined hereinbefore and hereinafter is administered to the patient.

According to another preferred embodiment of the present invention, there is provided a method for improving gycemic control in patients, in particular in adult patients, with type 2 diabetes mellitus as an adjunct to diet and exercise.

Therefore, the method and/or use according to this invention is advantageously applicable in those patients who show one, two or more of the ing conditions: (a) insufficient glycemic control with diet and exercise alone; (b) insufficient glycemic control despite oral monotherapy with metformin, in particular despite oral monotherapy at a maximal tolerated dose of metformin; (c) icient glycemic control despite oral monotherapy with another antidiabetic agent, in particular despite oral erapy at a maximal tolerated dose of the other antidiabetic agent.

The lowering of the blood e level by the administration of a pharmaceutical composition according to this ion is insulin-independent. Therefore, a pharmaceutical composition according to this invention is particularly suitable in the treatment of patients who are diagnosed having one or more of the following conditions - insulin resistance, - nsulinemia, - pre-diabetes, - type 2 diabetes mellitus, particular having a late stage type 2 diabetes mellitus, - type 1 diabetes mellitus.

Furthermore, a pharmaceutical composition ing to this ion is particularly suitable in the treatment of patients who are diagnosed having one or more of the ing conditions (a) obesity (including class I, ll and/or lll obesity), al obesity and/or abdominal obesity, (b) triglyceride blood level 2 150 mg/dL, (c) HDL-cholesterol blood level < 40 mg/dL in female patients and < 50 mg/dL in male patients, (d) a systolic blood pressure 2 130 mm Hg and a diastolic blood re 2 85 mm Hg, (e) a fasting blood glucose level 2 110 mg/dL.

It is assumed that patients diagnosed with impaired glucose tolerance (IGT), impaired fasting blood e (IFG), with n resistance and/or with metabolic syndrome suffer from an increased risk of developing a cardiovascular disease, such as for example myocardial infarction, ry heart disease, heart insufficiency, thromboembolic events. A glycemic control according to this invention may result in a reduction of the cardiovascular risks.

A pharmaceutical composition according to this invention exhibits a good safety profile.

Therefore, a treatment or prophylaxis according to this invention is advantageously possible in those patients for which the mono-therapy with another antidiabetic drug is indicated and/or who have an intolerance against such drugs at therapeutic doses. In particular, a treatment or prophylaxis according to this invention may be advantageously possible in those patients showing or having an increased risk for one or more of the following ers: renal insufficiency or diseases, cardiac diseases, cardiac failure, hepatic diseases, pulmonal es, catabolytic states and/or danger of lactate acidosis, or female patients being pregnant or during lactation.

Furthermore, it can be found that the administration of a pharmaceutical composition ing to this invention results in no risk or in a low risk of ycemia. Therefore, a treatment or laxis according to this invention is also advantageously possible in those patients showing or having an increased risk for hypoglycemia.

A pharmaceutical ition ing to this invention is ularly suitable in the long term treatment or prophylaxis of the diseases and/or conditions as bed hereinbefore and hereinafter, in particular in the long term glycemic l in patients with type 2 diabetes mellitus.

The term "long term" as used hereinbefore and hereinafter indicates a treatment of or administration in a patient within a period of time longer than 12 weeks, preferably longer than 25 weeks, even more preferably longer than 1 year. ore, a particularly preferred embodiment of the present invention provides a method for therapy, preferably oral therapy, for improvement, especially long term improvement, of glycemic control in patients with type 2 diabetes mellitus, especially in patients with late stage type 2 diabetes mellitus, in particular in patients additionally diagnosed of overweight, obesity (including class I, class II and/or class III obesity), visceral obesity and/or abdominal obesity. ing to another aspect of the invention, there is provided a method for preventing, slowing the progression of, delaying or treating of a condition or disorder selected from the group consisting of complications of diabetes mellitus such as cataracts and micro- and macrovascular diseases, such as dyslipidemia, nephropathy, retinopathy, neuropathy, tissue ischaemia, diabetic foot, arteriosclerosis, dial infarction, accute coronary syndrome, unstable angina pectoris, stable angina pectoris, stroke, peripheral arterial occlusive disease, 1O cardiomyopathy, heart failure, heart rhythm disorders and ar restenosis, in a patient in need thereof characterized in that a pharmaceutical composition according to the invention is administered to the patient. In particular one or more aspects of diabetic nephropathy such as hyperperfusion, proteinuria and albuminuria may be treated, their ssion slowed or their onset d or prevented. The term "tissue ischaemia" particularly comprises diabetic macroangiopathy, diabetic microangiopathy, impaired wound healing and diabetic ulcer. The terms "micro- and macrovascular diseases" and "micro- and ascular complications" are used interchangeably in this application.

According to another aspect of the invention, there is provided a method for preventing, g the ssion of, delaying or treating a metabolic disorder selected from the group consisting of type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, ight, obesity, lic syndrome, gestational diabetes and diabetes d to cystic fibrosis in a patient in need f characterized in that a pharmaceutical composition ing to the invention is administered to the patient.

According to another aspect of the ion, there is provided a method for improving glycemic control and/or for reducing of fasting plasma glucose, of postprandial plasma glucose and/or of glycosylated hemoglobin HbA1c in a patient in need thereof characterized in that a a pharmaceutical composition according to the invention is administered to the patient.

The pharmaceutical composition according to this ion may also have le disease- ing properties with respect to diseases or conditions related to impaired glucose WO 20040 tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and/or metabolic syndrome.

According to another aspect of the invention, there is provided a method for ting, g, delaying or reversing progression from ed glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and/or from metabolic syndrome to type 2 diabetes mellitus in a patient in need thereof characterized in that a pharmaceutical composition according to the invention is administered to the patient.

As by the use of a pharmaceutical composition according to this invention, an ement of the glycemic control in patients in need f is obtainable, also those conditions and/or diseases related to or caused by an increased blood glucose level may be treated.

By the administration of a pharmaceutical composition according to this invention excessive blood glucose levels are not converted to ble e forms, like fat, but excreted through the urine of the patient. It can be seen that loss of fat may account for the majority of the observed weight loss s no significant changes in body water or protein content are observed. Therefore, no gain in weight or even a reduction in body weight is the result.

According to r aspect of the invention, there is provided a method for reducing body weight and/or body fat or preventing an increase in body weight and/or body fat or facilitating a reduction in body weight and/or body fat in a patient in need f characterized in that a pharmaceutical composition according to the invention is administered to the patient.

By the stration of a combination or pharmaceutical composition according to the present invention, an abnormal accumulation of ectopic fat, in particular of the liver, may be reduced or inhibited. Therefore, according to another aspect of the present ion, there is provided a method for preventing, slowing, delaying or treating diseases or conditions attributed to an abnormal accumulation of ectopic fat, in particular of the liver, in a patient in need thereof characterized in that a pharmaceutical composition according to the invention is administered to the patient. Diseases or conditions which are attributed to an abnormal accumulation of liver fat are particularly selected from the group ting of general fatty liver, non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), hyperalimen- tation-induced fatty liver, diabetic fatty liver, alcoholic-induced fatty liver or toxic fatty liver.

WO 20040 Another aspect of the invention es a method for maintaining and/or improving the insulin sensitivity and/or for treating or preventing nsulinemia and/or insulin resistance in a patient in need thereof characterized in that a pharmaceutical composition according to the invention is administered to the patient.

According to another aspect of the invention, there is provided a method for preventing, slowing progression of, delaying, or treating new onset diabetes after transplantation ) and/or ransplant metabolic syndrome (PTMS) in a patient in need thereof characterized in that a pharmaceutical composition according to the invention is administered to the patient.

According to a further aspect of the invention, there is provided a method for preventing, delaying, or reducing NODAT and/or PTMS ated complications including micro- and macrovascular es and events, graft rejection, infection, and death in a patient in need thereof characterized in that a pharmaceutical composition according to the invention is administered to the patient.

The pharmaceutical composition according to the invention is capable of tating the lowering of serum total urate levels in the patient. Therefore according to another aspect of the invention, there is provided a method for treating hyperuricemia and hyperuricemia- associated conditions, such as for example gout, hypertension and renal failure, in a patient in need f characterized in that a pharmaceutical composition according to the invention is administered to the patient.

The administration of a pharmaceutical composition increases the urine excretion of glucose.

This increase in osmotic excretion and water release and the lowering of urate levels are beneficial as a treatment or prevention for kidney stones. Therefore in a further aspect of the invention, there is ed a method for treating or ting kidney stones in a patient in need thereof terized in that a pharmaceutical composition ing to the invention is administered to the patient.

The invention also s to a pharmaceutical composition according to this invention for use in a method as described hereinbefore and hereinafter.

The invention also relates to a use of a pharmaceutical ition according to this invention for the manufacture of a ment for use in a method as described hereinbefore and hereinafter.

Definitions The term "active ingredient" of a ceutical composition according to the present invention means the SGLT2 inhibitor, the DPP-4 inhibitor and/or min according to the present invention. 1O The term "body mass index" or "BMI" of a human t is defined as the weight in kilograms divided by the square of the height in meters, such that BMI has units of kg/m2.

The term "overweight" is defined as the condition wherein the individual has a BMI greater than or 25 kg/m2 and less than 30 kg/m2. The terms "ovenNeight" and "pre-obese" are used interchangeably.

The term "obesity" is defined as the condition wherein the individual has a BMI equal to or greater than 30 kg/m2. According to a WHO definition the term obesity may be categorized as follows: the term "class I y" is the condition wherein the BMI is equal to or greater than 30 kg/m2 but lower than 35 kg/m2; the term "class II obesity" is the condition wherein the BMI is equal to or greater than 35 kg/m2 but lower than 40 kg/m2; the term "class III obesity" is the condition wherein the BMI is equal to or greater than 40 kg/m2.

The term "visceral obesity" is defined as the condition wherein a to-hip ratio of greater than or equal to 1.0 in men and 0.8 in women is measured. It defines the risk for insulin resistance and the development of pre-diabetes.

The term "abdominal obesity" is usually defined as the condition n the waist circumference is > 40 inches or 102 cm in men, and is > 35 inches or 94 cm in women. Vlﬁth regard to a Japanese ethnicity or Japanese patients abdominal obesity may be defined as waist circumference 2 85 cm in men and 2 90 cm in women (see e.g. investigating committee for the sis of metabolic syndrome in Japan).

The term “euglycemia” is d as the condition in which a subject has a fasting blood glucose concentration within the normal range, greater than 70 mg/dL (3.89 mmol/L) and less than 100 mg/dL (5.6 mmol/L). The word “fasting” has the usual meaning as a medical term.

The term “hyperglycemia” is defined as the condition in which a subject has a fasting blood e concentration above the normal range, greater than 100 mg/dL (5.6 ). The word “fasting” has the usual g as a medical term. 1O The term “hypoglycemia” is d as the ion in which a subject has a blood glucose concentration below the normal range, in particular below 70 mg/dL (3.89 mmol/L) or even below 60 mg/dl.

The term "postprandial hyperglycemia" is defined as the condition in which a subject has a 2 hour postprandial blood glucose or serum glucose concentration r than 200 mg/dL (11.1 mmol/L).

The term “impaired fasting blood glucose” or "IFG" is defined as the condition in which a subject has a fasting blood glucose concentration or fasting serum glucose concentration in a range from 100 to 125 mg/dl (i.e. from 5.6 to 6.9 mmol/l), in particular r than 110 mg/dL and less than 126 mg/dl (7.00 mmol/L). A subject with l fasting glucose" has a fasting glucose concentration smaller than 100 mg/dl, i.e. smaller than 5.6 mmol/l.

The term “impaired glucose tolerance” or "IGT" is defined as the condition in which a subject has a 2 hour postprandial blood glucose or serum glucose concentration greater than 140 mg/dl (7.8 mmol/L) and less than 200 mg/dL (11.11 mmol/L). The abnormal glucose tolerance, i.e. the 2 hour postprandial blood glucose or serum glucose concentration can be measured as the blood sugar level in mg of glucose per dL of plasma 2 hours after taking 75 g of glucose after a fast. A subject with "normal e tolerance" has a 2 hour postprandial blood e or serum glucose concentration smaller than 140 mg/dl (7.8 mmol/L).

The term “hyperinsulinemia” is defined as the condition in which a subject with insulin resistance, with or without euglycemia, has fasting or postprandial serum or plasma insulin concentration elevated above that of normal, lean duals without insulin resistance, having a waist-to-hip ratio < 1.0 (for men) or < 0.8 (for women). 2012/053910 The terms "insulin-sensitizing Insulin resistance-improving" or "insulin resistance-lowering” are synonymous and used interchangeably.

The term “insulin resistance” is defined as a state in which circulating insulin levels in excess of the normal response to a glucose load are required to in the euglycemic state (Ford ES, et al. JAMA. (2002) 287:356-9). A method of determining insulin resistance is the euglycaemic—hyperinsulinaemic clamp test. The ratio of insulin to glucose is ined within the scope of a combined insulin-glucose infusion technique. There is found to be 1O insulin resistance if the glucose absorption is below the 25th percentile of the background population investigated (WHO definition). Rather less ous than the clamp test are so called minimal models in which, during an intravenous glucose tolerance test, the insulin and glucose concentrations in the blood are measured at fixed time intervals and from these the insulin ance is calculated. With this method, it is not possible to guish between hepatic and peripheral insulin resistance.

Furthermore, insulin resistance, the response of a patient with insulin ance to therapy, insulin sensitivity and hyperinsulinemia may be quantified by assessing the “homeostasis model assessment to n resistance (HOMA-IR)” score, a reliable indicator of insulin resistance (Katsuki A, et al. Diabetes Care 2001; 24: 362-5). Further reference is made to methods for the determination of the HOMA-index for insulin sensitivity (Matthews et al., Diabeto/ogia 1985, 28: ), of the ratio of intact proinsulin to insulin (Forst et al., Diabetes 2003, 52(Suppl. 1): A459) and to an euglycemic clamp study. In on, plasma adiponectin levels can be monitored as a potential surrogate of insulin ivity. The estimate of insulin resistance by the homeostasis assessment model (HOMA)-IR score is calculated with the formula (Galvin P, et al. Diabet Med 1992;9:921-8): HOMA-IR = ng serum insulin (uU/mL)] x [fasting plasma glucose(mmol/L)/22.5] As a rule, other parameters are used in everyday clinical practice to assess insulin resistance. Preferably, the patient's triglyceride concentration is used, for example, as increased triglyceride levels correlate significantly with the presence of n resistance.

Patients with a predisposition for the development of IGT or IFG or type 2 es are those having euglycemia with hyperinsulinemia and are by definition, n resistant. A typical t with insulin resistance is usually overweight or obese, but this is not always the case.

If insulin resistance can be detected, this is a particularly strong indication of the presence of pre-diabetes. Thus, it may be that in order to maintain glucose homoeostasis a person have e.g. 2-3 times as high endogenous insulin production as a healthy person, without this ing in any al ms.

The methods to investigate the function of pancreatic beta-cells are similar to the above methods with regard to insulin sensitivity, hyperinsulinemia or insulin resistance: An improvement of beta-cell function can be measured for example by determining a HOMA- index for beta-cell function (Matthews et al., Diabeto/ogia 1985, 28: 412-19), the ratio of intact proinsulin to n (Forst et al., Diabetes 2003, 52(Suppl. 1): A459), the insulin/C- peptide ion after an oral glucose nce test or a meal tolerance test, or by employing a lycemic clamp study and/or minimal modeling after a frequently sampled intravenous glucose tolerance test (Stumvo/I et al., EurJ Clin Invest 2001, 31: 380-81).

The term “pre-diabetes” is the condition n an individual is sposed to the development of type 2 es. Pre-diabetes extends the definition of impaired glucose tolerance to include individuals with a fasting blood glucose within the high normal range 2 100 mg/dL (J. B. Meigs, et al. Diabetes 2003; 52:1475-1484) and fasting hyperinsulinemia (elevated plasma n concentration). The scientific and medical basis for identifying pre- diabetes as a serious health threat is laid out in a Position Statement entitled "The Prevention or Delay of Type 2 Diabetes" issued jointly by the American es Association and the National Institute of Diabetes and Digestive and Kidney Diseases (Diabetes Care 2002; 25:742-749).

Individuals likely to have insulin resistance are those who have two or more of the following utes: 1) ight or obese, 2) high blood pressure, 3) hyperlipidemia, 4) one or more 1St degree relative with a diagnosis of IGT or IFG or type 2 diabetes. Insulin resistance can be confirmed in these individuals by calculating the HOMA-IR score. For the purpose of this invention, insulin resistance is defined as the clinical condition in which an individual has a HOMA-IR score > 4.0 or a HOMA-IR score above the upper limit of normal as defined for the laboratory performing the glucose and insulin assays.

The term “type 1 diabetes” is d as the condition in which a subject has, in the presence of autoimmunity towards the pancreatic beta-cell or insulin, a fasting blood glucose or serum glucose concentration greater than 125 mg/dL (6.94 mmol/L). If a glucose tolerance test is carried out, the blood sugar level of a diabetic will be in excess of 200 mg of e per dL (11.1 mmol/l) of plasma 2 hours after 75 g of glucose have been taken on an empty stomach, in the ce of autoimmunity towards the pancreatic beta cell or n. In a glucose tolerance test 75 g of glucose are administered orally to the patient being tested after 10-12 hours of fasting and the blood sugar level is recorded immediately before taking the glucose and 1 and 2 hours after taking it. The presence of autoimmunity towards the pancreatic beta-cell may be observed by detection of circulating islet cell autoantibodies [“type 1A diabetes mellitus”], i.e., at least one of: GAD65 [glutamic acid decarboxylase-65], 1O ICA [islet-cell cytoplasm], lA-2 [intracytoplasmatic domain of the tyrosine phosphatase-like protein lA-2], ZnT8 [zinc-transporter-8] or anti-insulin; or other signs of autoimmunity without the presence of l circulating autoantibodies [type 18 diabetes], i.e. as detected through atic biopsy or imaging). Typically a genetic predisposition is present (e.g. HLA, INS VNTR and PTPN22), but this is not always the case.

The term “type 2 diabetes” is defined as the condition in which a subject has a fasting blood glucose or serum glucose concentration greater than 125 mg/dL (6.94 mmol/L). The measurement of blood glucose values is a standard procedure in routine medical analysis. If a glucose tolerance test is carried out, the blood sugar level of a ic will be in excess of 200 mg of glucose per dL (11.1 mmol/l) of plasma 2 hours after 75 g of glucose have been taken on an empty stomach. In a glucose tolerance test 75 g of glucose are administered orally to the patient being tested after 10-12 hours of fasting and the blood sugar level is recorded immediately before taking the glucose and 1 and 2 hours after taking it. In a healthy subject, the blood sugar level before taking the glucose will be between 60 and 110 mg per dL of , less than 200 mg per dL 1 hour after taking the glucose and less than 140 mg per dL after 2 hours. If after 2 hours the value is between 140 and 200 mg, this is regarded as abnormal glucose tolerance.

The term "late stage type 2 es mellitus" includes patients with a secondary drug failure, indication for insulin therapy and progression to micro- and ascular complications e.g. diabetic nephropathy, or coronary heart disease (CHD).

The term "HbA1c" refers to the product of a non-enzymatic glycation of the lobin B chain. lts determination is well known to one skilled in the art. In monitoring the ent of diabetes mellitus the HbA1c value is of exceptional importance. As its production depends essentially on the blood sugar level and the life of the erythrocytes, the HbA1c in the sense of a "blood sugar memory" reflects the average blood sugar levels of the preceding 4-6 weeks. Diabetic ts whose HbA1c value is consistently well adjusted by intensive diabetes treatment (i.e. < 6.5 % of the total haemoglobin in the sample), are significantly better protected against diabetic microangiopathy. For example, metformin on its own achieves an average improvement in the HbA1c value in the ic of the order of 1.0 — 1.5 %. This reduction of the HbA1C value is not sufficient in all diabetics to achieve the desired target range of < 6.5 % and preferably < 6 % HbA1c. 1O The term "insufficient ic control" or "inadequate glycemic control" in the scope of the present invention means a condition wherein patients show HbA1c values above 6.5 %, in particular above 7.0 %, even more preferably above 7.5 %, especially above 8 %.

The “metabolic syndrome”, also called “syndrome X” (when used in the context of a metabolic disorder), also called the “dysmetabolic syndrome” is a me complex with the cardinal feature being insulin resistance onen DE, et al. Am J Epidemiol 2002;156:1070-7). According to the ATP Ill/NCEP guidelines (Executive Summary of the Third Report of the National Cholesterol ion Program (NCEP) Expert Panel on Detection, Evaluation, and ent of High Blood Cholesterol in Adults (Adult Treatment Panel lll) JAMA: Journal of the American Medical Association (2001) 285:2486-2497), diagnosis of the metabolic syndrome is made when three or more of the following risk factors are present: 1. Abdominal obesity, defined as waist circumference > 40 inches or 102 cm in men, and > 35 inches or 94 cm in women; or with regard to a Japanese ethnicity or Japanese patients d as waist circumference 2 85 cm in men and 2 90 cm in women; 2. cerides: 2 150 mg/dL 3 HDL-cholesterol < 40 mg/dL in men 4. Blood pressure 2 130/85 mm Hg (SBP 2 130 or DBP 2 85) 5 Fasting blood glucose 2 100 mg/dL The NCEP definitions have been validated (Laaksonen DE, et al. Am J Epidemiol. (2002) 156:1070-7). cerides and HDL cholesterol in the blood can also be determined by rd methods in medical analysis and are described for example in Thomas L (Editor): "Labor und Diagnose“, TH-Books Verlagsgesellschaft mbH, Frankfurt/Main, 2000.

According to a commonly used definition, hypertension is diagnosed if the ic blood pressure (SBP) exceeds a value of 140 mm Hg and diastolic blood pressure (DBP) exceeds a value of 90 mm Hg. If a patient is suffering from manifest diabetes it is currently recommended that the ic blood pressure be reduced to a level below 130 mm Hg and the diastolic blood pressure be d to below 80 mm Hg.

The definitions of NODAT (new onset diabetes after transplantation) and PTMS (post- transplant metabolic syndrome) follow y that of the American Diabetes ation diagnostic criteria for type 2 diabetes, and that of the ational Diabetes Federation (IDF) and the American Heart Association/National Heart, Lung, and Blood Institute, for the metabolic syndrome. NODAT and/or PTMS are associated with an increased risk of micro- and macrovascular disease and events, graft rejection, infection, and death. A number of predictors have been identified as potential risk factors related to NODAT and/or PTMS including a higher age at transplant, male gender, the pre-transplant body mass index, pretransplant diabetes, and immunosuppression.

The term "gestational es" (diabetes of pregnancy) denotes a form of the diabetes which develops during ncy and usually ceases again immediately after the birth.

Gestational diabetes is diagnosed by a screening test which is carried out between the 24th and 28th weeks of ncy. It is usually a simple test in which the blood sugar level is measured one hour after the administration of 50 g of glucose solution. If this 1 h level is above 140 mg/dl, gestational diabetes is suspected. Final confirmation may be obtained by a standard glucose tolerance test, for example with 75 g of glucose.

The term "hyperuricemia" denotes a ion of high serum total urate levels. In human blood, uric acid concentrations between 3.6 mg/dL (ca. 214 umol/L) and 8.3 mg/dL (ca. 494 umol/L) are considered normal by the American Medical Association. High serum total urate levels, or hyperuricemia, are often ated with several maladies. For example, high serum total urate levels can lead to a type of arthritis in the joints kown as gout. Gout is a condition created by a build up of monosodium urate or uric acid crystals on the articular cartilage ofjoints, tendons and surrounding tissues due to elevated trations of total urate levels in the blood stream. The build up of urate or uric acid on these tissues provokes an inflammatory reaction of these tissues. tion levels of uric acid in urine may result in kidney stone formation when the uric acid or urate crystallizes in the kidney. Additionally, high serum total urate levels are often associated with the so-called metabolic syndrome, including vascular disease and hypertension.

The term "hyponatremia" s a condition of a positive e of water with or without a deficit of sodium, which is recognized when the plasma sodium falls below the level of 135 mml/L. Hyponatremia is a condition which can occur in isolation in individuals that over- consume water; however, more often hyponatremia is a complication of tion or other underlying medical condition that leas to a diminished excretion of water. tremia may lead to water cation, which occurs when the normal tonicity of extracellular fluid falls 1O below the safe limit, due to retention of excess water. Water intoxication is a potentially fatal disturbance in brain function. Typical symptoms of water intoxication e nausea, vomiting, headache and malaise.

The terms "treatment" and "treating" comprise therapeutic treatment of patients having already developed said condition, in particular in manifest form. Therapeutic treatment may be symptomatic treatment in order to relieve the symptoms of the specific indication or causal treatment in order to reverse or partially reverse the conditions of the indication or to stop or slow down progression of the disease. Thus the itions and methods of the present invention may be used for instance as therapeutic treatment over a period of time as well as for chronic therapy.

The terms "prophylactically treating , preventivally treating" and nting" are used interchangeably and comprise a treatment of patients at risk to develop a condition mentioned hereinbefore, thus reducing said risk.

Claims

WE CLAIM:

1. A pharmaceutical ition comprising a) an inner extended release core comprising metformin, including metformin hydrochloride, and one or more excipients; b) an intermediate seal coating comprising a mixture of ypropyl cellulose and hydroxypropyl methylcellulose (HPMC); and c) an outer immediate release coating comprising: at least one active pharmaceutical ingredient, namely a DPP-4 inhibitor which is linagliptin, a plasticizer, and one or more excipients; wherein the inner extended release core a) is a formulation comprising metformin hydrochloride, a swellable and/or extended release polymer, and one or more further excipients, in which the ble and/or extended release polymer is a combination of poly(ethylene oxide) optionally in combination with hydroxypropyl methylcellulose (HPMC).

2. The pharmaceutical composition according to claim 1, wherein in the inner extended release core a) further comprises ypropyl methylcellulose (HPMC) and the weight ratio of the poly(ethylene oxide) and hydroxypropyl methylcellulose (HPMC) in ation constitutes from about 30% to about 65% by weight of the inner ed release core.

3. The pharmaceutical composition according to claim 2, wherein the weight ratio of the poly(ethylene oxide) and hydroxypropyl methylcellulose (HPMC) in ation constitutes from about 40% to about 50% by weight of the inner extended release core.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the outer ate release coating c) is a film coat formulation further comprising L-arginine as stabilizer, and a film-coating agent.

5. The pharmaceutical ition according to claim 4, wherein the film coat formulation further comprises a glidant. AH26(10574887_1):RTK

6. The pharmaceutical composition according to claim 4 or claim 5, wherein the weight ratio of the L-arginine to linagliptin is within the range from about 2:1 to about 1:1.

7. The pharmaceutical composition according to claim 4 or claim 5, wherein the weight ratio of the L-arginine to linagliptin is up to about 0.2:1.

8. The pharmaceutical composition according to any one of claims 4 to 7, wherein the filmcoating agent is ypropyl methylcellulose.

9. The pharmaceutical composition according to any one of claims 1 to 8, n the plasticizer in the outer immediate release coating c) is polyethylene glycol.

10. The pharmaceutical composition according to any one of claims 1 to 8, wherein the plasticizer in the outer immediate release coating c) is propylene glycol.

11. The pharmaceutical composition according to any one of claims 5 to 10, having a glidant which is talc.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the ediate seal coating b) comprises a film-coating agent, and a plasticizer.

13. The pharmaceutical ition according to claim 12, wherein the intermediate seal coating b) r comprises a glidant, one or more pigments and/or colors.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the metformin hydrochloride is t in a unit dosage strength of 500 mg.

15. The pharmaceutical composition according to any one of claims 1 to 13, wherein the metformin hydrochloride is present in a unit dosage strength of 750 mg.

16. The pharmaceutical composition according to any one of claims 1 to 13, wherein the metformin hloride is t in a unit dosage strength of 850 mg.

17. The pharmaceutical composition according to any one of claims 1 to 13, wherein the min hydrochloride is present in a unit dosage strength of 1000 mg. AH26(10574887_1):RTK

18. The pharmaceutical composition according to any one of claims 1 to 13, wherein the metformin hydrochloride is present in a unit dosage strength of 1500 mg.

19. The pharmaceutical composition according to any one of claims 1 to 18, wherein the linagliptin is present in a unit dosage strength of 0.5 mg.

20. The pharmaceutical composition according to any one of claims 1 to 18, wherein the linagliptin is present in a unit dosage strength of 1 mg.

21. The pharmaceutical composition according to any one of claims 1 to 18, wherein the linagliptin is t in a unit dosage strength of 2.5 mg.

22. The pharmaceutical composition according to any one of claims 1 to 18, wherein the linagliptin is present in a unit dosage strength of 5 mg.

23. The pharmaceutical composition according to any one of the preceding claims, which is a tablet for oral administration.

24. The tablet according to claim 23 further comprising an outer film over-coat.

25. The tablet according to claim 24, wherein the outer film over-coat comprises a film-coating agent, and a plasticizer.

26. The tablet according to claim 25, wherein the outer film over-coat further comprises a t, one or more pigments and/or colors.

27. The pharmaceutical composition according to any one of the preceding claims for use in treating and/or preventing (including slowing the progression and/or delaying the onset) of metabolic diseases, especially type 2 diabetes us and conditions related o ing diabetic cations, either in type 2 diabetes patients who have not been previously treated with an antihyperglycemic agent, or in type 2 diabetes ts with insufficient glycemic control despite therapy with one or two conventional antihyperglycemic agents selected from metformin, sulphonylureas, AH26(10574887_1):RTK thiazolidinediones (e.g. pioglitazone), glinides, alpha-glucosidase blockers, GLP-1 or GLP-1 analogues, and insulin or insulin analogues.

28. The pharmaceutical composition according to claim 4 or claim 5, wherein said pharmaceutical composition comprises 0.5 mg to 10 mg of L-arginine.

29. Use of a pharmaceutical composition according to any one of claims 1 to 26 and 28 for the manufacture of a medicament for treating and/or preventing (including slowing the progression and/or delaying the onset) of metabolic diseases, ally type 2 diabetes mellitus and conditions related thereto including diabetic complications, 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 l e therapy with one or two conventional antihyperglycemic agents selected from metformin, sulphonylureas, thiazolidinediones (e.g. pioglitazone), glinides, alpha-glucosidase blockers, GLP-1 or GLP-1 analogues, and insulin or n analogues.