Pharmaceutical extended-release formulations comprising linagliptin and metformin

Description

[0001] PHARMACEUTICAL EXTENDED-RELEASE FORMULATIONS COMPRISING LINAGLIPTIN AND METFORMIN

[0002] Field of Invention

[0003] The present invention relates to extended-release multilayer tablet formulations comprising linagliptin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof, and methods of manufacturing the same.

[0004] Background of the Invention

[0005] Linagliptin is an oral dipeptidyl peptidase - 4 (DPP - IV) inhibitor. DPP-IV inhibitors are a group of active substances used orally in the treatment of type 2 diabetes mellitus. DPP-IV inhibitors act by blocking the action of DPP-4, an enzyme involved in the inactivation of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 and GIP hormones are naturally produced by the body in response to food intake. Linagliptin binds very efficiently to DPP- IV, leading to a prolonged increase and prolongation of active incretin levels.

[0006] Linagliptin is a DPP-IV inhibitor with the chemical name (R)-8-(3-aminopiperidin-l-yl)-7-but-2-inyl-3- methyl-l-(4-methylquinazolin-2- ylmethyl)-3,7-dihydropurine-2, 6-dione. Also known by the code Bl - 1356. Linagliptin is a white to yellowish, slightly hygroscopic or non-hydroscopic solid. Very poorly soluble in water (0.9 mg / mL). Soluble in methanol, slightly soluble in ethanol, very poorly soluble in isopropranol and acetone. Its molecular weight is 472.54.

[0007] Linagliptin is administered once daily in fixed doses and no dose adjustment is required due to organ dysfunction. Linagliptin is used in the treatment of type 2 diabetes mellitus as monotherapy or in combination with other commonly used medications (e.g., metformin, sulfonylureas, and pioglitazone). In the U.S., the FDA approved linagliptin in May 2011 as TRAJENTA at a dose of 5 mg.

[0008] Metformin is an oral biguanide antidiabetic that is taken orally. Metformin is similar to phenformin, a biguanide drug that was withdrawn from the U.S. market in 1977 because of cases of lactic acidosis. However, metformin has a significantly lower risk of causing lactic acidosis. The effects of metformin are different from those of sulfonylureas and other antidiabetic medications. Compared with glibenclamide (glyburide) in type 2 diabetes, it was found to provide a similar level of glycemic control, but with a higher incidence of digestive complaints. Metformin has also been found useful in the treatment of polycystic ovary syndrome (POCS); it lowers serum androgen levels, restores normal menstrual cycles and ovulation, and may increase pregnancy rates. Metformin HCI was selected as the first-line treatment based on its efficacy, safety and cost-effectiveness.

[0009] The chemical name of Metformin with molecular weight of 129.16 g / mol is 1,1-dimethyl biguanide and has a structure as shown below;

[0010] Metformin

[0011] Linagliptin was first disclosed in patent numbered EP1532149 B9, which also discloses the molecule itself, its salts, uses in the treatment of type 1 and type 2 diabetes, methods of obtaining it, and combinations with metformin.

[0012] Metformin as an active substance was first described by Emil A. Werner and James Bell in J. Chem. Soc., 121, 1922, 1790-1794. Metformin hydrochloride was introduced in Europe in the 1950s, but was not approved by the FDA in the U.S. until November 1994.

[0013] JENTADUETO oral tablets, a combination of linagliptin and metformin as active substance, was approved by the FDA in January 2012 and by the EMA in July 2012. Jentadueto is indicated in adults with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control in the following cases:

[0014] • in patients inadequately controlled on their maximally tolerated dose of metformin alone,

[0015] • in combination with other medicinal products for the treatment of diabetes, including insulin, in patients inadequately controlled with metformin and these medicinal products,

[0016] • in patients already being treated with the combination of Linagliptin and metformin as separate tablets.

[0017] EP2285410 Bl numbered patent discloses the compositions comprising linagliptin and metformin HCI comprise a nucleophilic agent to prevent degradation of linagliptin, wherein the nucleophilic agent is L-arginine.

[0018] WO2017093419 Al numbered patent application discloses a rapid release coating comprising linagliptin on an extended-release core comprising metformin HCI in a solid oral dosage form.

[0019] WO2014 / 026939 Al numbered patent application discloses a pharmaceutical composition comprising linagliptin together with mannitol, copovidone and magnesium stearate.

[0020] Detailed Description of the Invention

[0021] While various compositions comprising linagliptin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof are available in the prior art, there is a need for extended-release formulations that are simple, inexpensive and favorable in terms of stability and dissolution.

[0022] As a result of their studies, the present inventors surprisingly discovered that tablet formulations comprising linagliptin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof as the active substance have similar or better dissolution and stability in terms of chemical analysis than the reference product when the controlled release agent is a combination of hydroxypropyl methylcellulose, sodium alginate, glycerol dibehenate and polyacrylic acid.

[0023] The present invention relates to stable oral extended-release multilayer tablet formulations comprising linagliptin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof. Specifically, the present invention discloses formulations comprising linagliptin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof, comprising a combination of hydroxypropyl methylcellulose, sodium alginate, glycerol dibehenate and polyacrylic acid as a controlled release agent.

[0024] As a result of the dissolution and stability studies, it was found that the pharmaceutical formulations according to the present invention are similar or even better than the prior art formulations in terms of chemical analysis.

[0025] Accordingly, a pharmaceutical formulation comprising linagliptin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof as the active substance, characterized in that the formulation consists of a combination of hydroxypropyl methylcellulose, sodium alginate, glycerol dibehenate and polyacrylic acid as a controlled release agent.

[0026] According to the present invention, the weight of the combination of hydroxypropyl methylcellulose, sodium alginate, glycerol dibehenate and polyacrylic acid used as controlled release agent in pharmaceutical formulations is between 15 and 25% by weight of the total formulation.

[0027] Pharmaceutical formulations according to the present invention comprise linagliptin or a pharmaceutical salt thereof as the active substance. Linagliptin used in pharmaceutical formulations according to the present invention is preferably present as a free base.

[0028] In pharmaceutical formulations according to the present invention, linagliptin may be present in crystalline, amorphous or any polymorphic mixture, preferably linagliptin is used as a mixture of crystalline forms A and B.

[0029] Pharmaceutical formulations according to the present invention comprise metformin or a pharmaceutical salt thereof as the active substance. The metformin used in the present invention is preferably used in the form of hydrochloride salt.

[0030] A further feature of the pharmaceutical formulations according to the present invention is that the formulation comprises 2.5 mg or 5 mg of linagliptin. According to another embodiment of the present invention, the pharmaceutical formulations comprise metformin or a pharmaceutically acceptable salt thereof in amounts of 500 mg, 850 mg or 1000 mg.

[0031] Pharmaceutical formulations according to the present invention may comprise at least one pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients according to the present invention may be selected from solvents, disintegrants, binders, fillers, lubricants, glidants, pH regulators, film coating agents, modified release agents, or combinations thereof.

[0032] Solvents for use in pharmaceutical formulations according to the present invention may be selected from pure water, propylene glycol, glycerin, ethanol, polyethylene glycol, or combinations thereof.

[0033] Disintegrants for use in pharmaceutical formulations according to the present invention may be selected from sodium starch glycolate, low substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, ion exchangers, sodium carboxymethyl cellulose, alginates, gums, pregelatinized starch, starch, or combinations thereof. Preferably, the disintegrant that can be used in the present invention can be sodium starch glycolate.

[0034] Binders for use in pharmaceutical formulations according to the present invention may be selected from ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxy propyl cellulose, microcrystalline cellulose, carboxymethyl cellulose, oxidized cellulose, or combinations thereof. Preferably, the binder that can be used in the present invention comprises a mixture of hydroxy propyl methyl cellulose and hydroxy propyl cellulose.

[0035] Fillers for use in pharmaceutical formulations according to the present invention may be selected from microcrystalline cellulose, lactose, lactose monohydrate, starch, corn starch, pregelatinized starch, mannitol, sorbitol, xylitol, maltodextrin, dibasic calcium phosphate, tribasic calcium phosphate, trehalose, isomalt, sodium carbonate, sodium bicarbonate, calcium carbonate, or combinations thereof.

[0036] Lubricants for use in pharmaceutical formulations according to the present invention may be selected from magnesium stearate, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, fumaric acid, glyceryl palmitostearate, hydrogenated natural oils, zinc stearate, calcium stearate, silica, talc, stearic acid, polyethylene glycol, paraffin, or combinations thereof. Preferably, the lubricant that can be used in the present invention can be magnesium stearate.

[0037] Glidants for use in pharmaceutical formulations according to the present invention may be selected from anhydrous colloidal silica (aerosil), starch, talc, or combinations thereof. Preferably, the glidant that can be used in the present invention can be aerosil.

[0038] The formulations according to the present invention do not comprise any essential amino acids.

[0039] Pharmaceutically acceptable pH regulators used in pharmaceutical formulations according to the present invention may be selected from acetic acid, monoethanolamine, diethanoleamine, triethanoleamine, meglumine, sodium citrate, citric acid, hydrochloric acid, lactic acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium bicarbonate, sodium borate, sodium hydroxide, THAM (tris(hydroxymethyl)aminomethane), or combinations thereof. Preferably, meglumine is used as the pharmaceutically acceptable pH regulator.

[0040] According to the present invention, the amount of meglumine used in pharmaceutical formulations is between 5 and 80 mg. According to the present invention, the ratio of the weight of meglumine used in pharmaceutical formulations to the total weight of the formulation is between 1-10%.

[0041] The pharmaceutical formulations according to the present invention may be in the form of tablets, film-coated tablets, double-layer tablets, triple-layer tablets, multi-layer tablets, orally disintegrating tablets, mini-tablets, pellets, chewable tablets, sublingual tablets, effervescent tablets, rapid-release tablets, extended-release tablets, sustained-release tablets, modified-release tablets, slow-release tablets, capsules, oral granules, sachets, powders, microtablets, dragees or orally disintegrating films, or combinations thereof.

[0042] The pharmaceutical formulations according to the present invention are preferably in the form of double-layer tablets.

[0043] The pharmaceutical formulations according to the present invention are preferably in the form of triple-layer tablets.

[0044] Multi-layer pharmaceutical formulations according to the present invention preferably comprise a film coating.

[0045] Film coating agents for use in pharmaceutical formulations according to the present invention may be selected from polymethacrylates, hydroxypropyl methyl cellulose, triacetin, glycerol triacetin, talc, red iron dioxide, yellow iron dioxide, propylene glycol, lactose monohydrate, hydroxypropyl cellulose, polyvinyl alcohol, polyethylene glycol, polyvinyl alcohol-polyethylene glycol copolymer (Kollicoat® IR), ethyl cellulose dispersions (Surelease®), polyvinyl pyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), all Opadry® varieties, pigments, dyes, titanium dioxide, macrogol or combinations thereof.A Modified release agents for use in pharmaceutical formulations according to the present invention may be selected from glycerol behenate, polymethacrylates (Eudragit), polyacrylic acid (carbomer), ethyl acetate, ethyl methacryl copolymer, ethyl cellulose, methyl cellulose, hypromellose phthalate, polydextrose, polyvinyl acetate phthalate, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, low weight hydroxypropyl methylcellulose (methocell), hydroxyethyl cellulose, hydroxymethyl cellulose, gelatin, polyethylene oxide, polyhydroxy methylmethacrylate, sodium carboxymethylcellulose, carboxymethyl cellulose, sodium alginate, alginic acid, polygalacturonic acid, acrylic acid polymer, agar, gum, nitrocellulose, methyl cellulose, glycerol, propylene glycol, phthalate esters, dibutyl sebacate, citrate esters, castor oil or mixtures thereof.

[0046] Pharmaceutical formulations according to the present invention may be prepared by any prior art manufacturing methods. Accordingly, the compositions may be prepared by wet granulation, dry granulation, fluid bed granulation, high shear mixer granulation, dry blending or a combination thereof.

[0047] The double-layer pharmaceutical formulations according to the present invention can be prepared by a manufacturing method comprising the following steps;

[0048] Linagliptin Layer: Linagliptin, one or more fillers and meglumine are sieved and taken into the granulator, Granulated using deionized water, Wet granules are sieved, dried and grinded, At least one excipient selected from disintegrant, glidant, filler and lubricant is added and mixed.

[0049] Metformin Layer: Metformin HCI is granulated with a granulation solution consisting of at least one cellulosederived binder, The granules obtained are dried and sieved, A combination of hydroxypropyl methylcellulose, sodium alginate, glycerol dibehenate and polyacrylic acid as a controlled release agent is mixed with a glidant and lubricant.

[0050] Double-layer tablets are manufactured by combining the linagliptin layer and the metformin layer, The tablets obtained are preferably film-coated.

[0051] The double-layer pharmaceutical formulations according to the present invention can be prepared by a manufacturing method comprising the following steps;

[0052] Linagliptin Layer: Linagliptin, one or more fillers and meglumine are sieved and mixed, Half of the lubricant is added and mixed, the powder mixture is pressed into briquettes and sieved, At least one excipient selected from disintegrant, glidant, filler and the remaining lubricant is added and mixed.

[0053] Metformin Layer: Metformin HCI is granulated with a granulation solution consisting of at least one cellulosederived binder, The granules obtained are dried and sieved, A combination of hydroxypropyl methylcellulose, sodium alginate, glycerol dibehenate and polyacrylic acid as a controlled release agent is mixed with a glidant and lubricant.

[0054] Double-layer tablets are manufactured by combining the linagliptin layer and the metformin layer, The tablets obtained are preferably film-coated.

[0055] The triple-layer pharmaceutical formulations according to the present invention can be prepared by a manufacturing method comprising the following steps;

[0056] Linagliptin Layer: 5 Linagliptin, one or more fillers and meglumine are sieved and taken into the granulator, Granulated using deionized water, Wet granules are sieved, dried and grinded, At least one excipient selected from disintegrant, glidant, filler and lubricant is added and mixed.

[0057] Barrier Layer: One or more fillers are sieved and mixed, The lubricant is added to the powder mixture and mixed.

[0058] Metformin Layer: Metformin HCI is granulated with a granulation solution consisting of at least one cellulosederived binder, The granules obtained are dried and sieved, A combination of hydroxypropyl methylcellulose, sodium alginate, glycerol dibehenate and polyacrylic acid as a controlled release agent is mixed with a glidant and lubricant.

[0059] Triple-layer tablets are manufactured by combining the linagliptin layer, the barrier layer and the metformin layer,

[0060] The tablets obtained are preferably film-coated.

[0061] The triple-layer pharmaceutical formulations according to the present invention can be prepared by a manufacturing method comprising the following steps;

[0062] Linagliptin Layer: Linagliptin, one or more fillers and meglumine are sieved and mixed, Half of the lubricant is added and mixed, the powder mixture is pressed into briquettes and sieved, At least one excipient selected from disintegrant, glidant, filler and the remaining lubricant is added and mixed.

[0063] Barrier Layer: One or more fillers are sieved and mixed, The lubricant is added to the powder mixture and mixed.

[0064] Metformin Layer: Metformin HCI is granulated with a granulation solution consisting of at least one cellulosederived binder, The granules obtained are dried and sieved, A combination of hydroxypropyl methylcellulose, sodium alginate, glycerol dibehenate and polyacrylic acid as a controlled release agent is mixed with a glidant and lubricant.

[0065] Triple-layer tablets are manufactured by combining the linagliptin layer, the barrier layer and the metformin layer,

[0066] The tablets obtained are preferably film-coated.

[0067] The pharmaceutical formulations according to the present invention can be administered orally, parenterally, intranasally, sublingually, transdermally, rectally or by inhalation.

[0068] The dosage form and route of administration of pharmaceutical formulations according to the present invention should be selected by a skilled person taking into account various factors such as weight, age, sex, medical condition of the patient to be treated.

[0069] Pharmaceutical formulations according to the present invention can be used to treat type 2 diabetes.

[0070] In pharmaceutical formulations according to another embodiment of the present invention, linagliptin or its pharmaceutically acceptable salt had a D(0.9) particle size between 5 pm and 200 pm. This size helps ensure dissolving properties and homogenization. As used here, D(0.9) refers to the size of 90% of the particles by volume. The volume average particle size of the linagliptin compound is determined using a Malvern Mastersizer 2000 laser diffraction particle size analyzer.

[0071] Examples of pharmaceutical formulations according to the present invention are given below for a clearer understanding of the subject matter of the invention and are in no way intended to limit the subject matter of the invention.

[0072] EXAMPLES

[0073] Example 1 - Double-layer tablet formulation comprising Linagliptin and Metformin HCI

[0074] Linagliptin Layer:

[0075] Linagliptin, one or more fillers and meglumine are sieved and taken into the granulator. Granulated using deionized water. Wet granules are sieved, dried and grinded. At least one excipient selected from disintegrant, glidant, filler and lubricant is added and mixed.

[0076] Metformin Layer:

[0077] Metformin HCI is granulated with a granulation solution consisting of at least one cellulose-derived binder. The granules obtained are dried and sieved. A combination of hydroxypropyl methylcellulose, sodium alginate, glycerol dibehenate and polyacrylic acid as a controlled release agent is mixed with a glidant and lubricant. Double-layer tablets are manufactured by combining the linagliptin layer and the metformin layer. The tablets obtained are preferably film-coated. Example 2 - Double-layer tablet formulation comprising Linagliptin and Metformin HCI

[0078] Linagliptin Layer:

[0079] Linagliptin, one or more fillers and meglumine are sieved and mixed. Half of the lubricant is added and mixed, the powder mixture is pressed into briquettes and sieved. At least one excipient selected from disintegrant, glidant, filler and the remaining lubricant is added and mixed.

[0080] Metformin Layer:

[0081] Metformin HCI is granulated with a granulation solution consisting of at least one cellulose-derived binder. The granules obtained are dried and sieved. A combination of hydroxypropyl methylcellulose, sodium alginate, glycerol dibehenate and polyacrylic acid as a controlled release agent is mixed with a glidant and lubricant. Double-layer tablets are manufactured by combining the linagliptin layer and the metformin layer. The tablets obtained are preferably film-coated.

[0082] Example 3 - Multi-layer tablet formulation comprising Linagliptin and Metformin HCI

[0083] Linagliptin Layer:

[0084] Linagliptin, one or more fillers and meglumine are sieved and taken into the granulator. Granulated using deionized water. Wet granules are sieved, dried and grinded. At least one excipient selected from disintegrant, glidant, filler and lubricant is added and mixed.

[0085] Barrier Layer:

[0086] One or more fillers are sieved and mixed. The lubricant is added to the powder mixture and mixed Metformin Layer:

[0087] Metformin HCI is granulated with a granulation solution consisting of at least one cellulose-derived binder. The granules obtained are dried and sieved. A combination of hydroxypropyl methylcellulose, sodium alginate, glycerol dibehenate and polyacrylic acid as a controlled release agent is mixed with a glidant and lubricant.

[0088] Triple-layer tablets are manufactured by combining the linagliptin layer, the barrier layer and the metformin layer. The tablets obtained are preferably film-coated. Example 4 - Multi-layer tablet formulation comprising Linagliptin and Metformin HCI

[0089] Linagliptin Layer:

[0090] Linagliptin, one or more fillers and meglumine are sieved and mixed. Half of the lubricant is added and mixed, the powder mixture is pressed into briquettes and sieved. At least one excipient selected from disintegrant, glidant, filler and the remaining lubricant is added and mixed.

[0091] Barrier Layer:

[0092] One or more fillers are sieved and mixed. The lubricant is added to the powder mixture and mixed Metformin Layer:

[0093] Metformin HCI is granulated with a granulation solution consisting of at least one cellulose-derived binder. The granules obtained are dried and sieved. A combination of hydroxypropyl methylcellulose, sodium alginate, glycerol dibehenate and polyacrylic acid as a controlled release agent is mixed with a glidant and lubricant.

[0094] Triple-layer tablets are manufactured by combining the linagliptin layer, the barrier layer and the metformin layer. The tablets obtained are preferably film-coated.

[0095] Pharmaceutical formulations according to the present invention were subjected to in vitro dissolution rate tests at a speed of 100 rpm in a simulated gastric fluid (pH 1.2) (degassed) medium without enzymes. The results are shown in the tables below in comparison to the reference product. Table 1 Comparative Dissolution Rate Results for Example 1 (for Linagliptin and Metformin)

[0096] Table 2. Comparative Dissolution Rate Results for Example 2 (for Linagliptin and Metformin)

[0097] Table 3. Comparative Dissolution Rate Results for Example 3 (for Linagliptin and Metformin)

[0098] Table 4. Comparative Dissolution Rate Results for Example 4 (for Linagliptin and Metformin)

[0099] According to in-vitro dissolution tests performed, the formulations according to the present invention show similar or even better dissolution rates than the reference product.

[0100] In addition, accelerated stability studies with formulations according to the present invention have shown that a stable product is obtained. Detailed information on these studies is as follows; Table 5. Comparative stability table for Example 1

[0101] *ND: Not Detected.

[0102] Table 6. Comparative stability table for Example 2

[0103] *ND: Not Detected. Table 7. Comparative stability table for Example 3

[0104] *ND: Not Detected.

[0105] Table 8. Comparative stability table for Example 4

[0106] *ND: Not Detected.

Claims

CLAIMS1. A multi-layer tablet formulation comprising linagliptin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof as the active substance, characterized in that the formulation comprises a combination of hydroxypropyl methylcellulose, sodium alginate, glycerol dibehenate and polyacrylic acid as a controlled release agent.

2. A pharmaceutical formulation according to claim 1, characterized in that the formulation comprises a combination of hydroxypropyl methylcellulose, sodium alginate, glycerol dibehenate and polyacrylic acid as a controlled release agent in a ratio of 15 to 25% by weight of the total formulation weight.

3. A pharmaceutical formulation according to claims 1 or 2, characterized in that the formulation comprises a crystalline, amorphous or free base of linagliptin as the active substance.

4. A pharmaceutical formulation according to claim 3, characterized in that the formulation comprises the free base of linagliptin as the active substance.

5. A pharmaceutical formulation according to any one of the preceding claims, characterized in that the pharmaceutically acceptable salt of metformin is the hydrochloride salt.

6. A pharmaceutical formulation according to any one of the preceding claims, characterized in that it additionally comprises at least one pharmaceutically acceptable excipient.

7. A pharmaceutical formulation according to claim 6, characterized in that the at least one pharmaceutically acceptable excipient is selected from solvents, dispersants, binders, fillers, lubricants, glidants, pH regulators, film coating agents, modified release agents or combinations thereof.

8. A pharmaceutical formulation according to claim 7, characterized in that the solvent is selected from pure water, propylene glycol, glycerin, ethanol, polyethylene glycol or combinations thereof.

9. A pharmaceutical formulation according to claim 7, characterized in that the dispersant is selected from sodium starch glycolate, low substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, ion exchangers, sodium carboxymethyl cellulose, alginates, gums, pregelatinized starch, starch or combinations thereof.

10. A pharmaceutical formulation according to claim 9, characterized in that the dispersant is preferably sodium starch glycolate.

11. A pharmaceutical formulation according to claim 7, characterized in that the binder is selected from ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxy propyl cellulose, microcrystalline cellulose, carboxymethyl cellulose, oxidized cellulose or combinations thereof.

12. A pharmaceutical formulation according to claim 11, characterized in that the binder is preferably selected from a mixture of hydroxypropyl methyl cellulose and hydroxy propyl cellulose.

13. A pharmaceutical formulation according to claim 7, characterized in that the filler is selected from microcrystalline cellulose, lactose, lactose monohydrate, starch, corn starch, pregelatinized starch, mannitol, sorbitol, xylitol, maltodextrin, dibasic calcium phosphate, tribasic calcium phosphate, trehalose, isomalt, sodium carbonate, sodium bicarbonate, calcium carbonate or combinations thereof.

14. A pharmaceutical formulation according to claim 7, characterized in that the lubricant is selected from magnesium stearate, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, fumaric acid, glyceryl palmitostearate, hydrogenated natural oils, zinc stearate, calcium stearate, silica, talc, stearic acid, polyethylene glycol, paraffin or combinations thereof.

15. A pharmaceutical formulation according to claim 14, characterized in that the lubricant is magnesium stearate.

16. A pharmaceutical formulation according to claim 7, characterized in that the glidant contained in the formulation is selected from colloidal silica anhydrous (aerosil), starch, talc or combinations thereof.

17. A pharmaceutical formulation according to claim 16, characterized in that the glidant is aerosil.

18. A pharmaceutical formulation according to claim 7 , characterized in that the pH regulator is selected from acetic acid, monoethanolamine, diethanoleamine, triethanoleamine, meglumine, sodium citrate, citric acid, hydrochloric acid, lactic acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium bicarbonate, sodium borate, sodium hydroxide, THAM (tris(hydroxymethyl)aminomethane) or combinations thereof.

19. A pharmaceutical formulation according to claim 18, characterized in that the pH regulator is meglumine.

20. A pharmaceutical formulation according to claim 18 or 19, characterized in that the amount of meglumine in the formulation is between 5 and 80 mg.

21. A pharmaceutical formulation according to any one of claims 18 to 20, characterized in that the ratio of the amount of meglumine in the formulation to the total weight of the formulation is between 1 and 10%.

22. A pharmaceutical formulation according to claim 7, characterized in that the formulation comprises a film coating.

23. A pharmaceutical formulation according to claim 22, characterized in that the film coating agents are selected from polymethacrylates, hydroxypropyl methyl cellulose, triacetin, glycerol triacetin, talc, red iron dioxide, yellow iron dioxide, propylene glycol, lactose monohydrate, hydroxypropyl cellulose, polyvinyl alcohol, polyethylene glycol, polyvinyl alcohol-polyethylene glycol copolymer (Kollicoat® IR), ethyl cellulose dispersions (Surelease®), polyvinyl pyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), all Opadry® varieties, pigments, dyes, titanium dioxide, macrogol or combinations thereof.

24. A pharmaceutical formulation according to any one of the preceding claims, characterized in that the formulation is one of the forms of tablet, film-coated tablets, double-layer tablets, triple-layer tablets, multi-layer tablets, orally disintegrating tablets, mini-tablets, pellets, chewable tablets, sublingual tablets, effervescent tablets, rapid-release tablets, extended-release tablets, sustained-release tablets, modified-release tablets, slow-release tablets, capsules, oral granules, sachets, powders, microtablets, dragees or orally disintegrating films.

25. A pharmaceutical formulation according to claim 24, characterized in that the formulation is in the form of a double-layer tablet.

26. A pharmaceutical formulation according to claim 24, characterized in that the formulation is in the form of a triple-layer tablet.

27. A pharmaceutical formulation according to any one of the preceding claims, characterized in that the formulation is prepared by a method which may be selected from wet granulation, dry granulation, fluid bed granulation, high shear mixer granulation, dry blending or combinations thereof.

28. A process for preparing a double-layer pharmaceutical formulation according to claim 27, characterized in that it comprises the following process steps;Linagliptin Layer: Linagliptin, one or more fillers and meglumine are sieved and taken into the granulator, Granulated using deionized water, Wet granules are sieved, dried and grinded, At least one excipient selected from dispersant, glidant, filler and lubricant is added and mixed. Metformin Layer: Metformin HCI is granulated with a granulation solution consisting of at least one cellulosederived binder, The granules obtained are dried and sieved, A combination of hydroxypropyl methylcellulose, sodium alginate, glycerol dibehenate and polyacrylic acid as a controlled release agent is mixed with a glidant and lubricant.Double-layer tablets are manufactured by combining the linagliptin layer and the metformin layer, The tablets obtained are preferably film-coated.

29. A process for preparing a double-layer pharmaceutical formulation according to claim 27 , characterized in that it comprises the following process steps;Linagliptin Layer: Linagliptin, one or more fillers and meglumine are sieved and mixed, Half of the lubricant is added and mixed, the powder mixture is pressed into briquettes and sieved, At least one excipient selected from dispersant, glidant, filler and the remaining lubricant is added and mixed.Metformin Layer: Metformin HCI is granulated with a granulation solution consisting of at least one cellulosederived binder, The granules obtained are dried and sieved, A combination of hydroxypropyl methylcellulose, sodium alginate, glycerol dibehenate and polyacrylic acid as a controlled release agent is mixed with a glidant and lubricant.Double-layer tablets are manufactured by combining the linagliptin layer and the metformin layer, The tablets obtained are preferably film-coated.

30. A process for preparing a triple-layer pharmaceutical formulation according to claim 27, characterized in that it comprises the following process steps;Linagliptin Layer: Linagliptin, one or more fillers and meglumine are sieved and taken into the granulator, Granulated using deionized water, Wet granules are sieved, dried and grinded, At least one excipient selected from dispersant, glidant, filler and lubricant is added and mixed. Barrier Layer: One or more fillers are sieved and mixed, The lubricant is added to the powder mixture and mixed.Metformin Layer: Metformin HCI is granulated with a granulation solution consisting of at least one cellulosederived binder, The granules obtained are dried and sieved, A combination of hydroxypropyl methylcellulose, sodium alginate, glycerol dibehenate and polyacrylic acid as a controlled release agent is mixed with a glidant and lubricant.Triple-layer tablets are manufactured by combining the linagliptin layer, the barrier layer and the metformin layer,The tablets obtained are preferably film-coated.

31. A process for preparing a triple-layer pharmaceutical formulation according to claim 27, characterized in that it comprises the following process steps;Linagliptin Layer: Linagliptin, one or more fillers and meglumine are sieved and mixed, Half of the lubricant is added and mixed, the powder mixture is pressed into briquettes and sieved, At least one excipient selected from dispersant, glidant, filler and the remaining lubricant is added and mixed.Barrier Layer: One or more fillers are sieved and mixed, The lubricant is added to the powder mixture and mixed.Metformin Layer: Metformin HCI is granulated with a granulation solution consisting of at least one cellulose-derived binder, The granules obtained are dried and sieved, A combination of hydroxypropyl methylcellulose, sodium alginate, glycerol dibehenate and polyacrylic acid as a controlled release agent is mixed with a glidant and lubricant.Triple-layer tablets are manufactured by combining the linagliptin layer, the barrier layer and the metformin layer,The tablets obtained are preferably film-coated.

32. A pharmaceutical formulation according to any one of the preceding claims, characterized in that the formulation is administered orally.

33. A pharmaceutical formulation according to any of the preceding claims for use in the treatment of type 2 diabetes.

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