WO2021160608A1

WO2021160608A1 - Pharmaceutical composition comprising linagliptin and metformin

Info

Publication number: WO2021160608A1
Application number: PCT/EP2021/053072
Authority: WO
Inventors: Tomasz KRUSIŃSKI; Szymon Przerada; Julia Hrakovsky; Przemysław SKOCZEŃ
Original assignee: Zakłady Farmaceutyczne POLPHARMA S.A.
Priority date: 2020-02-13
Filing date: 2021-02-09
Publication date: 2021-08-19
Also published as: CA3170233A1; EP4103157A1

Abstract

The present invention relates to a pharmaceutical composition comprising the combination of linagliptin and metformin as active ingredients.

Description

PHARMACEUTICAL COMPOSITION COMPRISING LINAGLIPTIN AND

METFORMIN

Technical field The present invention relates to a pharmaceutical composition comprising the combination of linagliptin and metformin as active ingredients.

State of the art

Among the available pharmacological options for treating type 2 diabetes mellitus, the combined use of two or anti-diabetic agents is often advantageous. In particular, the combined use linagliptin and metformin is a well-established therapeutic strategy, which is effective and well-tolerated (Haak T, Initial combination with linagliptin and metformin in newly diagnosed type 2 diabetes and severe hyperglycemia, Adv. Ther., 2012, 29 (12), 1005-15). Linagliptin is a selective, orally administered, xanthine-based inhibitor of dipeptidylpeptidase-4 (DPP-4) which is used for the treatment of type 2 diabetes. DPP- 4 inhibitors are antidiabetic agents that lower blood glucose by extending the short half- life of the incretin hormones GLP-1 and GIP (glucagon-like peptide-1 , glucose- dependent insulinotropic polypeptide). Metformin belongs to the class of drugs called biguanides and is also used to treat type 2 diabetes.

A convenient way for the combined administration of linagliptin and metformin is by using a fixed-dose combination of both drugs (Koliaki et al., Linagliptin/metformin fixed-dosed combination treatment: a dual attack to type 2 diabetes pathophysiology, Adv. Ther., 2012, 29 (12), 993-1004/

The medicinal product Jentadueto^® provides a fixed-dose combination of linagliptin and metformin hydrochloride and is available in the 2.5 mg/500 mg, 2.5 mg/850 mg and 2.5 mg/1000 mg strengths. Jentadueto^® is in the form of film-coated tablets, which comprise arginine, copovidone, magnesium stearate, maize starch and silica colloidal anhydrous as excipients in the tablet core. The film coating contains hypromellose, titanium dioxide, talc, red iron oxide and propylene glycol.

The international patent application WO2009/121945-A2 discloses fixed dose combinations of a DPP-4 inhibitor and a partner drug, for example metformin. It is disclosed that the preparation of pharmaceutical compositions comprising such combination may entail difficulties due to interactions between the DPP-4 inhibitor and the partner drug and/or excipients, and that such problems can be overcome by including a stabilizing agent to the composition, which can be a nucleophilic and/or basic agent. A preferred stabilizing agent is L-arginine. Several pharmaceutical compositions are described in the examples comprising linagliptin (BI-1356) and metformin hydrochloride, in the form of monolayer tablets, bilayer tablets or tablet-in- tablet (bull’s eye tablet).

Thus, for example, the preparation of 2.5/500 mg, 2.5/850 mg and 2.5/1000 mg strength mono-layer tablets is disclosed comprising linagliptin, metformin hydrochloride, L-arginine, a filler (corn starch), a binder (copovidone), a glidant (colloidal anhydrous silica) and a lubricant (magnesium stearate) in the core, and a film coat comprising hypromellose, propylene glycol, talc, titanium dioxide, iron oxide yellow and iron oxide red. The tablets are produced by conventional fluid-bed granulation of all core ingredients, except the glidant and the lubricant, which are added extra-granularly, and subsequent conventional compressing and film-coating. The bi-layer and tablet-in tablet formulations involve the preparation of separate linagliptin granules (comprising arginine as stabilizing agent) and metformin granules.

The international patent application W02014/080383-A1 also discloses fixed- dose combination formulations comprising a DPP-4 inhibitor and an additional antidiabetic agent, preferably the combination of linagliptin and metformin. The formulations are in the form of monolayer, bilayer or trilayer tablets and comprise an alkalinizing agent as stabilizer, which is not a basic amino acid. Several suitable alkalinizing agents are cited, and meglumine is said to be preferred.

Several examples are disclosed in W02014/080383-A1 . Examples 1 and 4, for example, disclose mono-layer tablets made of single granules comprising metformin, linagliptin together with the alkalinizing agent, which are subsequently mixed with extragranular ingredients (glidant, optionally disintegrant, and lubricant) and compressed. Another option for preparing mono-layer tablets is disclosed in Example 6, wherein two different granules, one with linagliptin and one with metformin, are prepared, and the alkalinizing agent (meglumine) is added extragranularly. Bilayer- tablets are disclosed in Example 2, wherein each layer is made of different kind of granules; the linagliptin layer comprises granules containing linagliptin and the alkalinizing agent, while the metformin layer comprises metformin granules which do not contain alkalinizing agent. Tri-layer tablets are similarly disclosed in Example 3, comprising an additional intermediate layer made of a mixture of a diluents, a disintegrant and a lubricant. The Chinese patent application CN104840960-A discloses pharmaceutical compositions comprising linagliptin and metformin hydrochloride, further comprising meglumine as stabilizer. The compositions disclosed are prepared by combining a first granule comprising linagliptin, meglumine as stabilizer, and a pharmaceutically acceptable excipient, and a second granule comprising metformin hydrochloride and a pharmaceutically acceptable excipient. Both granules are mixed, optionally with extragranular glidant and/or lubricant, compressed to form a tablet, and optionally film- coated.

Despite the solutions available so far in the art, there is still the need to provide further formulations comprising the combination of linagliptin and metformin, which remain stable, i.e., substantially free of degradation products, over time, and which are therefore suitable for the combined treatment of type 2 diabetes mellitus.

Object of the invention

The object of the present invention is an oral pharmaceutical dosage form comprising linagliptin and metformin. Another aspect of the invention is a process for the preparation of such pharmaceutical dosage form.

Another aspect of the invention is the combined pharmaceutical dosage form for use in the treatment of type 2 diabetes mellitus. Detailed description of the invention

The object of the present invention is an oral pharmaceutical dosage form comprising linagliptin and metformin, characterized in that it comprises: a) a first type of granule comprising linagliptin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient; and b) a second type of granule comprising metformin or a pharmaceutically acceptable salt thereof and meglumine.

The authors of the present invention have developed a pharmaceutical composition comprising linagliptin and metformin and comprising meglumine as stabilizing agent, made of separate granules for each active ingredient and wherein meglumine is included within the metformin granules. Surprisingly, it was found that the formulation was outstandingly stable despite the fact that meglumine was combined with metformin, rather than with linagliptin.

Along the present description, as well as in the claims, the singular expressions, generally preceded by the articles “a”, “an” or “the”, are meant to include also the plural forms, unless the context clearly indicates otherwise. Furthermore, numeric values preceded by the term “about” are meant to include the exact stated value and also a certain variation around such value, namely a variation or ±5% of the stated amount. Numeric ranges defined by lower and upper endpoints are meant to include also said stated endpoints. The percentages disclosed (%, wt%) are always weight percentages. Along the present invention, as well as in the claims, the amount (as weight, typically in mg) of linagliptin or a pharmaceutically acceptable salt thereof in the dosage form is always expressed as the equivalent weight of linagliptin free base, regardless of the form used, i.e., the linagliptin free base or a pharmaceutically acceptable salt. The “equivalent amount”, as is well-known in the art, means the weight of linagliptin free base which is the equimolar amount of the actual linagliptin form used. Analogously, the amount (as weight, typically in mg) of metformin or a pharmaceutically acceptable salt thereof in the dosage form is always expressed as the equivalent weight of metformin hydrochloride regardless of the form used, i.e., the metformin free base, the hydrochloride salt or another pharmaceutically acceptable salt. The “equivalent amount”, as is well-known in the art, means the weight of metformin hydrochloride which is the equimolar amount of the actual metformin form used.

Linagliptin granule

The pharmaceutical dosage form of the present invention comprises a first type of granule (the linagliptin granule) comprising linagliptin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

Linagliptin is the International Nonproprietary Name (INN) to designate the substance 8-[(3f?)-3-aminopiperidin-1 -yl]-7-(but-2-yn-1 -yl)-3-methyl1 -[(4-methyl quinazolin-2-yl)methyl]-3,7-dihydro-1 /-/-purine-2, 6-dione (CAS 668270-12-0). Linagliptin is a potent, selective, orally active, competitive, reversible and long- acting inhibitor of dipeptidyl-peptidase-4 (DPP-4) which is used to improve glycaemic control in adults with type 2 diabetes mellitus.

Methods for the manufacture of linagliptin are described, for example, in the international patent applications WO 2004/018468 A2 and WO 2006/048427 A1 . Linagliptin can be used as such, i.e., as the free base, or may be in the form of a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salts of linagliptin include nontoxic acid addition salts, for example, with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, salicylic acid, tartaric acid, glutamic acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, among others. In one embodiment of the invention, linagliptin is used as such, i.e., as the free base, rather than as a pharmaceutically acceptable salt thereof.

Both linagliptin and the pharmaceutically acceptable salts thereof are meant to include also hydrates and solvates thereof. In one embodiment of the invention, linagliptin or a pharmaceutically acceptable salt thereof is used as a non-hydrated, non-solvated form.

In one embodiment of the invention, the non-hydrated, non-solvated, free base form of linagliptin is used.

Linagliptin and the pharmaceutically acceptable salts thereof include any crystalline or amorphous form thereof.

Preferably, linagliptin or a pharmaceutically acceptable salt thereof is in crystalline form.

In one embodiment, linagliptin or a pharmaceutically acceptable salt thereof is in micronized form. For example, it may typically have a particle size volume distribution wherein D₉₀ is not more than 250 pm, preferably wherein D₉₀ is not more than 150 pm, and more preferably wherein D₉₀ is not more than 85 pm. Said particle size distribution may be determined, for example, by laser diffraction (Malvern, Mastersizer 2000 and Malvern, Mastersizer 3000 and sample prepared by wet dispersion). The content of linagliptin or a pharmaceutically acceptable salt thereof in the linagliptin granule is generally in the range 1-10 wt%, preferably in the range 2-8 wt%, and more preferably in the range 3-6 wt%, referred to the total weight of the linagliptin granule.

Granules, as is well known in pharmaceutical technology, comprise powder particles that have been aggregated to form larger particles. Thus, granulation is the process in which dry primary powder particles are processed to adhere to form larger multiparticle entities called granules. The size of the linagliptin granule is not critical; for example, the size of the granule may be comprised between 0.05 mm and 2.0 mm, or preferably comprised between 0.05 mm and 1 .0 mm. The granules may be prepared by conventional processes, typically by dry granulation or by wet granulation.

The linagliptin granules typically contain linagliptin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient can be selected, for example, from a filler, a binder, a disintegrant, and mixtures thereof. In one embodiment, the linagliptin granule comprises linagliptin or a pharmaceutically acceptable salt thereof and a filler.

A filler or diluent, as is well known in the art, is a pharmaceutical excipient generally used to increase the bulk volume of the formulation. The filler can be selected, for example, from calcium carbonate, calcium lactate, calcium phosphate dibasic, calcium phosphate tribasic, calcium silicate, calcium sulfate, microcrystalline cellulose, powdered cellulose, cellulose acetate, corn starch, pregelatinized starch, dextrin, dextrose, fructose, lactitol, lactose, maltodextrin, maltose, mannitol, sorbitol, sucrose, trehalose and xylitol, among others, and mixtures thereof. In one embodiment, the filler is selected from dextrose, mannitol, sorbitol, xylitol and mixtures thereof.

In one embodiment, the filler is mannitol.

The content of filler in the linagliptin granule is generally in the range 75-98 wt%, preferably in the range 80-95 wt%, more preferably in the range 85-93 wt%, and more preferably is about 90 wt%, referred to the total weight of the linagliptin granule.

In one embodiment, the linagliptin granule comprises linagliptin or a pharmaceutically acceptable salt thereof and a binder.

A binder, as is also well known in the art, is a pharmaceutical excipient generally used to adhere the powders forming the granule, to facilitate the granule formation. The binder can be selected, for example, from acacia, agar, alginic acid, carbomers, carrageenan, chitosan, copovidone, starch, pregelatinized starch, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glyceryl behenate, guar gum, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hypromellose, lactose, maltodextrin, maltose, methylcellulose, pectin, polyethylene oxide, povidone, sodium alginate, sucrose, among others, and mixtures thereof.

In one embodiment, the binder is selected from copovidone, hydroxypropyl cellulose, hypromellose, povidone and mixtures thereof, preferably selected from copovidone, povidone and mixtures thereof.

In one embodiment, the binder is copovidone. In another embodiment, the binder is povidone.

The content of binder in the linagliptin granule is generally in the range 1-15 wt%, preferably in the range 2-10 wt%, more preferably in the range 3-7 wt% and still more preferably is about 5 wt%, referred to the total weight of the linagliptin granule.

In one embodiment, the linagliptin granule comprises linagliptin or a pharmaceutically acceptable salt thereof and a disintegrant. Disintegrants are generally used to promote the disintegration of the dosage form in the gastrointestinal tract. The disintegrant can be selected, for example, from alginic acid, calcium alginate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, starch, pregelatinized starch, croscarmellose sodium, crospovidone, docusate sodium, hydroxypropyl cellulose low-substituted, polacrilin potassium, sodium alginate, and sodium starch glycolate, among others, and mixtures thereof.

In one embodiment, the disintegrant is selected from croscarmellose sodium, crospovidone, sodium starch glycolate and mixtures thereof.

In one embodiment, the disintegrant is sodium starch glycolate. In one embodiment, the disintegrant is crospovidone.

If the linagliptin granule contains a disintegrant, it is in an amount generally comprised in the range 0.5-6 wt%, preferably comprised in the range 1 -3 wt%, referred to the total weight of the linagliptin granule.

In one embodiment, the linagliptin granule comprises linagliptin or pharmaceutically acceptable salt thereof, a filler and a binder.

In one embodiment, the linagliptin granule essentially consists of linagliptin or a pharmaceutically acceptable salt thereof, a filler and a binder.

In one embodiment, the linagliptin granule comprises linagliptin or a pharmaceutically acceptable salt thereof, a filler, a binder and a disintegrant. In one embodiment, the linagliptin granule essentially consists of linagliptin or a pharmaceutically acceptable salt thereof, a filler, a binder and a disintegrant.

Metformin granule

The pharmaceutical dosage form of the present invention comprises a second type of granule (the metformin granule) comprising metformin or a pharmaceutically acceptable salt thereof and meglumine.

Metformin is the International Nonproprietary Name (INN) to designate the substance 1 ,1 -dimethylbiguanide (CAS 657-24-9). Metformin is a biguanide with antihyperglycaemic effects. Metformin, and its pharmaceutically acceptable salts, can be prepared by known methods, or may be obtained from commercial sources. For example, the synthesis of metformin is disclosed in the French patent application FR2322860-A1 .

Metformin can be used as such, i.e, as the free base, or may be in the form of a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salts of metformin include nontoxic acid addition salts, for example, with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, salicylic acid, tartaric acid, glutamic acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, among others.

In one embodiment of the invention, metformin is used as a salt, preferably, the hydrochloride salt (metformin hydrochloride) is used. Within the term metformin, or the pharmaceutically acceptable salts thereof, hydrates and solvates are also meant to be included.

In one embodiment of the invention, non-hydrated, non-solvated metformin hydrochloride is used.

Metformin and the pharmaceutically acceptable salts thereof include any crystalline or amorphous forms thereof.

In one embodiment, metformin or a pharmaceutically acceptable salt thereof in crystalline form is used.

Metformin or a pharmaceutically acceptable salt thereof, such as metformin hydrochloride, may be used in any particle size for preparing the metformin granules. For example, it may typically have a particle size distribution by volume wherein D₉₀ is not more than 500 pm, preferably wherein D₉₀ is not more than 300 pm. Said particle size distribution may be determined, for example, by laser diffraction (Malvern, Mastersizer 2000 and Malvern, Mastersizer 3000 and sample prepared by wet dispersion). The content of metformin or a pharmaceutically acceptable salt thereof in the metformin granule is generally in the range 70-99 wt%, preferably in the range 75-95 wt%, more preferably in the range 80-92 wt%, and still more preferably in the range 85- 90 wt%, referred to the total weight of the metformin granule.

The size of the metformin granule is not critical. For example, the granule may have a size comprised between 0.05 mm and 2.0 mm, preferably comprised between 0.05 mm and 1.0 mm.

The metformin granules may be prepared by conventional processes, typically by dry granulation or by wet granulation.

The metformin granule comprises the active ingredient and meglumine. Meglumine is also known as N-Methylglucamine or N-methyl-D-glucamine or as (2F?,3F?,4/^:?,5S)-6-(Methylamino)hexane-1 ,2,3,4, 5-pentol (CAS 6284-40-8). Within the meaning of the present invention, the term “meglumine” also includes any stereoisomer form thereof.

The weight ratio metformin or a pharmaceutically acceptable salt thereof: meglumine is generally comprised between 99:1 and 2:1 , preferably comprised between 85:1 and 15:1 , more preferably comprised between 70:1 and 20:1 , still more preferably comprised between 60:1 and 25:1 , still more preferably comprised between 50:1 and 30:1 , still more preferably comprised between 45:1 and 35:1 , and still more preferably is about 40:1 , wherein the weight of metformin or a pharmaceutically acceptable salt thereof is expressed as the equivalent weight of metformin hydrochloride.

In one embodiment, the metformin granules comprise metformin or a pharmaceutically acceptable salt thereof, meglumine and an additional pharmaceutically acceptable excipient. The additional pharmaceutically acceptable excipient may be, for example, a binder, a filler, a glidant, an antioxidant, a wetting agent, a disintegrant, or a mixture thereof. In one preferred embodiment, the additional pharmaceutically acceptable excipient is selected from a binder, a glidant, a wetting agent, a disintegrant, and mixtures thereof.

In one embodiment, the metformin granule comprises metformin or a pharmaceutically acceptable salt thereof, meglumine and a binder. The binder can be selected, for example, from acacia, agar, alginic acid, carbomers, carrageenan, chitosan, copovidone, starch, pregelatinized starch, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glyceryl behenate, guar gum, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hypromellose, lactose, maltodextrin, maltose, methylcellulose, pectin, polyethylene oxide, povidone, sodium alginate, sucrose, among others, and mixtures thereof.

In one embodiment, the binder is copovidone. In one embodiment, the binder is povidone.

When present, the content of binder in the metformin granule is generally in the range 2-20 wt%, preferably in the range 5-15 wt%, more preferably in the range 7- 12 wt% and still more preferably in the range 9-11 wt%, referred to the total weight of the metformin granule. In one embodiment, the metformin granule comprises metformin or a pharmaceutically acceptable salt thereof, meglumine, a binder and at least one additional excipient which is selected from a wetting agent, a disintegrant, a glidant, and mixtures thereof.

In one embodiment, the metformin granule comprises a wetting agent. Wetting agents typically are used in solid pharmaceutical compositions as an aid to the disintegration of the composition and to the dissolution of the drugs. The wetting agent can be selected, for example, from sodium lauryl sulfate, a polysorbate and mixtures thereof. Polysorbates are polyoxyethylene sorbitan fatty acid esters, which are nonionic surfactants. Examples of polysorbates are polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80. In one embodiment, the wetting agent is sodium lauryl sulfate. In another embodiment, the wetting agent is a polysorbate.

When present, the content of wetting agent in the metformin granule is generally in the range 0.1-4 wt%, preferably in the range 0.1-3 wt%, more preferably in the range 0.1-2 wt% and still more preferably in the range 0.1-1 wt%, referred to the total weight of the metformin granule.

In one embodiment, the metformin granule comprises a disintegrant. The disintegrant can be selected, for example, from alginic acid, calcium alginate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, starch, pregelatinized starch, croscarmellose sodium, crospovidone, hydroxypropyl cellulose low-substituted, polacrilin potassium, sodium alginate, and sodium starch glycolate, among others, and mixtures thereof. Preferably, the disintegrant is selected from starch, croscarmellose sodium, crospovidone, sodium starch glycolate and mixtures thereof, more preferably is selected from starch, sodium starch glycolate and crospovidone and still more preferably is selected form starch and sodium starch glycolate. In one particular embodiment the disintegrant is starch. In another particular embodiment, the disintegrant is sodium starch glycolate.

When present, the content of disintegrant in the metformin granule is generally in the range 1-15 wt%, preferably in the range 2-12 wt%, and more preferably in the range 3-10 wt%, referred to the total weight of the metformin granule. In one embodiment, the metformin granule comprises a glidant, for example selected from colloidal silicon dioxide (also known as silica colloidal anhydrous), silicon dioxide, magnesium silicate, talc and combinations thereof. Preferably, the glidant is colloidal silicon dioxide.

When the metformin granule comprises a glidant, it is in an amount generally comprised in the range 0.05-4 wt%, preferably comprised in the range 0.1-1 wt%.

In one embodiment, the metformin granule essentially consists of metformin or a pharmaceutically acceptable salt thereof, meglumine and a binder.

In one embodiment, the metformin granule comprises metformin or a pharmaceutically acceptable salt thereof, meglumine, a binder and a glidant. In one embodiment, the metformin granule essentially consists of metformin or a pharmaceutically acceptable salt thereof, meglumine, a binder and a glidant. In one embodiment, the metformin granule comprises metformin or a pharmaceutically acceptable salt thereof, meglumine, a binder, a disintegrant and a wetting agent.

In one embodiment, the metformin granule consists essentially of metformin or a pharmaceutically acceptable salt thereof, meglumine, a binder, a disintegrant and a wetting agent.

Dosage form

The pharmaceutical dosage form may be a granulate/powder mixture, typically available in mono-dose sachets, a capsule or a tablet, which can be coated or uncoated.

Optionally, the pharmaceutical dosage form according to the present invention may contain, besides the linagliptin granules and the metformin granules, additional extragranular pharmaceutically acceptable excipients, i.e., that are not included neither in the linagliptin granules nor in the metformin granules. The extragranular excipients are thoroughly mixed with the linagliptin granules and the metformin granules.

When there is an extragranular excipient, it is generally in an amount comprised between about 0.05 wt% and about 6 wt%.

Typically, the extragranular excipients are selected from fillers, colorants disintegrants, glidants, lubricants, and mixtures thereof.

Colorants, for example, may be added to distinguish between different strengths, when the dosage form is a non-coated tablet.

When there is an extragranular disintegrant, it can be selected, for example, from alginic acid, calcium alginate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, starch, pregelatinized starch, croscarmellose sodium, crospovidone, docusate sodium, hydroxypropyl cellulose low-substituted, polacrilin potassium, sodium alginate, and sodium starch glycolate, among others, and mixtures thereof.

When there is an extragranular disintegrant, it is typically in an amount in the range 0.05-5 wt%, preferably in the range 0.1-2 wt%, referred to the total weight of the dosage form.

The total weight of the dosage form as used herein means the weight of the capsule filling, when the dosage form is a capsule, or weight of the non-coated tablet core, when the dosage form is a tablet, or the weight of the mono-dose sachet filling, when the dosage form is in granulate/powder form. The role of glidants, as is well-known in the art, is to improve the flowability of dry mixtures, i.e. powders and/or granules. When there is an extragranular glidant, it is typically selected from colloidal silicon dioxide, silicon dioxide, magnesium silicate and talc, among others, and mixtures thereof. Preferably the glidant is colloidal silicon dioxide.

When there is an extragranular glidant, it is typically in an amount in the range 0.05-4 wt%, preferably in the range 0.1-1 wt%, referred to the total weight of the dosage form.

Lubricants are typically used when the dosage form is a tablet, to ensure that tablet formation and ejection can occur with low friction between the solid and the die wall. When there is a lubricant, it can be selected from calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, magnesium stearate, medium-chain triglycerides, myristic acid, palmitic acid, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, and zinc stearate, among others, and mixtures thereof. Preferably, the lubricant is selected from calcium stearate, glyceryl behenate, hydrogenated castor oil, magnesium stearate, sodium stearyl fumarate, stearic acid and mixtures thereof. A preferred lubricant is magnesium stearate.

When there is a lubricant, it is typically in an amount in the range 0.2-5 wt%, preferably in the range 1 -3 wt%, referred to the total weight of the dosage form.

In one embodiment, the composition comprises a glidant and a lubricant as extragranular excipients.

In one embodiment, the extragranular pharmaceutically acceptable excipients essentially consist of a glidant and a lubricant. Typically, the weight ratio metformi linagliptin in the dosage form is comprised between 500:1 and 100:1 , preferably comprised between 450:1 and 150:1 , and more preferably is comprised between 400:1 and 200:1 , wherein the weight of metformin is expressed as equivalent weight of metformin hydrochloride.

In one preferred embodiment, the weight ratio metformi linagliptin is about 400:1 , wherein the weight of metformin is expressed as equivalent weight of metformin.

In one preferred embodiment, the weight ratio metformi linagliptin is about 340:1 , wherein the weight of metformin is expressed as equivalent weight of metformin.

In one preferred embodiment, the weight ratio metformi linagliptin is about 200:1 , wherein the weight of metformin is expressed as equivalent weight of metformin. Generally, the weight ratio metformin-granule:linagliptin-graniile in the dosage form is comprised between 5:1 and 20:1 , preferably comprised between 6:1 and 17:1 and more preferably comprised between 7:1 and 16:1.

In one embodiment, the amount of metformin or a pharmaceutically acceptable salt thereof in the dosage form is comprised between 400 and 1100 mg, preferably comprised between 500 and 1000 mg, expressed as equivalent weight of metformin hydrochloride, and the amount of linagliptin or a pharmaceutically acceptable salt thereof is comprised between 1 and 5 mg, preferably comprised between 2 and 3 mg and more preferably is about 2.5 mg, expressed as equivalent weight of linagliptin free base. According to this embodiment, the amount of meglumine in the dosage form is preferably comprised between 5 and 35 mg, more preferably comprised between 10 and 30 mg.

In one preferred embodiment, the amount of metformin or a pharmaceutically acceptable salt thereof in the dosage form is comprised between 900 and 1100 mg, preferably is about 1000 mg, expressed as equivalent weight of metformin hydrochloride, and the amount of linagliptin or a pharmaceutically acceptable salt thereof is comprised between 1 and 5 mg, preferably comprised between 2 and 3 mg and more preferably is about 2.5 mg, expressed as equivalent weight of linagliptin free base. The amount of meglumine in the dosage form according this embodiment is preferably comprised between 20 and 30 mg, more preferably comprised between 22 and 28 mg.

In one preferred embodiment, the amount of metformin or a pharmaceutically acceptable salt thereof in the dosage form is comprised between 800 and 900 mg, preferably is about 850 mg, expressed as equivalent weight of metformin hydrochloride, and the amount of linagliptin or a pharmaceutically acceptable salt thereof is comprised between 1 and 5 mg, preferably comprised between 2 and 3 mg and more preferably is about 2.5 mg, expressed as equivalent weight of linagliptin free base. The amount of meglumine in the dosage form according this embodiment is preferably comprised between 15 and 25 mg, more preferably comprised between 20 and 23 mg.

In one preferred embodiment, the amount of metformin or a pharmaceutically acceptable salt thereof in the dosage form is comprised between 400 and 600 mg, preferably is about 500 mg, expressed as equivalent weight of metformin hydrochloride, and the amount of linagliptin or a pharmaceutically acceptable salt thereof is comprised between 1 and 5 mg, preferably comprised between 2 and 3 mg and more preferably is about 2.5 mg, expressed as equivalent weight of linagliptin free base. The amount of meglumine in the dosage form according this embodiment is preferably comprised between 8 and 20 mg, more preferably comprised between 11 and 14 mg.

In one embodiment, the pharmaceutical dosage form may comprise an additional active ingredient, as a further partner drug to linagliptin and metformin, in order to provide a fixed-dose combination of three or more active ingredients useful in therapy.

The additional partner drug may be, for example, a further anti-diabetic agent. Suitable anti-diabetic agents to be used in combination with linagliptin and metformin are, for example, sodium-glucose transport protein 2 (SGLT2) inhibitors, sulfonylureas, thiazolidinediones (TZD), glinides, alpha-glucosidase inhibitors, or glucagon-like peptide-1 (GLP-1) receptor agonists, among others.

Suitable SGLT2 inhibitors are for example, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin etabonate, sergliflozin etabonate, sotagliflozin or tofogliflozin, among others; suitable sulfonylureas are, for example, tolbutamide, tolazamide, acetohexamide, carbutamide, chlorpropamide, glycyclamide, metahexamide, glyburide (glibenclamide), gliclazide, glipizide, glibornuride, gliquidone, glisoxepide, glyclopyramide, glymidine or glimepiride among others; suitable thiazolidinediones are, for example, pioglitazone, rosiglitazone or lobeglitazone, among others; suitable glinides are repaglinide, nateglinide or mitiglinide, among others; suitable alpha-glucosidase inhibitors are, for example, acarbose, miglitol or voglibose, among others; suitable GLP-1 receptor agonists are, for example, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, among others. The additional active ingredient may be, typically, in the form of a further granule, which can be combined with the linagliptin granule, the metformin granule and, optionally, with the extragranular excipient, to prepare the combined dosage form.

The granule comprising the additional active ingredient may be prepared according to standard procedures. In one embodiment, the pharmaceutical oral dosage according to the present invention is in the form of granulate/powder mixture, typically available in mono-dose sachets.

In another embodiment, the pharmaceutical dosage form is in the form of a capsule, i.e., linagliptin granules, metformin granules and, optionally, extragranular excipients are enclosed within either a hard or soft soluble shell. Usually, the major component of capsules is gelatin, and typically they also comprise water, colorants, plasticizers, such as glycerine or sorbitol, and opacifying agents. Alternatively, hypromellose capsules may also be used.

In another embodiment, the pharmaceutical dosage form is in the form of a tablet.

Optionally, the tablets may have a film-coating layer (or overcoat, or finishing layer) applied onto the tablet core. This film-coating layer comprises conventional immediate-release polymers, as are well-known in the art, for example, hydroxypropyl methylcellulose (or hypromellose, HPMC), methyl cellulose (MC), hydroxypropyl cellulose (HPC), polyvinyl pyrrolidone (PVP), copovidone, polyvinyl alcohol (PVA) or, mixtures thereof. The film-coating layer may also contain other ingredients, as is well known by the skilled person in pharmaceutical formulation, such as an anti-tacking agent, a colourant, or a plasticizer, for example. The anti-tacking agent can be selected, for example, from calcium silicate, magnesium silicate, colloidal silicon dioxide magnesium stearate, calcium stearate, magnesium oxide, talc and mixtures thereof. Suitable plasticizers are, for example, polyethylene glycol, propylene glycol, diethyl phthalate, triethyl citrate, among others. Suitable colourants include, among others, iron oxide pigments and titanium dioxide.

When there is a film-coating layer, the weight of this layer amounts from about 2% to about 8% of the weight of the formulation (before applying said finishing layer).

As stated above, when there is an additional finishing layer, the percentages stated along the present description that refer to “total weight of the dosage form” are calculated without including the weight of the film-coating layer, i.e., they refer to the weight of the core tablet, before applying the finishing layer.

Preparation of the dosage form

Another aspect of the present invention is a process for the preparation of the combined oral pharmaceutical dosage form, as defined above, comprising the following steps: i) preparing granules comprising linagliptin, or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient; ii) preparing granules comprising metformin or a pharmaceutically acceptable salt thereof meglumine and, optionally, an additional pharmaceutically acceptable excipient; iii) mixing the granules obtained in steps i) and ii) and, optionally, an additional pharmaceutically acceptable excipient. As is well-known in the art, granules may be prepared, typically, by dry granulation or by wet granulation. In dry granulation, powders are aggregated at high pressure while in wet granulation, a granulation fluid is sprayed onto the particles as they are agitated, usually in a high-shear mixer or fluidized bed, which are common in the art.

The procedures used in the present invention for preparing the dosage form, including granulation, preparation of powder mixtures, tablets and capsules, are standard processes well-known in pharmaceutical technology, as disclosed in reference books in the field, for example, in the book Aulton’s Pharmaceutics. The design and manufacture of medicines, M.E. Aulton and K.M.G. Taylor, editors, Churchill Livingstone Elsevier, Fourth Edition, 2013; or in the book Remington Essentials of Pharmaceutics, L. Felton, editor, Pharmaceutical Press, 2013; or in the book Pharmaceutics. Basic principles and application to pharmacy practice. A.K. Dash, S. Singh, and J. Tolman, editors, Academic Press, Elsevier, 2014. In one preferred embodiment, the preparation of granules of steps i) and ii) are made by wet granulation, typically using a binder.

The granulation fluid is typically prepared by dissolving/dispersing the binder and optionally other pharmaceutically acceptable excipients in a suitable solvent. The granulation solvent can be selected from water and a mixture of water and an alcohol, such as isopropanol or ethanol, for example. Preferably the granulation solvent used in steps i) and ii) is water or a mixture of water and ethanol.

In one embodiment, step i) comprises the following steps: i1) mixing linagliptin, a filler and, optionally, an additional pharmaceutically acceptable excipient; i2) preparing the granulation fluid by dissolving/dispersing a binder and, optionally, an additional pharmaceutically acceptable excipient, in the solvent;

13) granulating by spraying the granulation fluid of step i2) onto the mixture of step i1); and

14) drying the granules obtained in step i3). In one embodiment, when there is a disintegrant in the linagliptin granule, it is preferably added in step i1), i.e., mixed with linagliptin.

In one embodiment, no additional pharmaceutically acceptable excipient is added in step i2).

In one embodiment, the binder may be divided in two parts and one part of binder is added to the granulation fluid (in step i2) and another part of the binder is mixed with linagliptin (in step i1). In one embodiment, step ii) comprises the following steps:

N1) mixing metformin with a pharmaceutically acceptable excipient;

N2) preparing the granulation fluid by dissolving/dispersing a binder and, optionally, an additional pharmaceutically acceptable excipient, in the solvent; N3) granulating by spraying the granulation fluid of step N2) onto the mixture of step ii1); and

N4) drying the granules obtained in step N3); wherein meglumine is either mixed with metformin (in step ii1), or is added to the granulation fluid (in step N2), or meglumine is divided in two parts and one part is mixed with metformin (in step ii1) and another part is added to the granulation fluid (in step N2).

In one embodiment, when there is a disintegrant in the metformin granule, it is preferably added in step ii1), i.e., it is mixed with metformin.

In one embodiment, when there is a glidant in the metformin granule, it is preferably added in step N2), i.e., it is added to the granulation fluid.

In one embodiment, when there is a wetting agent in the metformin granule, it is preferably added in step N2), i.e., it is added to the granulation fluid.

In one embodiment, the binder may be divided in two parts and one part of binder is added to the granulation fluid (in step N2) and another part of the binder is mixed with metformin (in step ii1).

When meglumine is divided in two parts and one is added in step ii1) and the other in step N2), the percentage of meglumine which is added in step ii1) can range from about 20 to about 70 wt%, preferably from about 40 to about 60 wt% of the total meglumine. Before the mixing step i1 ) and/or ii1 ), the ingredients may be previously sieved through a sieve, for example, of 0.5 mm-2.00 mm. Furthermore, after granulation step i3) and/or N3) and/or after drying step i4) and/or N4), the granules may be also screened through a wire mesh to break agglomerates of granules and for removing fine material which can be recycled. Step iii) comprises mixing the granules obtained in steps i) and ii) and, optionally, an additional pharmaceutically acceptable extragranular excipient.

The preparation of the final dosage form is also performed following standard methods.

Thus, for example, when the final dosage form is a granulate/powder mixture, the mixture obtained in step iii) is typically filled into mono-dose sachets, or when the final dosage form is a capsule, the mixture is filled, for example, into hard gelatine capsules, or when the final dosage form is a tablet, the mixture obtained in step iii) is compressed using a tabletting machine.

In one embodiment, the final dosage form is a tablet. According to this embodiment, the process comprises the additional steps: iv) compressing the mixture obtained in step iii) to form a tablet; and v) optionally, coating the tablet obtained in step iv)

The coating of tablets of step v) is performed according to standard process, typically, by spraying a coating solution or suspension onto the surface of the tablets.

The preferred excipients used in each step, and the preferred amounts thereof are as disclosed above under the “Nnagliptin granule”, “metformin granule” and “dosage form” sections.

Use of the dosage form

Surprisingly, the dosage form according to the present invention is outstandingly stable and is therefore particularly suitable for treating diabetes type 2.

For example, the stability test disclosed in Example 4 shows that the present invention provides a dosage form (tablets 1A, 1 B) with better purity than the commercial product Jentadueto^® (C2).

Furthermore, as shown in Example 4, the dosage form of the invention has particularly low levels of metformin-related impurities, including nitrosamines.

Therefore, another aspect of the invention is the oral pharmaceutical dosage form comprising linagliptin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof, according to the present invention, for use in medicine, in particular, for the treatment diabetes type 2. Another aspect of the present invention is a method for treating diabetes type

2 in a patient in need thereof comprising the step of administering therapeutically effective amount of the dosage form of the present invention.

The present invention relates to the following embodiments: 1.- An oral pharmaceutical dosage form comprising linagliptin and metformin, characterized in that it comprises: a) a first type of granule comprising linagliptin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient; and b) a second type of granule comprising metformin or a pharmaceutically acceptable salt thereof and meglumine. 2.- The oral pharmaceutical dosage form according to embodiment 1 , characterized in that linagliptin is in the form of free base.

3.- The oral pharmaceutical dosage form according to embodiments 1 or 2, characterized in that metformin is in the form of metformin hydrochloride.

4.- The oral pharmaceutical dosage form according to any one of embodiments 1 to 3, characterized in that the content of linagliptin or a pharmaceutically acceptable salt thereof in the linagliptin granule is in the range 1 -10 wt%, preferably in the range 2-8 wt%, and more preferably in the range 3-6 wt%, referred to the total weight of the linagliptin granule.

5.- The oral pharmaceutical dosage form according to any one of embodiments 1 to 4, characterized in that the pharmaceutically acceptable excipient in the linagliptin granule is selected from a filler, a binder, a disintegrant and mixtures thereof.

6.- The oral pharmaceutical dosage form according to embodiment 5, characterized in that the linagliptin granule comprises linagliptin or a pharmaceutically acceptable salt thereof, a filler, a binder and, optionally, a disintegrant.

7.- The oral pharmaceutical dosage form according to embodiments 5 or 6, characterized in that content of filler in the linagliptin granule is comprised in the range 75-98 wt%, preferably in the range 80-95 wt%, more preferably in the range 85-93 wt%, and more preferably is about 90 wt%, referred to the total weight of the linagliptin granule.

8.- The oral pharmaceutical dosage form according to any one of embodiments 5 to 7, characterized in that the filler in the linagliptin granule is selected from the group consisting of calcium carbonate, calcium lactate, calcium phosphate dibasic, calcium phosphate tribasic, calcium silicate, calcium sulfate, microcrystalline cellulose, powdered cellulose, cellulose acetate, corn starch, pregelatinized starch, dextrin, dextrose, fructose, lactitol, lactose, maltodextrin, maltose, mannitol, sorbitol, sucrose, trehalose, xylitol and mixtures thereof; preferably is selected from the group consisting of dextrose, mannitol, sorbitol, xylitol and mixtures thereof; and more preferably the filler is mannitol. 9.- The oral pharmaceutical dosage form according to any one of embodiments 5 to 8, characterized in that the content of binder in the linagliptin granule is in the range 1 -15 wt%, preferably in the range 2-10 wt%, more preferably in the range 3-7 wt% and still more preferably is about 5 wt%, referred to the total weight of the linagliptin granule.

10.- The oral pharmaceutical dosage form according to any one of embodiments 5 to 9, characterized in that the binder in the linagliptin granule is selected from the group consisting of acacia, agar, alginic acid, carbomers, carrageenan, chitosan, copovidone, starch, pregelatinized starch, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glyceryl behenate, guar gum, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hypromellose, lactose, maltodextrin, maltose, methylcellulose, pectin, polyethylene oxide, povidone, sodium alginate, sucrose, and mixtures thereof, preferably is selected from the group consisting of copovidone, hydroxypropyl cellulose, hypromellose and povidone; more preferably is selected from povidone, copovidone and mixtures thereof, and still more preferably, the binder is copovidone.

11 .- The pharmaceutically oral dosage form according to any one of embodiments 5 to 10, characterized in that the linagliptin granule comprises a disintegrant. 12.- The oral pharmaceutical dosage form according to embodiment 11 , characterized in that the amount of disintegrant is comprised in the range 0.5-6 wt%, preferably comprised in the range 1-3 wt%, referred to the total weight of the linagliptin granule.

13.- The oral pharmaceutical dosage form according to embodiments 11 or 12, characterized in that the disintegrant is selected from the group consisting of alginic acid, calcium alginate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, starch, pregelatinized starch, croscarmellose sodium, crospovidone, docusate sodium, hydroxypropyl cellulose low-substituted, polacrilin potassium, sodium alginate, sodium starch glycolate, and mixtures thereof; preferably the disintegrant is selected from croscarmellose sodium, crospovidone, sodium starch glycolate and mixtures thereof; and more preferably the disintegrant is sodium starch glycolate.

14.- The oral pharmaceutical dosage form according to any one of embodiments 1 to 13, characterized in that the content of metformin or a pharmaceutically acceptable salt thereof in the metformin granule is in the range 70-99 wt%, preferably in the range 75- 95 wt%, more preferably in the range 80-92 wt%, and still more preferably in the range 85-90 wt%, referred to the total weight of the metformin granule.

15.- The oral pharmaceutical dosage form according to any one of embodiments 1 to

14, characterized in that the weight ratio metformin or a pharmaceutically acceptable salt thereof:meglumine in the metformin granule is comprised between 99:1 and 2:1 , preferably comprised between 85:1 and 15:1 , more preferably comprised between 70:1 and 20:1 , still more preferably comprised between 60:1 and 25:1 , still more preferably comprised between 50:1 and 30:1 , still more preferably comprised between 45:1 and 35:1 , and still more preferably is about 40:1 , wherein the weight of metformin or a pharmaceutically acceptable salt thereof is expressed as the equivalent weight of metformin hydrochloride.

16.- The oral pharmaceutical dosage form according to any one of embodiments 1 to

15, characterized in that the metformin granule comprises an additional pharmaceutically acceptable excipient selected from a binder, a filler, a glidant, an antioxidant, a wetting agent, a disintegrant and mixtures thereof, preferably selected from a binder, a glidant, a wetting agent, a disintegrant and mixtures thereof.

17. The oral pharmaceutical dosage form according to embodiment 16, characterized in that the metformin granule comprises metformin or a pharmaceutically acceptable salt thereof, meglumine, a binder and at least one additional excipient which is selected from a wetting agent, a disintegrant, a glidant and mixtures thereof.

18.- The oral pharmaceutical dosage form according to embodiment 17, characterized in that the metformin granule comprises metformin or a pharmaceutically acceptable salt thereof, meglumine, a binder and a glidant, preferably the metformin granule essentially consists of metformin or a pharmaceutically acceptable salt thereof, meglumine, a binder and a glidant.

19.- The oral pharmaceutical dosage form according to embodiment 17, characterized in that the metformin granule comprises metformin or a pharmaceutically acceptable salt thereof, meglumine, a binder, a disintegrant and a wetting agent, preferably the metformin granule essentially consists of metformin or a pharmaceutically acceptable salt thereof, meglumine, a binder, a disintegrant and a wetting agent. 20.- The oral pharmaceutical dosage form according to any one of embodiments 16 to

19, characterized in that the content of binder in the metformin granule is in the range 2-20 wt%, preferably in the range 5-15 wt%, more preferably in the range 7-12 wt% and still more preferably in the range 9-11 wt%, referred to the total weight of the metformin granule.

21 .- The oral pharmaceutical dosage form according to any one of embodiments 16 to

20, characterized in that the binder in the metformin granule is selected from the group consisting of acacia, agar, alginic acid, carbomers, carrageenan, chitosan, copovidone, starch, pregelatinized starch, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glyceryl behenate, guar gum, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hypromellose, lactose, maltodextrin, maltose, methylcellulose, pectin, polyethylene oxide, povidone, sodium alginate, sucrose, and mixtures thereof; preferably is selected from the group consisting of copovidone, hydroxypropyl cellulose, hypromellose, povidone and mixtures thereof; more preferably is selected from povidone, copovidone and mixtures thereof, and still more preferably the binder is copovidone.

22.- The oral pharmaceutical dosage form according to any one of embodiments 16 to 21 , characterized in that the glidant is selected from colloidal silicon dioxide, silicon dioxide, magnesium silicate, talc, and combinations thereof, preferably the glidant is colloidal silicon dioxide.

23.- The oral pharmaceutical dosage form according to any one of embodiments 16 to 22, characterized in that the content of glidant in the metformin granule is comprised in the range 0.05-4 wt%, preferably comprised in the range 0.1 -1 wt%, referred to the total weight of the metformin granule.

24.- The oral pharmaceutical dosage form according to any one of embodiments 16 to 22, characterized in that the wetting agent is selected from sodium lauryl sulfate and a polysorbate. In one particular embodiment the wetting agent is sodium lauryl sulfate. In another particular embodiment the wetting agent is a polysorbate.

25.- The oral pharmaceutical dosage form according to any one of embodiments 16 to 24, characterized in that the content of wetting agent in the metformin granule is comprised in the range 0.1-4 wt%, preferably in the range 0.1-3 wt%, more preferably in the range 0.1-2 wt% and still more preferably in the range 0.1-1 wt%, referred to the total weight of the metformin granule.

26.- The oral pharmaceutical dosage form according to any one of embodiments 16 to 25, characterized in that the disintegrant is selected from starch, croscarmellose sodium, crospovidone, sodium starch glycolate and mixtures thereof, preferably is selected from starch, sodium starch glycolate and crospovidone and more preferably is selected from starch and sodium starch glycolate. In one particular embodiment the disintegrant is starch. In another particular embodiment, the disintegrant is sodium starch glycolate.

27.- The oral pharmaceutical dosage form according to any one of embodiments 16 to

26, characterized in that the content of disintegrant in the metformin granule is comprised in the range 1-15 wt%, preferably in the range 2-12 wt%, and more preferably in the range 3-10 wt%, referred to the total weight of the metformin granule.

28.- The oral pharmaceutical dosage form according to any one of embodiments 1 to

27, characterized in that it further comprises at least one extragranular excipient, which is preferably selected from a filler, a colorant, a disintegrant, a glidant, a lubricant and mixtures thereof, more preferably is selected from a glidant, a lubricant and mixtures thereof, and more preferably the extragranular excipient essentially consists of a glidant and a lubricant.

29.- The oral pharmaceutical dosage form according to embodiment 28, characterized in that it comprises an extragranular glidant and an extragranular lubricant; and more preferably the amount of glidant is in the range 0.05-4 wt%, preferably in the range 0.1- 1 wt% and the amount of lubricant is in the range 0.2-5 wt%, preferably in the range 1- 3 wt%, referred to the total weight of the dosage form. 30.- The oral pharmaceutical dosage form according to embodiment 29, characterized in that the glidant is selected from the group consisting of colloidal silicon dioxide, silicon dioxide, magnesium silicate, talc and mixtures thereof; preferably, the glidant is colloidal silicon dioxide; and the lubricant is selected from the group consisting of calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, magnesium stearate, medium-chain triglycerides, myristic acid, palmitic acid, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, zinc stearate, and mixtures thereof, preferably, the lubricant is selected from calcium stearate, glyceryl behenate, hydrogenated castor oil, magnesium stearate, sodium stearyl fumarate, stearic acid and mixtures thereof, and more preferably the lubricant is magnesium stearate.

31 The oral pharmaceutical dosage form according to any one of embodiments 1 to

30, characterized in that the weight ratio metformin :linagliptin in the dosage form is comprised between 500:1 and 100:1 , preferably comprised between 450:1 and 150:1 , and more preferably is comprised between 400:1 and 200:1 , wherein the weight of metformin is expressed as equivalent weight of metformin hydrochloride.

32.- The oral pharmaceutical dosage form according to any one of embodiments 1 to

31 , characterized in that the amount of metformin or a pharmaceutically acceptable salt thereof in the dosage form is comprised between 400 and 1100 mg, preferably comprised between 500 and 1000 mg, expressed as equivalent weight of metformin hydrochloride, and the amount of linagliptin or a pharmaceutically acceptable salt thereof is comprised between 1 and 5 mg, preferably comprised between 2 and 3 mg and more preferably is about 2.5 mg, expressed as equivalent weight of linagliptin free base.

33. The oral pharmaceutical dosage form according to any one of embodiments 1 to

32, characterized in that the amount of meglumine in the dosage form is comprised between 5 and 35 mg, preferably comprised between 10 and 30 mg.

34.- The oral pharmaceutical dosage form according to any one of embodiments 1 to

33, characterized in that the dosage form is a tablet.

35.- A process for the preparation of the pharmaceutical dosage form according to any one of embodiments 1 to 34, characterized in that it comprises the following steps: i) preparing granules comprising linagliptin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient; ii) preparing granules comprising metformin or a pharmaceutically acceptable salt thereof, meglumine and, optionally, an additional pharmaceutically acceptable excipient; iii) mixing the granules obtained in steps i) and ii) and, optionally, an additional pharmaceutically acceptable excipient. 36.- The process according to embodiment 35, characterized in that the granules of steps i) and ii) are prepared by wet granulation. 37.- The oral pharmaceutical dosage form according to any one of embodiments 1 to

34 for use in medicine.

38.- The oral pharmaceutical dosage form according to any one of embodiments 1 to 34 for use in the treatment of diabetes type 2.

Examples

Example 1 Preparation of tablets comprising metformin HCI and linaaliptin (850/2.5) Tablets 1A and 1 B comprising 850 mg of metformin and 2.5 mg of linagliptin HCI were prepared using the ingredients disclosed in Table 1. Tablets 1 B comprised less amount of meglumine.

^*solvent, added and removed during the manufacturing process *^*contains: HPMC, PEG, titanium dioxide, iron oxide yellow and iron oxide red

TABLE 1 Linagliptin granules were prepared by wet granulation in a high-shear granulation apparatus. Linagliptin, mannitol, sodium starch glycolate and half of the copovidone were weighed and sieved through a sieve of 800-1000 microns, and added to the high-shear granulation bowl, where they were mixed. The granulation fluid was prepared by suspending the remaining half of copovidone in water, and it was sprayed onto the powder pre-mixture, maintaining the agitation. The formed granules were dried in a fluidized-bed dryer.

The metformin granules were prepared by wet granulation in a fluidized bed granulation apparatus. Metformin HCI and half of meglumine were uniformly mixed in the fluid bed granulator. The granulation fluid was prepared by mixing copovidone, silica colloidal anhydrous and the remaining half of meglumine in water, and this granulation fluid was sprayed onto the powder mixture. After the granulation fluid was completely sprayed, the formed granules were maintained in the fluidized bed under airstream for drying the granules.

Linagliptin granules and metformin granules thus obtained were mixed in a vessel, silica colloidal anhydrous and magnesium stearate were successively added and mixed. The final mixture was compressed to form the tablets, using a rotary tableting machine with an oval, biconvex punch to produce a tablet weighting 1060 mg.

The Opadry^® coating blend was dispersed in water to prepare a film coating fluid. The coating fluid was sprayed onto the tablet in a film coating machine, to produce a 1091.80 mg film-coated tablet containing 850 mg of metformin hydrochloride and 2.5 mg of linagliptin.

Using analogous method, film-coated tablets 1C and 1 D of the same strength were prepared using the ingredients disclosed in Table 2:

TABLE 2

Using analogous method, film-coated tablets 1 E of the same strength were prepared using the ingredients disclosed in Table 3:

TABLE 3

In this case, for preparing the metformin granules, metformin HCI and sodium starch glycolate were uniformly mixed in the fluid bed granulator. The granulation fluid was prepared by mixing copovidone, meglumine, and sodium lauryl sulfate in a mixture of water and ethanol (30:70, by weight), and this granulation fluid was sprayed onto the powder mixture. Example 2 Preparation of tablets comprising metformin HCI and linaaliptin (1000/2.5)

Film-coated tablets 2A comprising 1000 mg of metformin HCI and 2.5 mg of linagliptin were prepared analogously as disclosed in Example 1 , using the ingredients of Table 4:

^*solvent, added and removed during the manufacturing process *^*contains HPMC, PEG, talc, titanium dioxide and iron oxide red

TABLE 4

Analogously, film-coated tablets 2B and 2C of the same strength were prepared using the ingredients disclosed in Table 5:

TABLE 5

Also analogously, film-coated tablets 2D, 2E and 2F of the same strength were prepared using the ingredients disclosed in Table 6:

TABLE 6

In this case, for preparing the metformin granules, metformin HCI and sodium starch glycolate were uniformly mixed in the fluid bed granulator. The granulation fluid was prepared by mixing copovidone, meglumine, and sodium lauryl sulfate in a mixture of water and ethanol (30:70, by weight), and this granulation fluid was sprayed onto the powder mixture.

Also analogously, film-coated tablets 2G, 2H and 21 of the same strength were prepared using the ingredients disclosed in Table 7:

TABLE 7

The preparation method was analogous as disclosed for Examples 2D, 2E and 2F, but replacing sodium lauryl sulfate with polysorbate 80 and/or sodium starch glycolate with maize starch, when appropriate.

Example 3 Preparation of tablets comprising metformin HCI and linaqliptin (500/2.5) Analogously, film-coated tablets 3A comprising 500 mg of metformin HCI and 2.5 mg of linagliptin were prepared using the ingredients disclosed in Table 8:

^*solvent, added and removed during the manufacturing process *^* contains HPMC, PEG, talc

TABLE 8

Analogously, film-coated tablets 3B and 3C of the same strength were prepared using the ingredients disclosed in Table 9:

TABLE 9

Comparative Example A comparative formulation example in the form of film-coated tablet comprising 850 mg of metformin and 2.5 mg of linagliptin HCI was prepared following the procedure disclosed in Example 1 , using the components disclosed for Example 1 B, but without using any amount of meglumine in the metformin granules. Example 4 Stability test

The stability of the dosage forms according to the invention was tested using two film-coated tablets containing 850 mg of metformin HCI and 2.5 mg of linagliptin disclosed in Example 1 (Examples 1A and 1 B), and was compared with the tablet disclosed in Comparative Example containing the same amount of actives but containing no meglumine (C2) and with a commercial Jentadueto^® film-coated tablet of the same strength (C1 ), as shown in Table 9 below.

The determinations were made at the following time points: initial (0), after 1 month at 40° C and 75% RH (1 ) after 1 month at 50° C and 75% RH (2), after 3 months at 25° C and 60% RH (3) after 3 months at 40° C and 75% RH (4), after 6 months at 25° C and 60% RH (5), after 6 months at 40° C and 75% RH (6), after 9 months at 25° C and 60% RH (7) and after 12 months at 25° C and 60% RH (8).

TABLE 10

In the above table, BRT means bellow reporting threshold. For metformin impurities, the reporting threshold is 0.01%. It can be observed that the film-coated tablets of the invention (1 A and 1 B) are stable, whereas the amount of linagliptin-related impurities was clearly increased in the comparative tablets C2, which contained no meglumine.

Furthermore, the film-coated tablets according to the invention (1A and 1 B) showed better purity profile than the commercial product Jentadueto^® (C1).

Claims

1.- An oral pharmaceutical dosage form comprising linagliptin and metformin, characterized in that it comprises: a) a first type of granule comprising linagliptin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient; and b) a second type of granule comprising metformin or a pharmaceutically acceptable salt thereof and meglumine.

2.- The oral pharmaceutical dosage form according to claim 1 , characterized in that linagliptin is in the form of free base.

3.- The oral pharmaceutical dosage form according to claims 1 or 2, characterized in that metformin is in the form of metformin hydrochloride.

4.- The oral pharmaceutical dosage form according to any one of claims 1 to 3, characterized in that the content of linagliptin or a pharmaceutically acceptable salt thereof in the linagliptin granule is in the range 1 -10 wt%, preferably in the range 2-8 wt%, and more preferably in the range 3-6 wt%, referred to the total weight of the linagliptin granule.

5.- The oral pharmaceutical dosage form according to any one of claims 1 to 4, characterized in that the pharmaceutically acceptable excipient in the linagliptin granule is selected from a filler, a binder, a disintegrant and mixtures thereof.

6.- The oral pharmaceutical dosage form according to any one claims 1 to 5, characterized in that the linagliptin granule comprises a filler, preferably selected from the group consisting of dextrose, mannitol, sorbitol, xylitol and mixtures thereof.

7.- The oral pharmaceutical dosage form according to claims 1 to 6, characterized in that the linagliptinin granule comprises a binder, preferably selected from the group consisting of copovidone, hydroxypropyl cellulose, hypromellose, povidone and mixtures thereof.

8.- The pharmaceutically oral dosage form according to claims 1 to 7, characterized in that the linagliptin granule comprises a disintegrant, preferably selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate and mixtures thereof.

9.- The oral pharmaceutical dosage form according to any one of claims 1 to 8, characterized in that the content of metformin or a pharmaceutically acceptable salt thereof in the metformin granule is in the range 70-99 wt%, preferably in the range 75- 95 wt%, more preferably in the range 80-92 wt%, and still more preferably in the range 85-90 wt%, referred to the total weight of the metformin granule.

10.- The oral pharmaceutical dosage form according to any one of claims 1 to 9, characterized in that the weight ratio metformin or a pharmaceutically acceptable salt thereof: meglumine in the metformin granule is comprised between 85:1 and 15:1 , wherein the weight of metformin or a pharmaceutically acceptable salt thereof is expressed as equivalent weight of metformin hydrochloride.

11.- The oral pharmaceutical dosage form according to any one of claims 1 to 10, characterized in that the weight ratio metformi linagliptin in the dosage form is comprised between 500:1 and 100:1 , wherein the weight of metformin is expressed as equivalent weight of metformin hydrochloride.

12.- The oral pharmaceutical dosage form according to any one of claims 1 to 11 , characterized in that the amount of metformin or a pharmaceutically acceptable salt thereof in the dosage form is comprised between 400 and 1100 mg, expressed as equivalent weight of metformin hydrochloride, and the amount of linagliptin or a pharmaceutically acceptable salt thereof is comprised between 1 and 5 mg, expressed as equivalent weight of linagliptin free base.

13.- The oral pharmaceutical dosage form according to any one of claims 1 to 12, characterized in that the dosage form is a tablet.

14.- A process for the preparation of the pharmaceutical dosage form according to any one of claims 1 to 13, characterized in that it comprises the following steps: i) preparing granules comprising linagliptin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient; ii) preparing granules comprising metformin or a pharmaceutically acceptable salt thereof, meglumine and, optionally, an additional pharmaceutically acceptable excipient; iii) mixing the granules obtained in steps i) and ii) and, optionally, an additional pharmaceutically acceptable excipient.

15.- The oral pharmaceutical dosage form according to any one of claims 1 to 13 for use in medicine.