HK1149485B

HK1149485B - Dpp-iv inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation

Info

Publication number: HK1149485B
Application number: HK11103606.7A
Authority: HK
Inventors: Thomas Friedl; Michael Braun; Kenji Egusa; Hikaru Fujita; Megumi Maruyama; Takaaki Nishioka
Original assignee: 勃林格殷格翰国际有限公司
Priority date: 2008-04-03
Filing date: 2009-04-02
Publication date: 2014-05-09

Description

DPP-IV inhibitors in combination with other antidiabetic agents, tablets comprising such formulations, and uses and methods for the preparation thereof

The present invention relates to pharmaceutical compositions comprising a fixed dose combination of a DPP-4 inhibitor drug and a partner drug (partner drug), processes for their preparation, and their use for the treatment of certain diseases.

In a more detailed aspect, the present invention relates to oral solid dosage forms of Fixed Dose Combinations (FDCs) of selected dipeptidyl peptidase-4 (DPP-4) inhibitor drugs with certain combination drugs. The FDC formulation is chemically stable and a) shows in vitro dissolution characteristics similar to and/or bioequivalent to free combination, or b) allows to adjust in vitro and in vivo performance to a desired level. In a preferred embodiment, the present invention relates to chemically stable FDC formulations that maintain the initial dissolution profile of the corresponding single tablet of each individual entity at reasonable tablet sizes.

The enzyme DPP-4 (also known as CD26) is a serine protease known to cause N-terminal cleavage of dipeptides from many proteins having proline or alanine residues at the N-terminus. Because of this property, DPP-4 inhibitors interfere with plasma levels of biologically active peptides, including the peptide GLP-1, and are considered promising drugs for the treatment of diabetes.

For example, DPP-4 inhibitors and uses thereof are disclosed in WO 2002/068420, WO 2004/018467, WO 2004/018468, WO 2004/018469, WO 2004/041820, WO 2004/046148, WO 2005/051950, WO 2005/082906, WO 2005/063750, WO 2005/085246, WO 2006/027204, WO 2006/029769 or WO 2007/014886; or in WO2004/050658, WO 2004/111051, WO 2005/058901, WO 2005/097798; WO2006/068163, WO 2007/071738, WO 2008/017670, WO 2007/128721 or WO 2007/128761.

As further DPP-4 inhibitors, the following compounds may be mentioned:

sitagliptin (Sitagliptin) (MK-0431) having the following structural formula a which is (3R) -3-amino-1- [3- (trifluoromethyl) -5.6.7.8-tetrahydro-5H- [1.2.4] triazolo [4.3-a ] pyrazin-7-yl ] -4- (2.4.5-trifluorophenyl) butan-1-one, also known as (2R) -4-oxo-4- [3- (trifluoromethyl) -5.6-dihydro [1.2.4] triazolo [4.3-a ] pyrazin-7 (8H) -yl ] -1- (2.4.5-trifluorophenyl) butan-2-amine,

in one embodiment, sitagliptin is in the form of its dihydrogen phosphate salt, namely sitagliptin phosphate. In another embodiment, sitagliptin phosphate is in the form of an anhydrous or monohydrate crystal. One class of this embodiment relates to sitagliptin phosphate monohydrate. Sitagliptin free base and pharmaceutically acceptable salts thereof are disclosed in U.S. patent No.6.699.871 and example 7 of WO 03/004498. Crystalline sitagliptin phosphate monohydrate is disclosed in WO 2005/003135 and WO 2007/050485.

These documents are incorporated herein by reference for details of, for example, the process for the preparation of the compound or a salt thereof.

Vildagliptin (LAF-237), having the following structural formula B, (2S) - { [ (3-hydroxyadamantan-1-yl) amino ] acetyl } pyrrolidine-2-carbonitrile, also known as (S) -1- [ (3-hydroxy-1-adamantyl) amino ] acetyl-2-cyano-pyrrolidine,

vildagliptin is specifically disclosed in us patent No.6.166.063 and example 1 of WO 00/34241. Specific salts of vildagliptin are disclosed in WO 2007/019255. Vildagliptin in crystalline form is disclosed in WO 2006/078593. Vildagliptin in crystalline form is disclosed in WO 2006/078593.

Saxagliptin (Saxagliptin) (BMS-477118) having the following structural formula C, which is (1s.3s.5s) -2- { (2S) -2-amino-2- (3-hydroxyadamantan-1-yl) acetyl } -2-azabicyclo [3.1.0] hexane-3-carbonitrile, also known as (S) -3-hydroxyadamantylglycine-L-cis-4.5-methyleneprolinecarbonitrile (methanstenotrophoritile),

saxagliptin is specifically disclosed in us patent No.6.395.767 and example 60 of WO 01/68603. In one embodiment saxagliptin is in its HCl salt or its monobenzoate salt form, as disclosed in WO 2004/052850. In another embodiment, saxagliptin is in the form of the free base. In another embodiment, saxagliptin is in the form of the monohydrate of the free base, as disclosed in WO 2004/052850. The HCl salt and the free base of saxagliptin in crystalline form are disclosed in WO 2008/131149. Processes for the preparation of saxagliptin are also disclosed in WO 2005/106011 and WO 2005/115982.

Digliptin (Denagliptin) (GSK-823093) having the following structural formula D, which is (2s.4s) -1- [ (2S) -2-amino-3.3-bis (4-fluorophenyl) propionyl ] -4-fluoropyrrolidine-2-carbonitrile, also known as (2s.4s) -4-fluoro-1- [ 4-fluoro- β - (4-fluorophenyl) -L-phenylalanyl ] -2-pyrrolidinecarbonitrile

Digogliptin is specifically disclosed in U.S. patent No.7.132.443 and WO 03/002531. In one embodiment, the digliptin is in its hydrochloride salt form (as disclosed in example 2 of WO 03/002531) or its tosylate salt form (as disclosed in WO 2005/009956). One class of this embodiment relates to digliptin tosylate. Crystalline anhydrous digliptin tosylate is disclosed in WO 2005/009956.

-Alogliptin (SYR-322), having the following structural formula E, which is 2- ({6- [ (3R) -3-aminopiperidin-1-yl ] -3-methyl-2.4-dioxo-3.4-dihydro-2H-pyrimidin-1-yl } methyl) benzonitrile

Alogliptin is specifically disclosed in U.S. patent No.2005/261271, european patent No.1586571 and WO 2005/095381. In one embodiment, alogliptin is in the form of its benzoate salt, its hydrochloride salt, or its tosylate salt, each disclosed in WO 2007/035629. One class of this embodiment relates to alogliptin benzoate. Polymorphic forms of alogliptin benzoate are disclosed in WO 2007/035372. A process for the preparation of alogliptin is disclosed in WO 2007/112368, and in particular in WO 2007/035629.

- (S) -1- ((2s.3s.11bs) -2-amino-9.10-dimethoxy-1.3.4.7.11 b-hexahydro-2H-pyrido [2.1-a ] isoquinolin-3-yl) -4-fluoromethyl-pyrrolidin-2-one or a pharmaceutically acceptable salt thereof:

this compound and its preparation are disclosed in WO 2005/000848. Processes for the preparation of this compound (in particular its dihydrochloride salt) are also disclosed in WO 2008/031749, WO 2008/031750 and WO 2008/055814.

- (R) -2- [6- (3-amino-piperidin-1-yl) -3-methyl-2.4-dioxo-3.4-dihydro-2H-pyrimidin-1-ylmethyl ] -4-fluoro-benzonitrile or a pharmaceutically acceptable salt thereof:

the compound and the preparation method and the application thereof are disclosed in WO 2005/095381, US 2007060530, WO2007/033350, WO2007/035629, WO 2007/074884, WO 2007/112368 and WO 2008/033851. Particularly claimed salts include succinate (WO 2008/067465), benzoate, benzenesulfonate, p-toluenesulfonate, (R) -mandelate and hydrochloride. These documents are incorporated herein by reference for details of, for example, the process for the preparation of the compound or a salt thereof.

The combination drug to be combined with the DPP-4 inhibitor within the pharmaceutical composition of the present invention is a biguanide (e.g., metformin, e.g., metformin hydrochloride), a thiazolidinone (e.g., pioglitazone, e.g., pioglitazone hydrochloride), a statin (e.g., atorvastatin), or an ARB (e.g., telmisartan).

Biguanide antihyperglycemic agents metformin are disclosed in U.S. patent No. 3.174.901. The preparation of metformin (dimethyldiguanide) and its hydrochloride salt is prior art and was first disclosed by Emil a. werner and James bell.j. chem. soc.121.1922.1790-1794. Other pharmaceutically acceptable salts of metformin can be found in U.S. application No.09/262.526 or U.S. patent No.3.174.901 filed 3/4 1999. Preferably, the metformin used herein is metformin hydrochloride.

Unless otherwise indicated, the terms "DPP-4 inhibitor", "biguanide", "thiazolidinone", "statin", "ARB" or any species thereof (e.g. "metformin", "pioglitazone") in the context of the present invention are also intended to include any pharmaceutically acceptable salt thereof, crystalline forms, hydrates, solvates, diastereomers or enantiomers thereof.

For the avoidance of any doubt, the disclosure of each of the above-cited documents is hereby specifically incorporated by reference in its entirety.

In an attempt to prepare pharmaceutical compositions of selected DPP-4 inhibitors, it has been observed that DPP-4 inhibitors having primary or secondary amino groups exhibit incompatibility, degradation problems or extraction problems with a variety of commonly used excipients, such as microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, tartaric acid, citric acid, glucose, fructose, sucrose, lactose, maltodextrin. Although these compounds are themselves very stable, they may react with incompatible drug combinations, or impurity products thereof, and/or with the various excipients and impurities of excipients used in solid dosage forms, especially when providing intimate contact in tablets and at high excipient/drug ratios. Amino groups are shown to react with reducing sugars, and with other reactive carbonyl groups, and with carboxylic acid functional groups (formed, for example, by oxidation on the surface of microcrystalline cellulose). These unexpected difficulties are mainly seen in the low dose range of the DPP-4 inhibitor used (which is required due to its surprising potency), and/or the high dose range of the combination drug used. Therefore, pharmaceutical compositions need to address these technical problems, which may be related to the undesired potency of selected DPP-4 inhibitor compounds.

Other objects of the present invention will become apparent to those skilled in the art from the context of the description.

It has now been found that the pharmaceutical compositions as set forth in more detail herein have surprising and particularly advantageous properties.

In particular, it has been found that problems such as incompatibility and poor stability, in particular decomposition and/or "assay reduction" (for example, by using nucleophiles and/or basic agents suitable for stabilization (for example, suitable buffers as stabilizers) can be solved in these pharmaceutical compositions, which can be caused, for example, by reacting (for example, by acylation, urea formation or Maillard reaction, etc.) the free base DPP-4 inhibitor with an incompatible combination drug, or an impurity product thereof, and/or a pharmaceutical excipient having such a functional group (for example, a reducing end group or acyl group of a sugar, for example, an acetyl or carbamoyl group) to form a derivative (for example, an N-acetyl or N-carbamoyl derivative) with the free base DPP-4 inhibitor. Thus, by using suitable nucleophiles and/or basic agents (e.g., buffering agents and/or pH adjusting agents) in these pharmaceutical compositions, protection against decomposition and degradation can be achieved.

Accordingly, the present invention relates to chemically stable FDC formulations comprising a DPP-4 inhibitor, a combination drug, and a nucleophilic and/or basic agent.

Thus, the present invention also relates to chemically stable FDC formulations comprising a DPP-4 inhibitor, a combination drug, and a suitable buffer.

Thus, the present invention also relates to chemically stable FDC formulations comprising a DPP-4 inhibitor, a combination drug and a pH adjusting agent.

DPP-4 inhibitors within the meaning of the present invention include, but are not limited to, any of those mentioned above and below, preferably DPP-4 inhibitors with oral activity.

In a more recent embodiment, DPP-4 inhibitors within the meaning of the present invention include DPP-4 inhibitors having an amino group, especially a free or primary amino group.

In another closer embodiment, the DPP-4 inhibitor in the context of the present invention is a DPP-4 inhibitor having a primary amino group, especially a free primary amino group.

The combination drug used is selected from: biguanides (e.g., metformin, e.g., metformin hydrochloride), thiazolidinones (e.g., pioglitazone, e.g., pioglitazone hydrochloride), statins (e.g., atorvastatin), and ARBs (e.g., telmisartan). A preferred combination drug within the meaning of the present invention is metformin, especially metformin hydrochloride (1, 1-dimethylbiguanide hydrochloride or metformin HCl).

The buffer used may be a basic amino acid having intramolecular amino and basic characteristics (isoelectric point, pI: 7.59-10.76), such as L-arginine, L-lysine or L-histidine. A preferred buffer within the meaning of the present invention is L-arginine. L-arginine has a particularly suitable stabilizing effect on the compositions of the invention, for example by inhibiting the degradation of DPP-4 inhibitors in the presence of a combination drug.

The present invention relates to pharmaceutical compositions comprising a DPP-4 inhibitor, a combination drug, a nucleophile and/or a basic agent and one or more pharmaceutical excipients.

The invention also relates to pharmaceutical compositions comprising a DPP-4 inhibitor, a combination drug, a suitable buffer, and one or more pharmaceutical excipients.

The invention also relates to pharmaceutical compositions comprising a DPP-4 inhibitor, a combination drug, a pH adjusting agent, and one or more pharmaceutical excipients.

In one embodiment, the present invention relates to a pharmaceutical composition (e.g., an oral solid dosage form, especially a tablet) comprising a DPP-4 inhibitor; combination drugs (especially metformin); and L-arginine for stabilizing the composition and/or the DPP-4 inhibitor, in particular against chemical degradation; and one or more pharmaceutical excipients.

In another embodiment, the invention relates to pharmaceutical compositions (e.g., oral solid dosage forms, especially tablets) obtainable from a DPP-4 inhibitor; combination drugs (especially metformin); and L-arginine for stabilizing the composition and/or the DPP-4 inhibitor, in particular against chemical degradation; and one or more pharmaceutical excipients.

In general, the pharmaceutical excipients that may be used may be selected from: one or more fillers, one or more binders or diluents, one or more lubricants, one or more disintegrants, and one or more glidants, one or more film coating agents, one or more plasticizers, one or more pigments, and the like.

The pharmaceutical compositions (tablets) of the invention generally comprise a binder.

In more detail, the pharmaceutical compositions (tablets) of the invention typically include one or more fillers (e.g., D-mannitol, corn starch, and/or pregelatinized starch), binders (e.g., copovidone), lubricants (e.g., magnesium stearate), and glidants (e.g., colloidal anhydrous silicon dioxide).

Suitable pharmaceutical excipients for use in the present invention are conventional substances such as D-mannitol, corn starch, pregelatinized starch as filler, copovidone as binder, magnesium stearate as lubricant, colloidal anhydrous silicon dioxide as glidant, hypromellose as film coating agent, propylene glycol as plasticizer, titanium dioxide, iron oxide red/yellow as pigment, talc and the like.

Typical compositions according to the invention comprise the binder copovidone (also known as copovidone or Kollidon VA 64).

In addition, a typical composition according to the invention comprises the filler corn starch, the binder copovidone, the lubricant magnesium stearate, and the glidant colloidal anhydrous silicon dioxide.

The pharmaceutical compositions according to embodiments of the invention are intended for the treatment of diabetes and/or to achieve glycemic control in type 1 or type 2 diabetic patients and comprise the formulations of the fixed dose combinations described herein and suitable pharmaceutical excipients. In addition, the compositions are useful for treating rheumatoid arthritis, obesity and osteoporosis, and for supporting allograft transplantation.

Thus, in particular, the present invention relates to a pharmaceutical composition (in particular an oral solid dosage form, in particular a tablet) comprising: a DPP-4 inhibitor, metformin hydrochloride, L-arginine and one or more pharmaceutical excipients, especially one or more fillers, one or more binders, one or more glidants, and/or one or more lubricants.

More particularly, the present invention relates to a pharmaceutical composition (especially an oral solid dosage form, especially a tablet) comprising: a DPP-4 inhibitor, metformin hydrochloride, L-arginine, copovidone as a binder and one or more other pharmaceutical excipients.

Typical pharmaceutical compositions according to the present invention may include 0.1-10% L-arginine (e.g., about 0.1%, 0.25%, 0.556%, 2.12%, 2.22%, or 10%) by weight of the total DPP-4 inhibitor portion, particularly about 2% (e.g., more particularly, 2.12% by weight of the total core of the uncoated mono-layer tablet) in the DPP-4 inhibitor portion.

Typical pharmaceutical compositions according to the present invention may comprise in the DPP-4 inhibitor fraction (in wt% of the total DPP-4 inhibitor fraction):

0.2-10% of a DPP-4 inhibitor, and

0.1-10% of L-arginine.

Typical pharmaceutical compositions according to the invention may comprise a DPP-4 inhibitor and L-arginine in a weight ratio of about 1: 20 to about 10: 1 or about 1: 15 to about 10: 1 or about 1: 10 to about 10: 1, especially from 1: 10 to 5: 2, for example in a weight ratio of 1: 10, 1: 8.5, 1: 5, 1: 1, or 1: 0.4, more especially in a weight ratio of 2.5 mg: 25 mg, 2.5 mg: 21.2 mg, 2.5 mg: 12.5 mg, 2.5 mg: 2.5mg, or 2.5 mg: 1 mg.

A typical pharmaceutical composition according to the invention may comprise metformin hydrochloride and L-arginine in a weight ratio of from about 40: 1 to about 1000: 1, for example in a weight ratio of 40: 1, 200: 1, 340: 1, 400: 1, 500: 1, 850: 1, or 1000: 1, more particularly in a weight ratio of 500 mg: 12.5 mg, 850 mg: 21.2 mg, 1000 mg: 25 mg, 500 mg: 2.5mg, 850 mg: 2.5mg, 1000 mg: 2.5mg, 500 mg: 1 mg, 850 mg: 1 mg, or 1000 mg: 1 mg.

Typical pharmaceutical compositions according to the present invention may comprise a DPP 4-inhibitor, metformin hydrochloride and L-arginine in a weight ratio of from about 1: 200: 0.4 to about 1: 200: 5 (e.g., 1: 200: 0.4, 1: 200: 1, 1: 200: 5), or from about 1: 340: 0.4 to about 1: 340: 8.5 (e.g., 1: 340: 0.4, 1: 340: 1, 1: 340: 8.5), or from about 1: 400: 0.4 to about 1: 400: 10 (e.g., 1: 400: 0.4, 1: 400: 1, 1: 400: 10).

A typical pharmaceutical composition according to the invention may comprise one or more of the following amounts (in weight% of the total coated tablet mass):

0.1-0.5% of DPP-4 inhibitor,

47-85% of metformin HCl, and the preparation method thereof,

0.07-2.2% of L-arginine,

3.9-8.1% binder (e.g. copovidone),

2.3-5.9% of bulking agent 1 (e.g. corn starch),

0-4.4% of filler 2 (e.g. pregelatinized starch),

0-33% of a filler 3 (e.g. D-mannitol),

0.7-1.5% of a lubricant (e.g., magnesium stearate), and

0.1-0.5% glidant (e.g. colloidal anhydrous silicon dioxide).

Further details regarding the FDC formulations of the present invention, such as the ingredients, ingredient ratios (e.g., ratios of DPP-4 inhibitor, metformin hydrochloride, L-arginine, and/or excipients), particularly regarding the specific dosage forms (tablets) used in the present invention and their preparation, will be apparent to those skilled in the art in light of the above and below disclosure, including, for example, the following examples and claims.

In a first embodiment (embodiment A), the DPP-4 inhibitor in the context of the present invention is any one of the following DPP-4 inhibitors:

formula (I)

Or formula (II)

Or formula (III)

Wherein R1 represents ([1.5] naphthyridin-2-yl) methyl, (quinazolin-2-yl) methyl, (quinoxalin-6-yl) methyl, (4-methyl-quinazolin-2-yl) methyl, 2-cyano-benzyl, (3-cyano-quinolin-2-yl) methyl, (3-cyano-pyridin-2-yl) methyl, (4-methyl-pyrimidin-2-yl) methyl or (4.6-dimethyl-pyrimidin-2-yl) methyl, and R2 represents 3- (R) -amino-piperidin-1-yl, (2-amino-2-methyl-propyl) -methylamino or (2- (S) -amino-propyl) -methylamino,

or a pharmaceutically acceptable salt thereof.

In a second embodiment (embodiment B), the DPP-4 inhibitor in the context of the present invention is a DPP-4 inhibitor selected from: sitagliptin, vildagliptin, saxagliptin and alogliptin,

or a pharmaceutically acceptable salt thereof.

With respect to the first embodiment (embodiment a), preferred DPP-4 inhibitors are any or all of the following compounds and pharmaceutically acceptable salts thereof:

● 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine (control WO 2004/018468, example 2 (142)):

● 1- [ ([1.5] naphthyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine (control WO 2004/018468, example 2 (252)):

● 1- [ (quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine (control WO 2004/018468, example 2 (80)):

● 2- ((R) -3-amino-piperidin-1-yl) -3- (but-2-ynyl) -5- (4-methyl-quinazolin-2-ylmethyl) -3.5-dihydro-imidazo [4.5-d ] pyridazin-4-one (control WO2004/050658, example 136):

● 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (2-amino-2-methyl-propyl) -methylamino ] -xanthine (control WO 2006/029769, example 2 (1)):

● 1- [ (3-cyano-quinolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine (control WO 2005/085246, example 1 (30)):

● 1- (2-cyano-benzyl) -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine (control WO 2005/085246, example 1 (39)):

● 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (S) - (2-amino-propyl) -methylamino ] -xanthine (control WO 2006/029769, example 2 (4)):

● 1- [ (3-cyano-pyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine (control WO 2005/085246, example 1 (52)):

● 1- [ (4-methyl-pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine (control WO 2005/085246, example 1 (81)):

● 1- [ (4.6-dimethyl-pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine (control WO 2005/085246, example 1 (82)):

● 1- [ (quinoxalin-6-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine (control WO 2005/085246, example 1 (83)):

these DPP-4 inhibitors differ from structurally comparable DPP-4 inhibitors in that they combine aberrant potency and long-lasting effect with favorable pharmacological properties, receptor selectivity and favorable side-effect profiles, or bring unexpected therapeutic advantages or improvements when combined with other pharmaceutically active substances. Their preparation is disclosed in the publications mentioned.

Among the above mentioned DPP-4 inhibitors according to embodiment a of the present invention, the more preferred DPP-4 inhibitor is 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine, especially its free base (which is also known as BI 1356).

With respect to the second embodiment (embodiment B), preferred DPP-4 inhibitors are selected from: vildagliptin, saxagliptin and alogliptin, and pharmaceutically acceptable salts thereof.

Unless otherwise indicated, it is to be understood that the definition of DPP-4 inhibitor as set forth above also includes pharmaceutically acceptable salts thereof, as well as hydrates, solvates and polymorphic forms thereof, in accordance with the present invention. For the salts, hydrates and polymorphic forms thereof, reference is made in particular to the references cited above and below.

With respect to embodiment a, methods for the synthesis of DPP-4 inhibitors according to embodiment a of the present invention are well known to those skilled in the art. Advantageously, the DPP-4 inhibitor according to embodiment a of the present invention may be prepared using synthetic methods as described in the literature. Thus, for example, purine derivatives of formula (I) may be obtained as described in WO 2002/068420, WO 2004/018468, WO 2005/085246, WO 2006/029769 or WO 2006/048427, the disclosures of which are incorporated herein by reference. Purine derivatives of formula (II) may be obtained as described in, for example, WO2004/050658 or WO 2005/110999, the disclosures of which are incorporated herein by reference. Purine derivatives of formula (III) may be obtained as described, for example, in WO2006/068163, WO 2007/071738 or WO 2008/017670, the disclosures of which are incorporated herein by reference. The preparation of those DPP-4 inhibitors mentioned above in particular is disclosed in the relevant said publication. Polymorphic crystal modifications and formulations of specific DPP-4 inhibitors are disclosed in WO 2007/128721 and WO 2007/128724, respectively, and are incorporated herein by reference in their entirety.

With respect to embodiment B, methods for the synthesis of DPP-4 inhibitors for embodiment B are disclosed in the scientific literature and/or published patent documents, some of which are incorporated herein by reference.

With respect to the first embodiment (embodiment a), when administered orally, typical desired doses of the DPP-4 inhibitors mentioned in embodiment a are in the range of 0.5 mg to 100 mg, preferably 2.5mg to 50mg or 0.5 mg to 10 mg, more preferably 2.5mg to 10 mg or 1 mg to 5mg, in each case 1 to 4 times per day. Thus, when administered orally, a desired dose of 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine is from 0.5 mg to 10 mg/patient/day, preferably from 2.5mg to 10 mg or from 1 mg to 5 mg/patient/day.

The dosage forms prepared using the pharmaceutical compositions comprising the DPP-4 inhibitors mentioned in embodiment a contain the active ingredient in a dosage range of 0.1 to 100 mg, especially 0.5 to 10 mg. Thus, the specific dose strength (dosage strength) of 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine was 0.5 mg, 1 mg, 2.5mg, 5mg and 10 mg. A more specific unit dose strength of 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine for use in the pharmaceutical compositions incorporated in the fixed dose combination of the invention is 2.5 mg.

With respect to the second embodiment (embodiment B), the dose of DPP-4 inhibitor mentioned in embodiment B to be administered to a mammal (e.g. a human, e.g. about 70 kg body weight) may generally be in the range of about 0.5 mg to about 350 mg, e.g. about 10 mg to about 250 mg, preferably 20-200 mg, more preferably 20-100 mg of active fraction per person per day, or about 0.5 mg to about 20 mg, preferably 2.5-10 mg per person per day, preferably divided into 1-4 separate doses, which may be, e.g., of the same size. Individual dosage strengths include, for example, 2.5, 5, 10, 25, 40, 50, 75, 100, 150, and 200 milligrams of the active portion of a DPP-4 inhibitor.

The dosage strength of the DPP-4 inhibitor sitagliptin is typically 25 to 200 mg of active fraction. The recommended dose of sitagliptin was 100 mg once daily calculated as the active fraction (free base anhydrate). The unit dosage strengths of sitagliptin free base anhydrate (active fraction) were 25, 50, 75, 100, 150 and 200 milligrams. Specific unit dose strengths of sitagliptin (e.g. per tablet) were 25, 50 and 100 mg. Sitagliptin phosphate monohydrate was used in the pharmaceutical composition in an amount equivalent to the sitagliptin free base anhydrous hydrate, namely 32.13, 64.25, 96.38, 128.5, 192.75 and 257 mg, respectively. Adjusted doses of 25 and 50mg of sitagliptin were used for patients with renal failure.

The dosage range of the DPP-4 inhibitor vildagliptin is typically 10 to 150 mg/day, in particular 25 to 150 mg, 25 to 100 mg or 25 to 50mg or 50 to 100 mg/day. Specific examples of daily oral doses are 25, 30, 35, 45, 50, 55, 60, 80, 100 or 150 mg. In a more specific aspect, the amount of vildagliptin administered per day is from 25 to 150 mg or from 50 to 100 mg. In another more specific aspect, the amount of vildagliptin administered per day is 50 or 100 mg. The active ingredient may be administered up to 3 times a day, preferably 1 or 2 times a day. Specific dosage strengths are 50mg or 100 mg vildagliptin.

Metformin is used in different dosage regimens, usually administered in doses of about 250 to 3000 mg, especially 500 to 2000 mg, and up to 2500 mg/day. The dosage range of the combination drug metformin is typically from 100 mg to 500mg or from 200 mg to 850mg (1-3 times a day), or from 300 mg to 1000mg (1 or 2 times a day). The unit dosage strength of metformin hydrochloride for use in the present invention may be in the range of 100 mg to 2000 mg or 250 mg to 2000 mg, preferably 250 mg to 1000 mg. Specific dosage strengths may be 250, 500, 625, 750, 850 and 1000 milligrams of metformin hydrochloride. These unit dosage strengths of metformin hydrochloride represent the dosage strengths approved for sale in the united states for the treatment of type 2 diabetes. More specific unit dose strengths of metformin hydrochloride for use in pharmaceutical compositions incorporating the fixed-dose combination of the present invention are 500, 850 and 1000 milligrams of metformin hydrochloride.

The dose of the combination drug pioglitazone is usually 1-10 mg, 15 mg, 30 mg, or 45 mg, 1 time a day.

The dose of the combination drug telmisartan is typically 20 mg to 320 mg or 40 mg to 160 mg per day.

The dosage of the combination drug atorvastatin is usually 1 mg to 40 mg or 10 mg to 80 mg 1 time a day.

The amounts of DPP-4 inhibitor and the combination drug in the pharmaceutical composition according to the present invention are in accordance with the respective dosage ranges provided above. For example, the pharmaceutical composition comprises 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine in an amount of 0.5 mg to 10 mg (i.e. 0.5 mg, 1 mg, 2.5mg, 5mg or 10 mg) and metformin hydrochloride in an amount of 250 mg to 1000mg (i.e. 250, 500, 625, 750, 850 or 1000 mg).

Specific embodiments of the dosage strengths of 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine and metformin hydrochloride in the fixed dose combination of the invention are as follows:

(1)2.5mg of 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine free base, and 500mg of metformin hydrochloride;

(2)2.5mg of 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine free base, and 850mg of metformin hydrochloride;

(3)2.5mg of 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine free base and 1000mg of metformin hydrochloride.

The specific fixed dose combination of BI1356 and metformin of the present invention may be administered to a patient 1 or 2 times per day, especially 2 times per day.

In a preferred aspect of the invention, the invention relates to a pharmaceutical composition (especially an oral solid dosage form, especially a tablet) comprising or obtainable from:

a DPP-4 inhibitor selected from: 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine free base, vildagliptin, saxagliptin and alogliptin,

the addition of the metformin hydrochloride to the aqueous solution of the metformin hydrochloride,

the L-arginine is added into the mixture of L-arginine,

and one or more pharmaceutical excipients, such as those described herein.

A particularly preferred DPP-4 inhibitor to be emphasized within the meaning of the present invention is 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine free base (also known as BI 1356).

In particular, L-arginine has been found to be effective as a stabilizer for FDC combinations of 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine free base with metformin HCl. L-arginine is effective in inhibiting the degradation of 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine free base even after 6 months of storage under accelerated conditions. This effect appears to be concentration dependent. Thus, L-arginine is useful as a stabilizer and a buffer in formulations.

In a more preferred aspect of the invention, the invention relates to a pharmaceutical composition (especially an oral solid dosage form, especially a tablet) comprising or made from:

1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine free base (BI 1356),

the L-arginine is added into the mixture of L-arginine,

and one or more pharmaceutical excipients, such as those described herein.

A typical pharmaceutical composition according to the present invention comprises any one of the following amounts (1), (2) or (3) of active ingredient and L-arginine, or is prepared by mixing any one of the following amounts (1), (2) or (3) of active ingredient and L-arginine:

(1)2.5mg of 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine free base, 500mg of metformin hydrochloride and 1.0 mg to 12.5 mg of L-arginine (especially 1.0 mg, 2.5mg or 12.5 mg of L-arginine);

(2)2.5mg of 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine free base, 850mg of metformin hydrochloride and 1.0 mg to 21.2 mg of L-arginine (especially 1.0 mg, 2.5mg or 21.2 mg of L-arginine);

(3)2.5mg of 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine free base, 1000mg of metformin hydrochloride and 1.0 mg to 25.0 mg of L-arginine (especially 1.0 mg, 2.5mg or 25 mg of L-arginine).

In another aspect of the present invention, the present invention provides a process for preparing the compositions, formulations, blends or dosage forms of the present invention, e.g. by using methods well known to those skilled in the art and/or in the manner described herein, e.g. which may be obtained by a process comprising the use (e.g. mixing (mixing), combining, blending (blending) and/or composing) of the components and/or ingredients mentioned above and below, or a pre-mixture thereof. And the invention further provides compositions, formulations, blends or dosage forms obtainable by these methods or processes and/or obtained from the components, ingredients, premixes and/or mixtures mentioned hereinbefore and hereinafter.

In another aspect of the present invention, the present invention provides a pharmaceutical composition, formulation, blend or dosage form of the present invention that is substantially free of or contains only trace amounts of impurities and/or degradation products; this means, for example, that the composition, formulation, blend or dosage form comprises about < 5%, or about < 4%, or about < 3%, or less than about 2%, preferably less than about 1%, more preferably less than about 0.5%, even more preferably less than about 0.2%, of any individual or total impurities or degradation products (by total weight), such as N-acetyl and/or N-carbamoyl derivatives of free base DPP-4 inhibitors. The content and/or degradation can be determined by known analytical methods, for example using HPLC methods.

In this context, in a further aspect of the invention, the invention provides derivatives of DPP-4 inhibitors having an amino group, especially a free primary amino group, which derivatives may be prepared by acetylation of the amino group (e.g. to give the group-nhc (o) CH), as described herein₃) Or by carbamoylation of amino groups (e.g. to give the group-NHC (O) NH₂) And (4) obtaining.

Dosage forms of the FDC formulations of the invention:

it is another object of the present invention to develop FDC formulations of the present invention with reasonable tablet size, with good tablet properties (e.g., stability, hardness, friability, disintegration, content uniformity, etc.), and in a preferred embodiment, without interfering with the initial dissolution characteristics of each individual tablet with the minimum risk of failure while ensuring the desired bioequivalence.

The design of the dosage form is an important way not only to optimize the tablet size and dissolution profile but also to minimize the amount of stabilizer, as the dissolution profile of the DPP-4 inhibitor or combination drug may be affected by pH changes of the dissolution buffer. The choice of formulation depends on the dosage strength of the active ingredient used and its physicochemical and solid-state characteristics.

Conventional methods (i.e., physical isolation) may not be useful for stabilizing certain DPP-4 inhibitors of the present invention. A buffer (e.g., L-arginine) may need to be added to the formulation to inhibit degradation, however, the amount of L-arginine may have to be minimized because its basic character negatively impacts the dissolution profile or stability of the DPP-4 inhibitor or combination drug.

Thus, it has been found that suitable dosage forms of the FDC formulations of the invention are film-coated tablets (film-coating for drug loading, e.g. especially loading of the DPP-4 inhibitor drug onto a core comprising the combination drug by film coating), mono-, bi-layer tablets, tri-layer tablets and press-coated tablets (e.g. bi-layer tablets (tablet-in-tablets) or bull's eye tablets) with a DPP-4 inhibitor core), which are good measures for achieving the object, taking into account the desired pharmaceutical properties and characteristics of the DPP-4 inhibitor and the combination drug used.

The dosage forms have been found to be suitable for FDC formulations, which allow to maintain the initial dissolution profile of each single tablet or to adjust these profiles to a desired level, e.g. including extended release profile and reasonable tablet size.

Typical mono-layer tablets of the invention comprise a DPP-4 inhibitor, metformin hydrochloride, L-arginine, one or more fillers (e.g. corn starch), one or more binders (e.g. copovidone), one or more glidants (e.g. colloidal anhydrous silicon dioxide) and one or more lubricants (e.g. magnesium stearate).

In a preferred embodiment of the present invention, the present invention relates to an oral solid pharmaceutical composition, preferably a tablet, especially a mono-layer tablet, comprising or made from:

1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine (also known as BI1356 in an amount of 2.5 mg),

metformin (especially metformin hydrochloride, for example in an amount of 500mg, 850mg or 1000 mg),

the L-arginine is added into the mixture of L-arginine,

and one or more pharmaceutical excipients, in particular one or more fillers (e.g. corn starch), one or more binders (e.g. copovidone), one or more glidants (e.g. colloidal anhydrous silicon dioxide) and/or one or more lubricants (e.g. magnesium stearate), and, optionally, a film coating comprising, for example, one or more film-coating agents (e.g. hypromellose), one or more plasticizers (e.g. propylene glycol), one or more pigments (e.g. titanium dioxide, red and/or yellow iron oxide) and/or one or more glidants (e.g. talc).

The process for making the tablets of the present invention comprises tableting (e.g. compressing) one or more of the final blend in granular form. The granules of the (final) blend according to the invention can be prepared by methods well known to the person skilled in the art, such as high shear wet granulation or fluid bed granulation. The details of the granulate according to the invention and of the granulation process for preparing the granulate according to the invention, including the separation steps thereof, are illustrated by way of example in the following examples.

An exemplary granulation process for preparing granules comprising a monolayer composition comprises

i.) mixing (e.g., dissolving or dispersing) L-arginine, a binder (e.g., copovidone), and optionally a DPP-4 inhibitor (e.g., BI1356) in a solvent or mixture of solvents (e.g., purified water) at ambient temperature to produce a granulation liquid;

ii) blending metformin HCl, a filler (e.g., corn starch), and optionally a DPP-4 inhibitor (e.g., BI1356) in a suitable mixer (e.g., a fluid bed granulator) to produce a premix;

wherein a DPP-4 inhibitor (e.g. BI1356) may be included in the granulation liquid obtained in i.) or in the premix obtained in ii.), preferably the BI1356 is dispersed in the granulation liquid and is not present in the premix;

iii.) spraying the granulation liquid into the premix and granulating the mixture, e.g. in a fluid bed granulator, preferably under dry conditions;

iv) drying the particles, for example at an inlet air temperature of about 70 ℃, until a desired drying loss value in the range of 1-2% is obtained;

v.) removing agglomerates of the dried particles (delumping), for example by sieving through a sieve having a mesh size of 0.5-1.0 mm;

vi.) blending the sieved granules and preferably a sieved flow aid (e.g. colloidal anhydrous silicon dioxide) in a suitable mixer;

vii.) a preferably sieved lubricant (e.g. magnesium stearate) is added to the granules, e.g. in a free-fall mixer, for final blending.

Preferably, the mono-layer tablet according to the invention comprises or is obtainable from a mixture of the active ingredient and L-arginine in any of the following amounts (1), (2) or (3):

(1)2.5mg of 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine free base, 500mg of metformin hydrochloride and 12.5 mg of L-arginine;

(2)2.5mg of 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine free base, 850mg of metformin hydrochloride and 21.2 mg of L-arginine;

(3)2.5mg of 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine free base, 1000mg of metformin hydrochloride and 25 mg of L-arginine.

A typical bilayer tablet of the present invention comprises

A DPP-4 inhibitor portion comprising a DPP-4 inhibitor, L-arginine, one or more fillers (e.g., D-mannitol, pregelatinized starch, and corn starch), one or more binders (e.g., copovidone), and one or more lubricants (e.g., magnesium stearate),

and

a metformin HCl moiety comprising metformin hydrochloride, one or more fillers (e.g., corn starch), one or more binders (e.g., copovidone), one or more glidants (e.g., colloidal anhydrous silicon dioxide), and one or more lubricants (e.g., magnesium stearate).

Preferably, the bilayer tablet according to the invention comprises or is obtainable from a mixture of the active ingredient and L-arginine in any of the following amounts (1), (2) or (3):

(1)2.5mg of 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine free base, 500mg of metformin hydrochloride and 2.5mg of L-arginine;

(2)2.5mg of 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine free base, 850mg of metformin hydrochloride and 2.5mg of L-arginine;

(3)2.5mg of 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine free base, 1000mg of metformin hydrochloride and 2.5mg of L-arginine.

Typical press-coated tablets (bilayer tablets or bull's eye tablets) of the invention include

A DPP-4 inhibitor core portion comprising a DPP-4 inhibitor, L-arginine, one or more fillers (e.g., D-mannitol, pregelatinized starch, and corn starch), one or more binders (e.g., copovidone), and one or more lubricants (e.g., magnesium stearate),

and

Preferably, the press-coated tablets (bilayer tablets or bull's eye tablets) according to the invention comprise or are obtainable from a mixture of the active ingredient and L-arginine in any of the following amounts (1), (2) or (3):

(1)2.5mg of 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine free base, 500mg of metformin hydrochloride and 1.0 mg of L-arginine;

(2)2.5mg of 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine free base, 850mg of metformin hydrochloride and 1.0 mg of L-arginine;

(3)2.5mg of 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine free base, 1000mg of metformin hydrochloride and 1.0 mg of L-arginine.

Typical film coated tablets of the invention (with the DPP-4 inhibitor coated on the metformin HCl tablet, i.e. with the drug coating by a film coating for drug loading) comprise

A metformin HCl core portion comprising metformin hydrochloride, one or more fillers (e.g., corn starch), one or more binders (e.g., copovidone), one or more glidants (e.g., colloidal anhydrous silicon dioxide), and one or more lubricants (e.g., magnesium stearate),

wherein the tablet core is seal coated with a film coating comprising one or more film coating agents (e.g., hypromellose), one or more plasticizers (e.g., propylene glycol), one or more pigments (e.g., titanium dioxide, red and/or yellow iron oxide), and one or more glidants (e.g., talc);

and

a DPP-4 inhibitor layer comprising a DPP-4 inhibitor, L-arginine, one or more film-coating agents (e.g., hypromellose), and one or more plasticizers (e.g., propylene glycol).

Preferably, the film-coated tablet (loaded with DPP 4-inhibitor drug) according to the present invention comprises or is obtainable from a mixture of the active ingredient and L-arginine in any of the following amounts (1), (2) or (3):

Preferably, these above-described tablets (mono-, bi-, press-coated tablets and drug-coated tablets) are further overcoated with a final film coating comprising a film coating agent (e.g., hypromellose), a plasticizer (e.g., propylene glycol), a pigment (e.g., titanium dioxide, red and/or yellow iron oxide), and a glidant (e.g., talc). Typically, this additional film overcoat may comprise 1-4%, preferably 1-2% of the total mass of the composition.

Based on the characteristics of the drug substance and the requirements for the desired pharmaceutical properties, the following dosage forms of the invention are applicable to FDC formulations of 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine free base (BI 1356) and metformin hydrochloride:

a) single-layer tablet

The monolayer tablets containing L-arginine showed satisfactory stability results, good dissolution characteristics and good Content Uniformity (CU). The mono-layer tablets may be prepared using conventional techniques, including fluid bed granulation for the DPP-4 inhibitor and metformin hydrochloride, e.g. including adding the DPP-4 inhibitor to a fluid bed granulator as a powder or as an aqueous suspension in a granulation liquid.

b) Bilayer tablet

Bilayer tablets containing L-arginine show promising stability results, good dissolution characteristics and good CU. Bilayer tablets may be prepared using conventional bilayer tableting techniques (e.g. a rotary bilayer tablet press).

c) Compression coated tablets

Press coated tablets (bilayer tablets and pre-press coated bull's eye tablets) show promising stability, good CU and dissolution. Press-coated tablets may be prepared using conventional press-coating techniques, for example on a Kilian tablet press to obtain bi-layer tablets or on other conventional press-coating machines (press-coated) to obtain eye tablets. As an advantage of this approach, the amount of L-arginine in the formulation can be easily minimized and the testing of the DPP-4 inhibitor portion and CU (minimal drug load; 2.5 mg/tablet with metformin HCl dose strengths of 500, 850 and 1000 mg/tablet) can be controlled. Another advantage is the flexibility in designing the DPP-4 inhibitor portion and the metformin HCl portion to minimize tablet size. The improved press coated tablets, referred to as "bull's eye tablets", may be a versatile dosage form potentially useful for bi-layer tablets as well as other FDCs. The bull's eye tablets may be prepared in a one-step compression coating without separately forming the core (as in a double-layer compression).

It should be noted that the term "bull's eye tablet" as used herein is understood by the skilled artisan within the meaning of the present invention. As is well known to the skilled person, such tablets, also called inlay tablets (inlay tablets) or discs (dots), consist of an outer coating and an inner core, and wherein, unlike the area of the inner core which is completely surrounded by the outer coating, one surface of the area corresponding to the area of the inner core is exposed.

d) Film coated tablets (drug coating by film coating for drug loading)

The coating of the DPP-4 inhibitor drug substance on metformin HCl tablets showed acceptable dissolution results and promising stability data. L-arginine needs to be added to the film coating for stabilization purposes. As an advantage of this approach, the DPP-4 inhibitor moiety may be integrated as such into the combination drug moiety even if the dosage form is a modified/controlled release formulation. During the film coating process, the coating endpoint needs to be determined analytically.

The process of coating a DPP-4 inhibitor by a film coating as described herein, including the steps of seal coating, drug loading and optional outer coating, may be applied to any type of core or tablet, which may include the active ingredient (e.g., a combination drug as described herein), e.g., a metformin core or tablet, e.g., an immediate release (metformin release) metformin tablet, a sustained release (sustained release) metformin tablet, an extended release (extended release) metformin tablet, a modified release (modified release) metformin tablet, a controlled release (controlled release) metformin tablet or a delayed release (delayed release) metformin tablet. The invention therefore also relates to a tablet comprising a film coating comprising a DPP-4 inhibitor, a film forming agent (e.g. hypromellose), a plasticizer (e.g. propylene glycol) and L-arginine, or which is obtainable by using a method as described herein for coating with a DPP-4 inhibitor by film coating. The present invention also relates to an FDC tablet comprising an immediate release or extended release metformin core, a seal coat, a film coating layer comprising a DPP-4 inhibitor and optionally an outer coating; for example, each as described herein, and the FDC tablet is prepared by a process comprising the steps of: seal coating on the metformin tablet core, coating of the DPP-4 inhibitor by film coating, and optionally outer coating, e.g., as described herein for each step.

The pharmaceutical immediate release dosage form of the present invention preferably has the following dissolution profile: after 45 minutes at least 75% by weight, more preferably at least 90% by weight, of the respective active ingredient is dissolved per active ingredient. In a particular embodiment, after 30 minutes, for each active ingredient of the especially mono-layer tablets according to the invention (including core and film-coated tablets), at least 70-75% by weight (preferably at least 80% by weight) of the respective active ingredient is dissolved. In another embodiment, after 15 minutes, for each active ingredient according to the invention, especially for single layer tablets (including core and film coated tablets), at least 55-60% by weight of the respective active ingredient is dissolved. The dissolution characteristics may be determined in standard dissolution tests as according to standard pharmacopoeia (e.g. using a paddle method with an agitation speed of 50rpm, at a temperature of 37 ℃, with 0.1M hydrochloric acid as dissolution medium, and analyzing the samples using HPLC (BI 1356) and UV (metformin)).

In the pharmaceutical compositions and pharmaceutical dosage forms according to the invention, BI1356, e.g. in crystalline form, preferably has a particle size distribution (preferably by volume) in which at least 90% of the individual active pharmaceutical ingredients have a particle size of less than 200. mu.m, i.e. X90 < 200. mu.m, preferably X90. ltoreq.150. mu.m. More preferably, the particle size distribution is such that X90 ≦ 100 microns, even more preferably X90 ≦ 75 microns. Furthermore, the particle size distribution is preferably such that X90 > 0.1 microns, preferably X90. gtoreq.1 microns, most preferably X90. gtoreq.5 microns. Thus, preferred particle size distributions are such that 0.1 micron < X90 < 200 microns, specifically 0.1 micron < X90 ≦ 150 microns, more preferably 1 micron ≦ X90 ≦ 150 microns, and even more preferably 5 microns ≦ X90 ≦ 100 microns. A preferred embodiment of the particle size distribution of BI1356 is such that X90 ≦ 50 microns or 10 microns ≦ X90 ≦ 50 microns. It can be found that the pharmaceutical composition comprising BI1356 and having a particle size distribution as shown above exhibits the desired characteristics (e.g., with respect to dissolution, content uniformity, yield, etc.). The particle size characteristics shown are determined by laser diffraction methods, in particular small angle laser light scattering (i.e. Fraunhofer diffraction). Alternatively, the particle size characteristics can also be determined by microscopy (e.g., electron microscopy or scanning electron microscopy). The results of the particle size distributions determined by different techniques can be correlated with each other.

Optimized formulation of metformin HCl moiety:

it is another object of the present invention to provide an improved formulation of the metformin HCl moiety of the pharmaceutical composition according to the present invention.

For the metformin HCl moiety, high drug loading is favored as a primary factor for reasonable small tablet size.

Thus, it has been found that the drug loading and compressibility (compression force-crushing strength characteristics) of metformin HCl of the tablets of the present invention can be improved by surface treating metformin HCl with a water-soluble polymer, especially copovidone.

Several water-soluble polymers including polyvinyl alcohol (PVA), Hypromellose (HPMC), hydroxypropyl cellulose (HPC), Methyl Cellulose (MC), povidone (PVP) and copovidone can be tested to improve compressibility (compression force-crush strength characteristics). As a result, PVA shows the best effect in compressibility, but manufacturability may be poor due to adhesion problems during fluid bed granulation. Furthermore, PVA may not be selected last because it has a negative effect on the stability of certain DPP-4 inhibitors of the invention.

Formulation optimization studies have identified compositions that allow for metformin HCl drug loading in excess of 84% and improved crush strength by surface treating metformin HCl with a water soluble polymer copovidone.

Thus, finally, copovidone is chosen and its amount can be optimized, advantageously resulting in a stable formulation, and the viscosity of the granulation solution is sufficiently low to prepare an aqueous solution and to operate spraying through a fluid bed granulator.

Also optionally, it has been found that heating/drying of the metformin HCl drug substance is effective in improving the stability of certain DPP-4 inhibitors of the present invention in combination with metformin HCl. The metformin HCl is pretreated before starting the granulation with the DPP-4 inhibitor. Heating/drying at 80 ℃ with a fluid bed granulator can help reduce the excess volatile impurities (which may be urea) in metformin HCl.

The scope of the invention is not limited to the specific embodiments described herein. Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from this disclosure. Such modifications are also intended to be included within the scope of the appended claims.

All patent applications cited herein are incorporated herein by reference in their entirety.

Other implementations, features, and advantages of the invention will become apparent from the following examples. The following examples are given by way of illustration only, and not by way of limitation, to illustrate the principles of the invention.

Examples

1. Single-layer tablet

The composition of the mono-layer tablets of DPP-4 inhibitor of the invention (BI 1356) + metformin HCl FDC (film coated tablets) is shown in table 1.

Table 1: composition of BI1356 + metformin HCl FDC mono-layer tablets

^**Removed during the addition process and does not appear in the final product

Preparation process (single layer tablet):

the DPP-4 inhibitor (e.g. BI1356) + metformin HCl FDC mono-layer tablets of the present invention are obtained by fluid bed granulation process and conventional tabletting process using a rotary tablet press. Optionally, metformin HCl and corn starch may be pretreated by heating in the chamber of a fluid bed granulator to remove excess HCl and/or impurity products and then mixed with the active DPP-4 inhibitor component. After optional pretreatment of metformin HCl and corn starch, either the DPP-4 inhibitor is added as a powder and pre-mixed, followed by fluid bed granulation by spraying a "granulation liquid" consisting of copovidone (Kollidon VA64), L-arginine and purified water, or by dispersing it directly in the "granulation liquid". After the fluid bed granulation is complete, the granules are sieved using a suitable sieve. The sieved granules were blended with colloidal anhydrous silicon dioxide (Aerosil200) and magnesium stearate as a lubricant. The final mixture is compressed into tablets using a conventional rotary tablet press.

The tablet cores may be film coated by an aqueous film coating suspension comprising hypromellose as film former, propylene glycol as plasticizer, talc as glidant and the pigments iron oxide yellow and/or iron oxide red and titanium dioxide.

A more detailed description of a preferred method of preparation of a mono-layer tablet:

a) metformin HCl and corn starch were sieved using a sieve with a mesh size of 0.5-1 mm before dispersion.

b) L-arginine, BI1356 and finally copovidone were dissolved, respectively dispersed in purified water at ambient temperature using a propeller mixer to obtain a "granulation liquid".

c) Metformin HCl and corn starch were drawn into a suitable chamber of a fluid bed granulator and preheated to a target product temperature of about 36 ℃.

d) Immediately after the target product temperature is reached, the "granulation liquid" is sprayed to the mixture under dry conditions for fluid bed granulation to avoid sticking during granulation.

e) At the end of the spraying, the resulting granules were dried at approximately 70 ℃ inlet air temperature until the desired LOD value (i.e. 1-2%) was reached.

f) The granules were sieved using a sieve with a mesh size of 0.5-1.0 mm.

g) The sieved particles and colloidal anhydrous silica (Aerosil200) were blended with a suitable mixer. Prior to use, Aerosil200 should be pre-sieved and a small portion of the sieved particles passed through a 0.8 mm sieve.

h) Magnesium stearate was passed through a 0.8 mm screen and added to the granules. The "final blend" obtained by final blending in a free-fall mixer is then obtained.

i) The "final blend" was compressed into tablets using a rotary tablet press.

j) Dispersing titanium dioxide, propylene glycol and iron oxide (yellow iron oxide, red iron oxide or yellow iron oxide and red iron oxide) in purified water by using a high-shear homogeneous mixer. Hypromellose and talc were then added and dispersed at ambient temperature with a homomixer and propeller mixer to produce a "coating suspension".

k) The tablet cores are coated with a "coating suspension" to a target weight gain to produce "film-coated tablets". The "coating suspension" should be stirred again before use, and kept under slow stirring during the coating (spraying) process.

A more specific narrative description of an alternative manufacturing process for single-layer tablets:

a) metformin HCl was sieved using a sieve with a mesh size of 0.5-1 mm before weighing.

b) L-arginine and copovidone were dissolved in purified water using a propeller mixer at ambient temperature to produce a "granulation liquid".

c) Metformin HCl and corn starch were heated in the chamber of the fluid bed granulator at 70-80 ℃ for more than 15 minutes until the product temperature reached 60 ℃.

d) BI1356 was added to the container and then blended with metformin HCl and corn starch in a fluid bed granulator.

e) Under dry conditions, the "granulation liquid" is sprayed to the mixture for fluid bed granulation to avoid sticking during granulation.

f) At the end of the spraying, the resulting granules are dried at 70-80 ℃ until the desired LOD value (i.e. 1-2%) is reached, in case the LOD is greater than 2%.

g) The granules were sieved using a sieve with a mesh size of 0.5-1.0 mm.

h) The sieved particles and colloidal anhydrous silica (Aerosil200) were blended with a suitable mixer. Prior to use, Aerosil200 was sieved using a 0.5 mm sieve.

i) Magnesium stearate was passed through a 0.5 mm screen and added to the granules. Then, a "final blend" is obtained by final blending in a mixer.

j) The "final blend" was compressed into tablets using a rotary tablet press.

k) Hypromellose and propylene glycol were dissolved in purified water using a propeller mixer. Talc, titanium dioxide and iron oxide (yellow iron oxide, or yellow and red iron oxide) were dispersed in purified water using a homomixer. The suspension was added to the hypromellose solution and then mixed with a propeller mixer at ambient temperature to produce a "coating suspension".

l) coating the core tablets with a "coating suspension" to a target weight gain to produce "film coated tablets". The "coating suspension" should be stirred again before use, and kept under slow stirring during the coating (spraying) process.

2. Bilayer tablet

The composition of the inventive bilayered tablets (film coated tablets) of DPP-4 inhibitor (BI 1356) + metformin HCl FDC is shown in table 2.

Table 2: composition of BI1356 + metformin HCl FDC bilayer tablet

Preparation process (bilayer tablet):

the inventive DPP-4 inhibitor (e.g. BI1356) + metformin HCl FDC bilayer tablets are obtained by a high shear wet granulation process (for DPP-4 inhibitor-granulate), a fluid bed granulation process (for metformin HCl-granulate) and a bilayer tableting process using a multilayer rotary tablet press.

DPP-4 inhibitor-particles: the active DPP-4 inhibitor component is premixed with the diluent D-mannitol and pregelatinized starch by using a high shear granulator. The mixture is wetted with a granulation liquid containing purified water and copovidone as a binder. After further mixing, drying and sieving, the dry granules are blended with magnesium stearate as a lubricant.

A more specific narrative description of the preparation of BI 1356-granules:

a. at ambient temperature, copovidone and L-arginine were dissolved in purified water to produce a granulation liquid.

b. Blend BI1356, mannitol and pregelatinized starch in a suitable mixer to create a premix.

c. The premix is wetted with a granulation liquid and then granulated.

d. The wet granules are sieved to pass through a suitable sieve.

e. The granules are dried in a suitable dryer at about 50 c (up to 60 c) until the desired dry weight loss value is obtained.

f. The dried granules were sieved to pass through a sieve having a mesh size of 1.0 mm.

g. Magnesium stearate was passed through a 1.0 mm screen and added to the granules. Then, by final blending in a suitable mixer, "final blend a" is obtained.

Metformin HCl-particles: metformin HCl and corn starch were pre-treated by heating in the chamber of a fluid bed granulator to remove excess HCl and/or impurity products. After pre-treatment of metformin HCl and corn starch, fluid bed granulation was performed by spraying a "granulation liquid" consisting of copovidone (Kollidon VA64) and purified water. After the fluid bed granulation is complete, the granules are sieved using a suitable sieve. The sieved granules were blended with colloidal anhydrous silicon dioxide (Aerosil200) and magnesium stearate as a lubricant.

A more specific description of the process for the preparation of metformin HCl-particles is described:

b) At ambient temperature, copovidone was dissolved in purified water using a propeller mixer to produce a "granulation liquid".

d) Under dry conditions, the "granulation liquid" is sprayed to the mixture for fluid bed granulation to avoid sticking during granulation.

e) At the end of the spraying, the resulting granules are dried at 70-80 ℃ until the desired LOD value (i.e. 1-2%) is reached, in case the LOD is greater than 2%.

f) The granules were sieved using a sieve with a mesh size of 0.5-1.0 mm.

g) The sieved particles and colloidal anhydrous silica (Aerosil200) were blended with a suitable mixer. Aerosil200 was sieved using a 0.5 mm screen before use.

h) Magnesium stearate was passed through a 0.5 mm screen and added to the granules. Then, a "final blend B" was obtained by final blending in a mixer.

The "final blend a" and "final blend B" were compressed into bilayer tablets using a multilayer rotary tablet press. The tablet cores may be film coated by an aqueous film coating suspension comprising hypromellose as film former, propylene glycol as plasticizer, talc as glidant and the pigments iron oxide yellow and/or iron oxide red and titanium dioxide.

A more specific narrative description of the film coating preparation method:

a) hypromellose and propylene glycol were dissolved in purified water using a propeller mixer. Talc, titanium dioxide and iron oxide (yellow, red or yellow and red) were dispersed in purified water using a homomixer. The suspension was added to the hypromellose solution and then mixed at ambient temperature using a propeller mixer to produce a "coating suspension".

b) The tablet cores are coated with a "coating suspension" to a target weight gain to produce "film-coated tablets". The "coating suspension" is stirred again before use, and is kept under slow stirring during the coating (spraying).

3. Bilayer tablet or bull's eye tablet

The composition of the inventive DPP-4 inhibitor (BI 1356) + metformin HCl FDC BI-layer tablet or bull's eye tablet (film coated tablet) is shown in table 3.

Table 3: composition of BI1356 + metformin HCl FDC bilayer tablet or bull's eye tablet

Preparation process (double-layer tablet or bullye tablet):

the inventive DPP-4 inhibitor (e.g. BI1356) + metformin HCl FDC bilayer tablet or bull's eye tablet is obtained by a high shear wet granulation process (for DPP-4 inhibitor-granulate), a rotary tablet press (for DPP-4 inhibitor core-tablet), a fluid bed granulation process (for metformin HCl-granulate), and a press coating process using a press coater.

DPP-4 inhibitor core-tablet: the active DPP-4 inhibitor component is premixed with the diluent D-mannitol and pregelatinized starch by using a high shear granulator. The mixture is wetted with a granulation liquid containing purified water and copovidone as a binder. After further mixing, drying and sieving, the dry granules are blended with magnesium stearate as a lubricant.

A more specific narrative description of the preparation of BI1356 core-tablets:

c. The premix is wetted with a granulation liquid and then granulated.

d. The wet granules are screened through a suitable screen.

f. The dried granules were sieved through a sieve with a mesh size of 1.0 mm.

g. Magnesium stearate was passed through a 1.0 mm screen and added to the granules. The "final blend" is then obtained by final blending in a suitable mixer.

h. The "final blend" was compressed into "BI 1356 core-tablets" with a rotary tablet press.

f) The granules were sieved using a sieve with a mesh size of 0.5-1.0 mm.

g) The sieved particles and colloidal anhydrous silica (Aerosil200) were blended with a suitable mixer. Prior to use, Aerosil200 was sieved using a 0.5 mm sieve.

h) Magnesium stearate was passed through a 0.5 mm screen and added to the granules. The "metformin HCl" granules "(final blend) are then obtained by final blending in a mixer.

The "DPP-4 inhibitor tablet core-tablet" and the "metformin HCl-granule" are compressed into a double-layer tablet or a bull's eye tablet using an extrusion coating machine. The difference between the bilayer tablet and the bull's eye tablet is the location of the core tablet.

A more specific description of the preparation process of the bilayer tablet is described:

a) half of the metformin HCl-particles were loaded into the mold.

b) BI1356 core-tablets were placed on the metformin HCl-granule surface.

c) The core-tablets were covered with the other half of the metformin HCl-granules and then compressed into tablets (bi-layer tablets).

A more specific narrative description of the process for the preparation of the bull's eye tablet:

a) the metformin HCl-granules were loaded into a mold.

b) BI1356 core-tablets were placed on metformin HCl-granules in a mould and then compressed into tablets (bull's eye tablets).

The tablets may be film coated by an aqueous film coating suspension comprising hypromellose as film former, propylene glycol as plasticizer, talc as glidant and the pigments iron oxide yellow and/or iron oxide red and titanium dioxide.

A more specific narrative description of the method of preparation of the film coating:

b) The tablet cores were coated with a "coating suspension" to a target weight gain to produce "film coated tablets". The "coating suspension" is stirred again before use, and is kept under slow stirring during the coating (spraying).

4. DPP-4 inhibitor-drug coating (film coating for drug Loading) on metformin HCl tablets

The composition of the inventive DPP-4 inhibitor (BI 1356) + metformin HCl FDC (film coated tablets) prepared by film coating the drug onto metformin HCl tablets is shown in table 4.

Table 4: composition of coating of BI1356 + metformin HCl FDC BI1356 on metformin HCl tablets

Preparation process (DPP-4 inhibitor-drug coating by film coating on metformin HCl tablets):

DPP-4 inhibitors with drug coating (e.g. BI1356) + metformin HCl FDC are obtained by a fluid bed granulation process, a conventional tabletting process and a film coating process using the following three steps: seal coat, drug loading and outer coat. If stability is acceptable, the outer coating can be skipped by combining with drug loading.

Metformin HCl tablet: metformin HCl and corn starch were pre-treated by heating in the chamber of a fluid bed granulator to remove excess HCl and/or impurity products. After pre-treatment of metformin HCl and corn starch, fluid bed granulation was performed by spraying a "granulation liquid" consisting of copovidone (Kollidon VA64) and purified water. After the fluid bed granulation is complete, the granules are sieved using a suitable sieve. The sieved granules were blended with colloidal anhydrous silicon dioxide (Aerosil200) and magnesium stearate as a lubricant. The final blend is compressed into tablets using a conventional rotary tablet press.

f) The granules were sieved using a sieve with a mesh size of 0.5-1.0 mm.

g) The sieved particles and colloidal anhydrous silica (Aerosil200) were blended with a suitable mixer. Prior to use, Aerosil200 should be sieved using a 0.5 mm screen.

h) Magnesium stearate was passed through a 0.5 mm screen and added to the granules. The "final blend" is then obtained by final blending in a mixer.

i) The "final blend" is compressed into tablets using a conventional rotary tablet press.

Film coating: the tablets were film coated by the following steps: (1) and (3) sealing and coating: by an aqueous film coating suspension containing hypromellose as film former, propylene glycol as plasticizer, talc as glidant and the pigments iron oxide yellow and/or iron oxide red and titanium dioxide, (2) drug loading: by an aqueous film coating suspension containing hypromellose as film former, propylene glycol as plasticizer, BI1356 as drug substance and L-arginine as stabilizer, and (3) over-coating: by means of an aqueous film coating suspension containing hypromellose as film former, propylene glycol as plasticizer, talc as glidant and the pigments iron oxide yellow and/or iron oxide red and titanium dioxide.

A more specific narrative description of the preparation process for film coating using a coater:

a) hypromellose and propylene glycol were dissolved in purified water using a propeller mixer. Talc, titanium dioxide and iron oxide (yellow, red or yellow and red) were dispersed in purified water using a homomixer. The suspension was added to the hypromellose solution and then mixed at ambient temperature using a propeller mixer to produce a "coating suspension" for "seal coating" and "over coating".

b) Hypromellose, propylene glycol and L-arginine were dissolved in purified water using a propeller mixer. BI1356 (active drug) was added to the hypromellose solution and then dispersed at ambient temperature using a propeller mixer to create a "drug suspension" for "drug loading".

c) The metformin HCl tablets were coated with a "coating suspension" to a target weight gain to form a "seal coat". The "coating suspension" should be stirred again before use, and kept under slow stirring during the coating (spraying) process.

d) After seal coating, the "drug suspension" was applied to the surface of the metformin HCl tablet to form a "drug layer" (drug loaded). The "drug suspension" is stirred again before use, and is kept under slow stirring during the coating (spraying) process. The coating endpoint can be determined by the available PAT (Process analysis technology).

e) After drug loading, the "coating suspension" was applied to the BI1356 drug-loaded tablets to form the "outer coating" and to produce "film coated tablets". The "coating suspension" is stirred again before use, and is kept under slow stirring during the coating (spraying).

Product description:

product descriptions of BI1356 + metformin HCl FDC mono-layer tablets (core and film coated tablets) are shown in table 8 and table 9, respectively.

Table 8: product description of BI1356 + metformin HCl FDC monolayered tablets (core)

Table 9: product description of BI1356 + metformin HCl FDC monolayer tablets (coating)

Stability data:

the stability data of BI1356 + metformin HCl FDC mono-layer tablets (core) with or without L-arginine are shown in the following table (over 2 weeks, 1 month and 3 months):

2.5+500 mg tablet +12.5 mg arginine:

2.5+500 mg tablet + 0mg arginine:

2.5+1000 mg tablet +25 mg arginine:

2.5+1000 mg tablet + 0mg arginine:

Claims

1. A pharmaceutical composition comprising or made from: a DPP-4 inhibitor, a combination drug, one or more pharmaceutical excipients, and a nucleophile and/or an alkaline agent for stabilizing said DPP-4 inhibitor against degradation, wherein said DPP-4 inhibitor is 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine free base, said combination drug is metformin hydrochloride, said nucleophile and/or alkaline agent is selected from L-arginine, L-lysine and L-histidine.

2. A pharmaceutical composition comprising a DPP-4 inhibitor, a combination drug, one or more pharmaceutical excipients, wherein the DPP-4 inhibitor is 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine free base, and a buffer for stabilizing the DPP-4 inhibitor against degradation, the combination drug being metformin hydrochloride, the buffer being selected from L-arginine, L-lysine and L-histidine.

3. The pharmaceutical composition according to claim 1, wherein said DPP-4 inhibitor is stabilized against chemical degradation.

4. The pharmaceutical composition according to claim 2, wherein said DPP-4 inhibitor is stabilized against chemical degradation.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the DPP-4 inhibitor is present in a dosage range of 0.5 mg to 20 mg.

6. The pharmaceutical composition according to claim 5, wherein the DPP-4 inhibitor is present in a dosage range of 0.5 mg to 10 mg.

7. The pharmaceutical composition according to claim 6, wherein the DPP-4 inhibitor is present in a dosage strength of 0.5, 1, 2.5, 5 or 10 mg.

8. The pharmaceutical composition according to claim 7, wherein the DPP-4 inhibitor is present in a dosage strength of 2.5 mg.

9. The pharmaceutical composition of any one of claims 1-4, wherein metformin hydrochloride is present in a dosage range of 100 mg to 1500 mg.

10. The pharmaceutical composition of claim 9, wherein metformin hydrochloride is present in a dosage strength of 250, 500, 625, 750, 850 or 1000 mg.

11. The pharmaceutical composition of claim 10, wherein metformin hydrochloride is present in a dosage strength of 500mg, 850mg or 1000 mg.

12. The pharmaceutical composition of claim 5, wherein metformin hydrochloride is present in a dosage range of 100 mg to 1500 mg.

13. The pharmaceutical composition of any one of claims 1-4, wherein the nucleophile and/or alkaline agent or buffer is L-arginine.

14. The pharmaceutical composition of claim 5, wherein the nucleophile and/or alkaline agent or buffer is L-arginine.

15. The pharmaceutical composition of claim 9, wherein the nucleophile and/or alkaline agent or buffer is L-arginine.

16. The pharmaceutical composition of claim 12, wherein the nucleophile and/or alkaline agent or buffer is L-arginine.

17. The pharmaceutical composition of claim 13, wherein L-arginine is present in the range of 1 mg to 50 mg.

18. The pharmaceutical composition of claim 14, wherein L-arginine is present in the range of 1 mg to 50 mg.

19. The pharmaceutical composition of claim 15, wherein L-arginine is present in the range of 1 mg to 50 mg.

20. The pharmaceutical composition of claim 16, wherein L-arginine is present in the range of 1 mg to 50 mg.

21. The pharmaceutical composition of claim 17, wherein L-arginine is present in the range of 1 mg to 25 mg.

22. The pharmaceutical composition according to claim 13, wherein the DPP-4 inhibitor and L-arginine are present in a weight ratio of 1: 20 to 10: 1.

23. The pharmaceutical composition according to claim 14, wherein the DPP-4 inhibitor and L-arginine are present in a weight ratio of 1: 20 to 10: 1.

24. The pharmaceutical composition according to claim 15, wherein the DPP-4 inhibitor and L-arginine are present in a weight ratio of 1: 20 to 10: 1.

25. The pharmaceutical composition according to claim 16, wherein the DPP-4 inhibitor and L-arginine are present in a weight ratio of 1: 20 to 10: 1.

26. The pharmaceutical composition according to claim 13, wherein the DPP-4 inhibitor and L-arginine are present in a weight ratio of 1: 15 to 10: 1.

27. The pharmaceutical composition according to claim 22, wherein the DPP-4 inhibitor and L-arginine are present in a weight ratio of 1: 10 to 10: 1.

28. The pharmaceutical composition of any one of claims 1-4, wherein the excipient is selected from the group consisting of: one or more fillers; a binder; a lubricant; and a glidant.

29. The pharmaceutical composition of claim 5, wherein the excipient is selected from the group consisting of: one or more fillers; a binder; a lubricant; and a glidant.

30. The pharmaceutical composition of claim 9, wherein the excipient is selected from the group consisting of: one or more fillers; a binder; a lubricant; and a glidant.

31. The pharmaceutical composition of claim 12, wherein the excipient is selected from the group consisting of: one or more fillers; a binder; a lubricant; and a glidant.

32. The pharmaceutical composition of claim 13, wherein the excipient is selected from the group consisting of: one or more fillers; a binder; a lubricant; and a glidant.

33. The pharmaceutical composition of claim 14, wherein the excipient is selected from the group consisting of: one or more fillers; a binder; a lubricant; and a glidant.

34. The pharmaceutical composition of claim 18, wherein the excipient is selected from the group consisting of: one or more fillers; a binder; a lubricant; and a glidant.

35. The pharmaceutical composition of claim 23, wherein the excipient is selected from the group consisting of: one or more fillers; a binder; a lubricant; and a glidant.

36. The pharmaceutical composition of claim 28, wherein the one or more bulking agents are selected from the group consisting of D-mannitol, corn starch, and pregelatinized starch; the adhesive is copovidone; the lubricant is magnesium stearate; and the glidant is colloidal anhydrous silicon dioxide.

37. The pharmaceutical composition according to any one of claims 1 to 4, comprising copovidone as a binder.

38. The pharmaceutical composition of claim 37, further comprising one or more of the following: corn starch as filler, magnesium stearate as lubricant, and colloidal anhydrous silicon dioxide as glidant.

39. The pharmaceutical composition of any one of claims 1-4 in a tablet dosage form.

40. The pharmaceutical composition of claim 39, wherein the tablet is selected from the group consisting of a single layer tablet, a bilayer tablet, a compression coated tablet, and a film coated tablet for drug loading.

41. The pharmaceutical composition of claim 39, wherein the tablet comprises a film coating.

42. The pharmaceutical composition of claim 41, wherein the film coating comprises a film coating agent; a plasticizer; optionally a glidant; and optionally one or more pigments.

43. The pharmaceutical composition of claim 42, wherein the film coating agent is hypromellose; the plasticizer is propylene glycol; optionally the glidant is talc; and optionally one or more pigments selected from titanium dioxide, red iron oxide and/or yellow iron oxide.

44. The pharmaceutical composition of any one of claims 1-4, wherein the pharmaceutical composition is a mono-layer tablet, wherein one or more of the following can be performed:

the percentage of metformin hydrochloride is 85% by weight of the entire tablet core,

-the percentage of DPP-4 inhibitor is 0.2% -0.4% by weight of the entire tablet core,

the percentage of L-arginine is 2% by weight of the entire tablet core,

-the tablet breaking strength is higher than or equal to 100N,

-the friability of the tablets is lower than or equal to 0.5%,

-the tablet thickness is 5.7-8.4 mm,

the tablet core weight is 590-1180 mg, and

-the tablet disintegration time is less than or equal to 15 minutes.

45. A pharmaceutical composition according to claim 39, which is an immediate release dosage form, characterized in that in the dissolution test, at least 75% by weight of each active ingredient is dissolved after 45 minutes.

46. A solid pharmaceutical composition comprising or made from:

1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine,

the L-arginine is added into the mixture of L-arginine,

and one or more fillers, one or more binders, one or more glidants, and/or one or more lubricants.

47. The pharmaceutical composition according to claim 1, 2 or 46, wherein 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine has a particle size distribution of X90 < 200 microns.

48. A method of preparing the pharmaceutical composition of claim 13, 28 or 46, comprising incorporating the active ingredient and L-arginine into one or more pharmaceutical excipients.

49. The method of claim 48, wherein the one or more pharmaceutical excipients are selected from the group consisting of D-mannitol, corn starch, pregelatinized starch, copovidone, magnesium stearate, and colloidal anhydrous silicon dioxide.

50. A process for preparing the pharmaceutical composition of any one of claims 1-47, wherein the pharmaceutical composition is made by mixing the ingredients.

51. The pharmaceutical composition of claim 1, 2 or 46, comprising the active ingredients in the following amounts:

(1)2.5mg of 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine, and 500mg of metformin hydrochloride; or

(2)2.5mg of 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine and 850mg of metformin hydrochloride; or

(3)2.5mg of 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine and 1000mg of metformin hydrochloride.