Patent Description:
Reference is made to the present claims for further embodiments of the present invention. The invention and its scope is set out and defined by the appended claims.

The references to methods of medical treatment in the following description are to be interpreted as references to the compounds, pharmaceutical compositions, combinations, medicaments, formulations, dosage forms etc. of the present invention for use in those methods.

The present disclosure relates to pharmaceutical compositions comprising fixed dose combinations of a DPP-<NUM> inhibitor drug and a partner drug, processes for the preparation thereof, and their use to treat certain diseases.

In a more detailed aspect, the present disclosure relates to oral solid dosage forms for fixed dose combination (FDC) of a selected dipeptidyl peptidase-<NUM> (DPP-<NUM>) inhibitor drug and a certain partner drug. The FDC formulations are chemically stable and either a) display similarity of in-vitro dissolution profiles and/or are bioequivalent to the free combination, or b) allow to adjust the in-vitro and in-vivo performance to desired levels. In a preferred embodiment the disclosure relates to chemically stable FDC formulations maintaining the original dissolution profiles of corresponding mono tablets of each individual entity, with a reasonable tablet size.

The enzyme DPP-<NUM> also known as CD26 is a serine protease known to lead to the cleavage of a dipeptide from the N-terminal end of a number of proteins having at their N-terminal end a prolin or alanin residue. Due to this property DPP-<NUM> inhibitors interfere with the plasma level of bioactive peptides including the peptide GLP-<NUM> and are considered to be promising drugs for the treatment of diabetes mellitus.

For example, DPP-<NUM> inhibitors and their uses are disclosed in <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT> or <CIT>; or in <CIT>, <CIT>, <CIT>, <CIT>; <CIT>, <CIT>, <CIT>; <CIT> or <CIT>.

As further DPP-<NUM> inhibitors the following compounds can be mentioned:.

In one embodiment, sitagliptin is in the form of its dihydrogenphosphate salt, i.e. sitagliptin phosphate. In a further embodiment, sitagliptin phosphate is in the form of a crystalline anhydrate or monohydrate. A class of this embodiment refers to sitagliptin phosphate monohydrate. Sitagliptin free base and pharmaceutically acceptable salts thereof are disclosed in <CIT> and in Example <NUM> of <CIT>. Crystalline sitagliptin phosphate monohydrate is disclosed in <CIT> and in <CIT>.

For details, e.g. on a process to manufacture this compound or a salt thereof, reference is thus made to these documents.

Vildagliptin is specifically disclosed in <CIT> and in Example <NUM> of <CIT>. Specific salts of vildagliptin are disclosed in <CIT>. A crystalline form of vildagliptin is disclosed in <CIT>. A crystalline form of vildagliptin is disclosed in <CIT>.

Saxagliptin is specifically disclosed in <CIT> and in Example <NUM> of <CIT>. In one embodiment, saxagliptin is in the form of its HCl salt or its mono-benzoate salt as disclosed in <CIT>. In a further embodiment, saxagliptin is in the form of the free base. In a yet further embodiment, saxagliptin is in the form of the monohydrate of the free base as disclosed in <CIT>. Crystalline forms of the HCl salt and the free base of saxagliptin are disclosed in <CIT>. A process for preparing saxagliptin is also disclosed in <CIT> and <CIT>.

Denagliptin is specifically disclosed in <CIT> and in <CIT>.

In one embodiment, denagliptin is in the form of its hydrochloride salt as disclosed in Example <NUM> of <CIT> or its tosylate salt as disclosed in <CIT>. A class of this embodiment refers to denagliptin tosylate. Crystalline anhydrous denagliptin tosylate is disclosed in <CIT>.

Alogliptin is specifically disclosed in <CIT>, <CIT> and in <CIT>. In one embodiment, alogliptin is in the form of its benzoate salt, its hydrochloride salt or its tosylate salt each as disclosed in <CIT>. A class of this embodiment refers to alogliptin benzoate. Polymorphs of alogliptin benzoate are disclosed in <CIT>. A process for preparing alogliptin is disclosed in <CIT> and, specifically, in <CIT>.

This compound and methods for its preparation are disclosed in <CIT>. A process for preparing this compound (specifically its dihydrochloride salt) is also disclosed in <CIT>, <CIT> and <CIT>.

This compound and methods for its preparation and use are disclosed in <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT> and <CIT>. Specifically claimed salts include the succinate (<CIT>), benzoate, benzenesulfonate, p-toluenesulfonate, (R)-mandelate and hydrochloride. For details, e.g. on a process to manufacture this compound or a salt thereof, reference is thus made to these documents.

Partner drugs to be combined with the DPP-<NUM> inhibitors within the pharmaceutical compositions according to this disclosure are biguanides (e.g. metformin such as metformin hydrochloride), thiazolidinones (e.g. pioglitazone such as pioglitazone hydrochloride), statines (e.g. atorvastatin) or ARBs (e.g. telmisartan).

The biguanide antihyperglycemic agent metformin is disclosed in <CIT>. The preparation of metformin (dimethyldiguanide) and its hydrochloride salt is state of the art and was disclosed first by <NPL>. Other pharmaceutically acceptable salts of metformin can be found in <CIT> or <CIT>. It is preferred that the metformin employed herein be the metformin hydrochloride salt.

Unless specifically noted, in the present context the terms "DPP-<NUM> inhibitor(s)", "biguanide(s)", "thiazolidinone(s)", "statine(s)", "ARB(s)", or any species thereof like "metformin", "pioglitazone", are also intended to comprise any pharmaceutically acceptable salt thereof, crystal form, hydrate, solvate, diastereomer or enantiomer thereof.

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

In attempts to prepare pharmaceutical compositions of selected DPP-<NUM> inhibitors it has been observed, that the DPP-<NUM> inhibitors with a primary or secondary amino group show incompatibilities, degradation problems, or extraction problems with a number of customary excipients such as microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, tartaric acid, citric acid, glucose, fructose, saccharose, lactose, maltodextrines. Though the compounds themselves are very stable, they react with incompatible partner drug, or its impurity product, and/or with many excipients used in solid dosage forms and with impurities of excipients, especially in tight contact provided in tablets and at high excipient/drug ratios. The amino group appears to react with reducing sugars and with other reactive carbonyl groups and with carboxylic acid functional groups formed for example at the surface of microcrystalline cellulose by oxidation. These unforeseen difficulties are primarily observed in low dosage ranges of the DPP-<NUM> inhibitor used, which are required due to their surprising potency, and/or high dosage ranges of the partner drug used. Thus, pharmaceutical compositions are required to solve these technical problems, which may be associated with the unexpected potency of selected DPP-<NUM> inhibitor compounds.

Other aims of the present disclosure will become apparent to the skilled man from the foregoing and following remarks.

It has now been found that the pharmaceutical compositions, which are described in greater details herein, have surprising and particularly advantageous properties.

In particular, it has been found that by the use of a nucleophilic and/or basic agent, which may be suitable for stabilizing, such as e.g. a suitable buffering agent as stabilizer, within these pharmaceutical compositions one can overcome these problems, e.g. of incompatibility and poor stability, especially decomposition and/or "assay decrease" which may be caused e.g. by reaction (e.g. by acylation, urea formation or Maillard reaction, or the like) of free base type DPP-<NUM> inhibitors when combined with an incompatible partner drug, or its impurity product and/or a pharmaceutical excipient having such functional group (such as a reducing end of a sugar or an acyl group, such as e.g. an acetyl or carbamoyl group) to form derivatives with the free base type DPP-<NUM> inhibitors, such as e.g. N-acetyl or N-carbamoyl derivatives. Therefore, by the use of a suitable nucleophilic and/or basic agent (e.g. a buffering and/or pH modifying agent) within these pharmaceutical compositions protection against decomposition and degradation can be achieved.

Thus, the present disclosure is directed to a chemically stable FDC formulation comprising a DPP-<NUM> inhibitor, a partner drug, and a nucleophilic and/or basic agent.

Thus, the present disclosure is also directed to a chemically stable FDC formulation comprising a DPP-<NUM> inhibitor, a partner drug, and a suitable buffering agent.

Thus, the present disclosure is also directed to a chemically stable FDC formulation comprising a DPP-<NUM> inhibitor, a partner drug, and a pH modifying agent.

A DPP-<NUM> inhibitor within the meaning of the present disclosure includes, without being limited to, any of those DPP-<NUM> inhibitors mentioned hereinabove and hereinbelow, preferably orally active DPP-<NUM> inhibitors.

In a closer embodiment, a DPP-<NUM> inhibitor within the meaning of the present disclosure includes a DPP-<NUM> inhibitor with an amino group, especially a free or primary amino group.

In a yet closer embodiment, a DPP-<NUM> inhibitor in the context of the present disclosure is a DPP-<NUM> inhibitor with a primary amino group, particularly with a free primary amino group.

The partner drug used is selected from the group consisting of a biguanide (e.g. metformin such as metformin hydrochloride), a thiazolidinone (e.g. pioglitazone such as pioglitazone hydrochloride), a statine (e.g. atorvastatin) and an ARB (e.g. telmisartan). A preferred partner drug within the meaning of this disclosure is metformin, particularly metformin hydrochloride (<NUM>,<NUM>-dimethylbiguanide hydrochloride or metformin HCl).

The buffering agent used may be a basic amino acid, which has an intramolecular amino group and alkaline characteristics (isoelectric point, pl: <NUM>-<NUM>), such as e.g. L-arginine, L-lysine or L-histigine. A preferred buffering agent within the meaning of this disclosure is L-arginine. L-Arginine has a particular suitable stabilizing effect on the compositions of this disclosure, e.g. by suppressing degradation of the DPP-<NUM> inhibitor in the presence of the partner drug.

The present disclosure is directed to a pharmaceutical comprising a DPP-<NUM> inhibitor, a partner drug, a nucleophilic and/or basic agent, and one or more pharmaceutical excipients.

The present disclosure is also directed to a pharmaceutical composition comprising a DPP-<NUM> inhibitor, a partner drug, a suitable buffering agent, and one or more pharmaceutical excipients.

The present disclosure is also directed to a pharmaceutical comprising a DPP-<NUM> inhibitor, a partner drug, a pH modifying agent, and one or more pharmaceutical excipients.

In an embodiment, the present disclosure is directed to a pharmaceutical composition (e.g. an oral solid dosage form, particularly a tablet) comprising a DPP-<NUM> inhibitor; a partner drug (particularly metformin); and L-arginine for stabilizing the composition and/or the DPP-<NUM> inhibitor, particularly against chemical degradation; as well as one or more pharmaceutical excipients.

In another embodiment, the present disclosure is directed to a pharmaceutical composition (e.g. an oral solid dosage form, particularly a tablet) obtainable from a DPP-<NUM> inhibitor; a partner drug (particularly metformin); and L-arginine for stabilizing the composition and/or the DPP-<NUM> inhibitor, particularly against chemical degradation; as well as one or more pharmaceutical excipients.

In general, pharmaceutical excipients which may be used may be selected from the group consisting of 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 this disclosure comprise usually a binder.

In more detail, the pharmaceutical compositions (tablets) of this disclosure comprise usually one or more fillers (e.g. D-mannitol, corn starch and/or pregelatinized starch), a binder (e.g. copovidone), a lubricant (e.g. magnesium stearate), and a glidant (e.g. colloidal anhydrous silica).

Suitably the pharmaceutical excipients used within this disclosure are conventional materials such as D-mannitol, corn starch, pregelatinized starch as a filler, copovidone as a binder, magnesium stearate as a lubricant, colloidal anhydrous silica as a glidant, hypromellose as a film-coating agent, propylene glycol as a plasticizer, titanium dioxide, iron oxide red/yellow as a pigment, and talc, etc..

A typical composition according to the present disclosure comprises the binder copovidone (also known as copolyvidone or Kollidon VA64).

Further, a typical composition according to the present disclosure comprises the filler corn starch, the binder copovidone, the lubricant magnesium stearate, and the glidant colloidal anhydrous silica.

A pharmaceutical composition according to an embodiment of the present disclosure is intended for the treatment of diabetes and/or to achieve glycemic control in a type <NUM> or type <NUM> diabetes mellitus patient and comprises a fixed dose combination formulation as described herein together with suitable pharmaceutical excipients. Additionally the compositions can be used to treat rheumatoid arthritis, obesity and osteoporosis as well as to support allograft transplantation.

Thus, in particular, the present disclosure is directed to a pharmaceutical composition (especially an oral solid dosage form, particularly a tablet) comprising a DPP-<NUM> inhibitor, metformin hydrochloride, L-arginine and one or more pharmaceutical excipients, particularly one or more fillers, one or more binders, one or more glidants, and/or one or more lubricants.

In more particular, the present disclosure is directed to a pharmaceutical composition (especially an oral solid dosage form, particularly a tablet) comprising a DPP-<NUM> inhibitor, metformin hydrochloride, L-arginine, copovidone as binder and one or more further pharmaceutical excipients.

Typical pharmaceutical compositions of this disclosure may comprise in the DPP-<NUM> inhibitor portion <NUM>-<NUM> % L-arginine (such as e.g. about <NUM> %, <NUM> %, <NUM> %, <NUM> %, <NUM> % or <NUM> %) by weight of total DPP-<NUM> inhibitor portion, particularly about <NUM> % (e.g. more specifically, <NUM> % by weight of total tablet core of uncoated monolayer tablet).

Typical pharmaceutical compositions of this disclosure may comprise in the DPP-<NUM> inhibitor portion (% by weight of total DPP-<NUM> inhibitor portion):.

Typical pharmaceutical compositions of this disclosure may comprise the DPP-<NUM> inhibitor and L-arginine in a weight ratio of from about <NUM>:<NUM> to about <NUM>:<NUM> or from about <NUM>:<NUM> to about <NUM>:<NUM> or from about <NUM>:<NUM> to about <NUM>:<NUM>, especially from <NUM>:<NUM> to <NUM>:<NUM>, such as e.g. in a weight ratio of <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, or <NUM>:<NUM>, more detailed in a weight ratio of <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, or <NUM>:<NUM>.

Typical pharmaceutical compositions of this disclosure may comprise metformin hydrochloride and L-arginine in a weight ratio of from about <NUM>:<NUM> to about <NUM>:<NUM>, such as e.g. in a weight ratio of <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, or <NUM>:<NUM>, more detailed in a weight ratio of <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, or <NUM>:<NUM>.

Typical pharmaceutical compositions of this disclosure may comprise the DPP4-inhibitor, metformin hydrochloride and L-arginine in a weight ratio of from about <NUM> :<NUM>:<NUM> to about <NUM>:<NUM>:<NUM> (e.g. <NUM>:<NUM>:<NUM>, <NUM>:<NUM>:<NUM>, <NUM>:<NUM>:<NUM>), or from about <NUM>:<NUM>:<NUM> to about <NUM>:<NUM>:<NUM> (e.g. <NUM>:<NUM>:<NUM>, <NUM>:<NUM>:<NUM>, <NUM>:<NUM>:<NUM>), or from about <NUM>:<NUM>:<NUM> to about <NUM>:<NUM>:<NUM> (e.g. <NUM>:<NUM>:<NUM>, <NUM>:<NUM>:<NUM>, <NUM>:<NUM>:<NUM>).

Typical pharmaceutical compositions of this disclosure may comprise one or more of the following amounts (% by weight of total coated tablet mass):.

Further details about the FDC formulations of this disclosure, e.g. the ingredients, ratio of ingredients (such as e.g. ratio of DPP-<NUM> inhibitor, metformin hydrochloride, L-arginine and/or excipients), particularly with respect to special dosage forms (tablets) used within this disclosure as well as their preparation, become apparent to the skilled person from the disclosure hereinbefore and hereinafter (including by way of example the following examples as well as the claims).

In a first embodiment (embodiment A), a DPP-<NUM> inhibitor in the context of the present disclosure is any DPP-<NUM> inhibitor of.

In a second embodiment (embodiment B), a DPP-<NUM> inhibitor in the context of the present disclosure is a DPP-<NUM> inhibitor selected from the group consisting of.

Regarding the first embodiment (embodiment A), preferred DPP-<NUM> inhibitors are any or all of the following compounds and their pharmaceutically acceptable salts:.

These DPP-<NUM> inhibitors are distinguished from structurally comparable DPP-<NUM> inhibitors, as they combine exceptional potency and a long-lasting effect with favourable pharmacological properties, receptor selectivity and a favourable side-effect profile or bring about unexpected therapeutic advantages or improvements when combined with other pharmaceutical active substances. Their preparation is disclosed in the publications mentioned.

A more preferred DPP-<NUM> inhibitor among the abovementioned DPP-<NUM> inhibitors of embodiment A of this disclosure is <NUM>-[(<NUM>-methyl-quinazolin-<NUM>-yl)methyl]-<NUM>-methyl-<NUM>-(<NUM>-butyn-<NUM>-yl)-<NUM>-(<NUM>-(R)-amino-piperidin-<NUM>-yl)-xanthine, particularly the free base thereof (which is also known as BI <NUM>).

Regarding the second embodiment (embodiment B), preferred DPP-<NUM> inhibitors are selected from the group consisting of vildagliptin, saxagliptin and alogliptin, and their pharmaceutically acceptable salts.

Unless otherwise noted, according to this disclosure it is to be understood that the definitions of the above listed DPP-<NUM> inhibitors also comprise their pharmaceutically acceptable salts as well as hydrates, solvates and polymorphic forms thereof. With respect to salts, hydrates and polymorphic forms thereof, particular reference is made to those which are referred to hereinabove and hereinbelow.

With respect to embodiment A, the methods of synthesis for the DPP-<NUM> inhibitors according to embodiment A of this disclosure are known to the skilled person. Advantageously, the DPP-<NUM> inhibitors according to embodiment A of this disclosure can be prepared using synthetic methods as described in the literature. Thus, for example, purine derivatives of formula (I) can be obtained as described in <CIT>, <CIT>, <CIT>, <CIT> or <CIT>, the disclosures of which are incorporated herein.

Purine derivatives of formula (II) can be obtained as described, for example, in <CIT> or <CIT>, the disclosures of which are incorporated herein.

Purine derivatives of formula (III) can be obtained as described, for example, in <CIT>, <CIT> or <CIT>, the disclosures of which are incorporated herein. The preparation of those DPP-<NUM> inhibitors, which are specifically mentioned hereinabove, is disclosed in the publications mentioned in connection therewith. Polymorphous crystal modifications and formulations of particular DPP-<NUM> inhibitors are disclosed in <CIT> and <CIT>, respectively, the disclosures of which are incorporated herein in their entireties.

With respect to embodiment B, the methods of synthesis for the DPP-<NUM> inhibitors of embodiment B are described in the scientific literature and/ or in published patent documents, particularly in those cited herein.

With respect to the first embodiment (embodiment A), the dosage typically required of the DPP-<NUM> inhibitors mentioned herein in embodiment A when administered orally is <NUM> to <NUM>, preferably <NUM> to <NUM> or <NUM> to <NUM>, more preferably <NUM> to <NUM> or <NUM> to <NUM>, in each case <NUM> to <NUM> times a day. Thus, the dosage required of <NUM>-[(<NUM>-methyl-quinazolin-<NUM>-yl)methyl]-<NUM>-methyl-<NUM>-(<NUM>-butyn-<NUM>-yl)-<NUM>-(<NUM>-(R)-amino-piperidin-<NUM>-yl)-xanthine when administered orally is <NUM> to <NUM> per patient per day, preferably <NUM> to <NUM> or <NUM> to <NUM> per patient per day.

A dosage form prepared with a pharmaceutical composition comprising a DPP-<NUM> inhibitor mentioned herein in embodiment A contain the active ingredient in a dosage range of <NUM>-<NUM>, in particular <NUM> to <NUM>. Thus, particular dosage strengths of <NUM>-[(<NUM>-methyl-quinazolin-<NUM>-yl)methyl]-<NUM>-methyl-<NUM>-(<NUM>-butyn-<NUM>-yl)-<NUM>-(<NUM>-(R)-amino-piperidin-<NUM>-yl)-xanthine are <NUM>, <NUM>, <NUM>, <NUM> and <NUM>. A more particular unit dosage strength of <NUM>-[(<NUM>-methyl-quinazolin-<NUM>-yl)methyl]-<NUM>-methyl-<NUM>-(<NUM>-butyn-<NUM>-yl)-<NUM>-(<NUM>-(R)-amino-piperidin-<NUM>-yl)-xanthine for inclusion into fixed dose combination pharmaceutical compositions of the present disclosure is <NUM>.

With respect to the second embodiment (embodiment B), the doses of DPP-<NUM> inhibitors mentioned herein in embodiment B to be administered to mammals, for example human beings, of, for example, approximately <NUM> body weight, may be generally from about <NUM> to about <NUM>, for example from about <NUM> to about <NUM>, preferably <NUM>-<NUM>, more preferably <NUM>-<NUM>, of the active moiety per person per day, or from about <NUM> to about <NUM>, preferably <NUM>-<NUM>, per person per day, divided preferably into <NUM> to <NUM> single doses which may, for example, be of the same size. Single dosage strengths comprise, for example, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> of the DPP-<NUM> inhibitor active moiety.

A dosage strength of the DPP-<NUM> inhibitor sitagliptin is usually between <NUM> and <NUM> of the active moiety. A recommended dose of sitagliptin is <NUM> calculated for the active moiety (free base anhydrate) once daily. Unit dosage strengths of sitagliptin free base anhydrate (active moiety) are <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>. Particular unit dosage strengths of sitagliptin (e.g. per tablet) are <NUM>, <NUM> and <NUM>. An equivalent amount of sitagliptin phosphate monohydrate to the sitagliptin free base anhydrate is used in the pharmaceutical compositions, namely, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>, respectively. Adjusted dosages of <NUM> and <NUM> sitagliptin are used for patients with renal failure.

A dosage range of the DPP-<NUM> inhibitor vildagliptin is usually between <NUM> and <NUM> daily, in particular between <NUM> and <NUM>, <NUM> and <NUM> or <NUM> and <NUM> or <NUM> and <NUM> daily. Particular examples of daily oral dosage are <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM>. In a more particular aspect, the daily administration of vildagliptin is between <NUM> and <NUM> or between <NUM> and <NUM>. In another more particular aspect, the daily administration of vildagliptin is <NUM> or <NUM>. The application of the active ingredient may occur up to three times a day, preferably one or two times a day. Particular dosage strengths are <NUM> or <NUM> vildagliptin.

Metformin is usually given in doses varying from about <NUM> to <NUM>, particularly from <NUM> to <NUM> up to <NUM> per day using various dosage regimens.

A dosage range of the partner drug metformin is usually from <NUM> to <NUM> or <NUM> to <NUM> (<NUM>-<NUM> times a day), or from <NUM> to <NUM> once or twice a day.

The unit dosage strengths of the metformin hydrochloride for use in the present disclosure may be from <NUM> to <NUM> or from <NUM> to <NUM>, preferably from <NUM> to <NUM>. Particular dosage strengths may be <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> of metformin hydrochloride. These unit dosage strengths of metformin hydrochloride represent the dosage strengths approved in the US for marketing to treat type <NUM> diabetes. More particular unit dosage strengths of metformin hydrochloride for incorporation into the fixed dose combination pharmaceutical compositions of the present disclosure are <NUM>, <NUM> and <NUM> of metformin hydrochloride.

A dosage of the partner drug pioglitazone is usually <NUM>-<NUM>, <NUM>, <NUM>, or <NUM> once a day.

A dosage of the partner drug telmisartan is usually from <NUM> to <NUM> or <NUM> to <NUM> per day.

A dosage of the partner drug atorvastatin is usually from <NUM> to <NUM> or <NUM> to <NUM> once a day.

The amount of the DPP-<NUM> inhibitor and of the partner drug in the pharmaceutical composition according to this disclosure correspond to the respective dosage ranges as provided hereinbefore. For example, a pharmaceutical composition comprises <NUM>-[(<NUM>-methyl-quinazolin-<NUM>-yl)methyl]-<NUM>-methyl-<NUM>-(<NUM>-butyn-<NUM>-yl)-<NUM>-(<NUM>-(R)-amino-piperidin-<NUM>-yl)-xanthine in an amount of <NUM> to <NUM> (namely <NUM>, <NUM>, <NUM>, <NUM> or <NUM>) and of metformin hydrochloride in an amount of <NUM> to <NUM> (namely <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM>).

Specific embodiments of dosage strengths for <NUM>-[(<NUM>-methyl-quinazolin-<NUM>-yl)methyl]-<NUM>-methyl-<NUM>-(<NUM>-butyn-<NUM>-yl)-<NUM>-(<NUM>-(R)-amino-piperidin-<NUM>-yl)-xanthine and metformin hydrochloride in the fixed dose combinations of the present disclosure are the following:.

The particular fixed dose combinations of BI <NUM> and metformin of the present disclosure may be administered once or twice daily to the patient, in particular twice daily.

In a preferred aspect of the present disclosure, the present disclosure is directed to a pharmaceutical composition (especially an oral solid dosage form, particularly a tablet) comprising or obtainable from.

A particularly preferred DPP-<NUM> inhibitor to be emphasized within the meaning of this disclosure is <NUM>-[(<NUM>-methyl-quinazolin-<NUM>-yl)methyl]-<NUM>-methyl-<NUM>-(<NUM>-butyn-<NUM>-yl)-<NUM>-(<NUM>-(R)-amino-piperidin-<NUM>-yl)-xanthine free base (also known as BI <NUM>).

In particular, it has been found that L-arginine is effective as stabilizing agent for FDC combinations of <NUM>-[(<NUM>-methyl-quinazolin-<NUM>-yl)methyl]-<NUM>-methyl-<NUM>-(<NUM>-butyn-<NUM>-yl)-<NUM>-(<NUM>-(R)-amino-piperidin-<NUM>-yl)-xanthine free base with metformin HCl. Even after <NUM> months storage at accelerated conditions L-arginine is able to suppress degradation of <NUM>-[(<NUM>-methyl-quinazolin-<NUM>-yl)methyl]-<NUM>-methyl-<NUM>-(<NUM>-butyn-<NUM>-yl)-<NUM>-(<NUM>-(R)-amino-piperidin-<NUM>-yl)-xanthine free base effectively. The effect seems to be concentration dependent. Thus, L-arginine may act as stabilizing and buffering agent in the formulation.

In a more preferred aspect of the present disclosure, the present disclosure is directed to a pharmaceutical composition (especially an oral solid dosage form, particularly a tablet) comprising or made from.

Typical pharmaceutical compositions according to this disclosure comprise or are made by comprising combining any one of the following amounts (<NUM>), (<NUM>) or (<NUM>) of active ingredients and L-arginine:.

In a further aspect of the present disclosure, the present disclosure provides methods of manufacturing of the compositions, formulations, blends or dosage forms of this disclosure, such as e.g. by using methods known to one skilled in the art and/or in a manner as described herein, for example they may be obtained by processes comprising using (e.g. mixing, combining, blending and/or composing) the components and/or ingredients, or pre-mixtures thereof, mentioned hereinbefore and hereinafter, as well as the present disclosure further provides compositions, formulations, blends or dosage forms obtainable by these methods or processes and/or obtainable from the components, ingredients, pre-mixtures and/or mixtures mentioned hereinbefore and hereinafter.

In a further aspect of the present disclosure, the present disclosure provides a pharmaceutical composition, formulation, blend or dosage form of this disclosure which is substantially free of or only marginally comprises impurities and/or degradation products; that means, for example, that the composition, formulation, blend or dosage from includes about <<NUM>%, or about <<NUM>%, or about <<NUM>%, or less than about <NUM>%, preferably less than about <NUM>%, more preferably less than about <NUM>%, even more preferably less than about <NUM>% of any individual or total impurity or degradation product(s) by total weight, such as e.g. N-acetyl and/or N-carbamoyl derivative of the free base type DPP-<NUM> inhibitor. The content and/or degradation can be determined by well-known analytical methods, for example using HPLC methods.

In this context, in a further aspect of the present disclosure, the present disclosure provides derivatives of a DPP-<NUM> inhibitor having an amino group, particularly a free primary amino group, as mentioned herein, said derivatives being obtainable by acetylation of the amino group (e.g. to yield the group -NHC(O)CH<NUM>) or by carbamoylation of the amino group (e.g. to yield the group -NHC(O)NH<NUM>).

Dosage forms for the FDC formulations of this disclosure:
Another purpose of this disclosure is to develop the FDC formulations of this disclosure with a reasonable tablet size, with good tablet properties (e.g. stability, hardness, friability, disintegration, content uniformity and the like) and, in a preferred embodiment, without disturbing the original dissolution profiles of each mono tablet in case of desired proof of bioequivalence with minimized risk of failure.

Designing of the dosage form is an important matter not only to optimize the tablet size and dissolution profiles but also to minimize the amount of stabilizing agent, because the pH change by dissolving of buffering agent may affect the dissolution profiles of the DPP-<NUM> inhibitor or a partner drug. The selection of the dosage form is depending on the dose strengths of the active ingredients used and their physicochemical and solid state characteristics.

A conventional approach (i.e. physical separation) may not be useful for stabilization of certain DPP-<NUM> inhibitors of this disclosure. A buffering agent like L-arginine need to be added into the formulation for suppressing degradation, however it may be necessary to minimize the amount of L-arginine because its alkaline characteristics give a negative impact on the dissolution profiles or the stability of the DPP-<NUM> inhibitor or a partner drug.

Thus, it has been found that suitable dosage forms for the FDC formulations of this disclosure are film-coated tablets (film-coating for drug loading, such as particularly DPP-<NUM> inhibitor drug loading by film coating on tablet cores containing the partner drug), mono-layer tablets, bi-layer tablets, tri-layer tablets and press-coated tablets (e.g. tablet-in-tablet or bull's eye tablet with DPP-<NUM> inhibitor core) , which dosage forms are good measures to achieve the goal under consideration of desired pharmaceutical profiles and characteristics of a DPP-<NUM> inhibitor and a partner drug used.

Said dosage forms have been found to be applicable to the FDC formulations either keeping the original dissolution profiles of each mono tablet or adjusting the profiles to desired levels, e.g. including extended release characteristics, and a reasonable tablet size.

A typical mono-layer tablet of this disclosure comprises a DPP-<NUM> inhibitor, metformin hydrochloride, L-arginine, one or more fillers (such as e.g. corn starch), one or more binders (such as e.g. copovidone), one or more glidants (such as e.g. colloidal anhydrous silica) and one or more lubricants (such as e.g. magnesium stearate).

In a preferred embodiment of the present disclosure, the present disclosure is directed to an oral solid pharmaceutical composition, preferably a tablet, particularly a mono-layer tablet comprising or made from.

A method of manufacturing a tablet of this disclosure comprises tabletting (e.g. compression) of one or more final blends in form of granules. Granules of the (final) blend(s) according to this disclosure may be prepared by methods well-known to one skilled in the art (e.g. high shear wet granulation or fluid bed granulation). Granules according to this disclosure as well as details of granulation processes (including their separate steps) for the preparation of granules of this disclosure are described by way of example in the following examples.

An illustrative granulation process for the preparation of granules comprising the mono-layer composition comprises.

Preferentially, a mono-layer tablet according to this disclosure comprises or is obtainable from a mixture comprising any one of the following amounts (<NUM>), (<NUM>) or (<NUM>) of active ingredients and L-arginine:.

A typical bi-layer tablet of this disclosure comprises.

Preferentially, a bi-layer tablet according to this disclosure comprises or is obtainable from a mixture comprising any one of the following amounts (<NUM>), (<NUM>) or (<NUM>) of active ingredients and L-arginine:.

A typical press-coated tablet (tablet-in-tablet or bull's eye tablet) of this disclosure comprises.

Preferentially, a press-coated tablet (tablet-in-tablet or bull's eye tablet) according to this disclosure comprises or is obtainable from a mixture comprising any one of the following amounts (<NUM>), (<NUM>) or (<NUM>) of active ingredients and L-arginine:.

A typical film-coated tablet (DPP-<NUM> inhibitor coating on metformin HCl tablet, i.e. drug layering by film-coating for drug loading) of this disclosure comprises.

Preferentially, a film-coated tablet (DPP4-inhibitor drug loading) according to this disclosure comprises or is obtainable from a mixture comprising any one of the following amounts (<NUM>), (<NUM>) or (<NUM>) of active ingredients and L-arginine:.

Preferably, these abovementioned tablets (mono-, bi-layer, press-coated and drug-coated tablets) are further over-coated with a final film coat, which comprises a film-coating agent (such as e.g. hypromellose), a plasticizer (such as e.g. propylene glycol), pigments (such as e.g. titanium dioxide, iron oxide red and/or iron oxide yellow) and a glidant (such as e.g. talc). Typically this additional film over-coat may represent <NUM>-<NUM> %, preferentially <NUM>-<NUM> %, of the total mass of the composition.

The following dosage forms of the disclosure can be applied to the FDC formulation of <NUM>-[(<NUM>-methyl-quinazolin-<NUM>-yl)methyl]-<NUM>-methyl-<NUM>-(<NUM>-butyn-<NUM>-yl)-<NUM>-(<NUM>-(R)-amino-piperidin-<NUM>-yl)-xanthine free base (Bl <NUM>) and metformin hydrochloride based on the characteristics of drug substances and requirements of the desired pharmaceutical profiles:.

Mono-layer tablets with L-arginine show satisfactory stability results, good dissolution properties and good content uniformity (CU). Mono-layer tablets can be manufactured using conventional technologies (including fluid-bed granulation for the DPP-<NUM> inhibitor and metformin hydrochloride, e.g. comprising adding the DPP-<NUM> inhibitor as powder or as an aqueous suspension in the granulation liquid to the fluid bed granulator).

Bi-layer tablets with L-arginine show promising stability results, good dissolution properties and good CU. Bi-layer tablets can be manufactured using conventional bi-layer tableting technologies (e.g. rotary bi-layer tableting machine).

Press-coated tablets (tablet-in-tablets and advanced press-coated bull's eye tablets) show promising stability, good CU and dissolution. Press-coated tablets can be manufactured using conventional press-coating technology, such as e.g. on a Kilian tablet press to obtain tablet-in-tablet or on other conventional press-coater to obtain bull's eye tablet. As an advantage of this approach, it is easy to minimize the amount of L-arginine in the formulation and control the assay and CU of the DPP-<NUM> inhibitor portion (very small amount of drug loading; <NUM>/tablet where the dose strengths of metformin HCl are <NUM>, <NUM> and <NUM>/tablet). Another advantage is that DPP-<NUM> inhibitor- and metformin HCl- portion can be designed flexibly to minimize the tablet size. A modified press-coated tablet named "bull's eye tablet" may be a universal dosage potentially for bi-layer tablets as well as other FDC. Bull's eye tablet can be manufactured in a one-step press-coating without separate core formation (like in bi-layer tableting) being necessary.

It is to be noted that within the meaning of this disclosure the skilled person is aware about what is meant with the phrase "bull's eye tablet" used herein. As it known to the skilled person, this tablet (also referred to as an inlay tablet or a dot) is composed of an outer coat and an inner core, and in which, instead of the inner core zone being completely surrounded by the outer coat, one surface of the zone corresponding to the inner core zone is exposed.

Coating of DPP-<NUM> inhibitor drug substance on the metformin HCl tablets shows acceptable dissolution results and promising stability data. L-arginine needs to be added into film-coating for stabilization. As an advantage for this approach, it is possible to integrate DPP-<NUM> inhibitor portion into a partner drug portion as it is, even if the dosage form is a modified/controlled release formulation. Within the film-coating process coating endpoint determination is necessary via analytics.

The method of layering of the DPP-<NUM> inhibitor by film-coating as described herein (including the steps of seal-coating, drug-loading and, optional, over-coating) may be applied to any kind of cores or tablets which may comprise an active ingredient (e.g. a partner drug as mentioned herein), for example metformin cores or tablets, such as e.g. immediate release metformin tablets, sustained release metformin tablets, extended release metformin tablets, modified release metformin tablets, controlled release metformin tablets or delayed release metformin tablets. Thus, the present disclosure further relates to a tablet which comprises a film-coat layer comprising the DPP-<NUM> inhibitor, a film-forming agent (e.g. hypromellose), a plasticizer (e.g. propylene glycol) and L-arginine, or which is obtainable by comprising using such a method of layering of the DPP-<NUM> inhibitor by film-coating as described herein. The present disclosure also relates to a FDC tablet comprising an immediate or extended release metformin tablet core, a seal coat, a film-coat layer comprising the DPP-<NUM> inhibitor, and, optionally, an over-coat; e.g. each as described herein, as well as to such a FDC tablet made by a process comprising the following steps of seal-coating on a metformin tablet core, layering of a DPP-<NUM> inhibitor by film-coating and, optional, over-coating, e.g. each step such as described herein.

Pharmaceutical immediate release dosage forms of this disclosure preferably have dissolution properties such that after <NUM> minutes for each of the active ingredients at least <NUM> %, even more preferably at least <NUM> % by weight of the respective active ingredient is dissolved. In a particular embodiment, after <NUM> minutes for each of the active ingredients especially of the mono-layer tablet according to this disclosure (including tablet core and film-coated tablet) at least <NUM>-<NUM> % (preferably at least <NUM> %) by weight of the respective active ingredient is dissolved. In a further embodiment, after <NUM> minutes for each of the active ingredients especially of the mono-layer tablet according to this disclosure (including tablet core and film-coated tablet) at least <NUM>-<NUM> % by weight of the respective active ingredient is dissolved. The dissolution properties can be determined in standard dissolution tests, e.g. according to standard pharmacopeias (e.g. using paddle method with agitation speed of <NUM> rpm, <NUM> hydrochloric acid as dissolution medium at a temperature of <NUM>, and HPLC (Bl <NUM>) and UV (metformin) analysis of the samples).

In the pharmaceutical compositions and pharmaceutical dosage forms according to the disclosure BI <NUM>, for example a crystalline form thereof, preferably has a particle size distribution (preferably by volume) such that at least <NUM> % of the respective active pharmaceutical ingredient has a particle size smaller than <NUM>, i.e. X90 < <NUM>, more preferably X90 ≤ <NUM>. More preferably the particle size distribution is such that X90 ≤ <NUM>, even more preferably X90 ≤ <NUM>. In addition the particle size distribution is preferably such that X90 > <NUM>, more preferably X90 ≥ <NUM>, most preferably X90 ≥ <NUM>. Therefore preferred particle size distributions are such that <NUM> < X90 < <NUM>, particularly <NUM> < X90 ≤ <NUM>, more preferably <NUM> ≤ X90 ≤ <NUM>, even more preferably <NUM> ≤ X90 ≤ <NUM>. A preferred example of a particle size distribution of BI <NUM> is such that X90 ≤ <NUM> or <NUM> ≤ X90 ≤ <NUM>. It can be found that a pharmaceutical composition comprising BI <NUM> with a particle size distribution as indicated hereinbefore shows desired properties (e.g. with regard to dissolution, content uniformity, production, or the like). The indicated particle size properties are determined by laser-diffraction method, in particular low angle laser light scattering, i.e. Fraunhofer diffraction. Alternatively, the particle size properties can be also determined by microscopy (e.g. electron microscopy or scanning electron microscopy). The results of the particle size distribution determined by different techniques can be correlated with one another.

Another purpose of this disclosure is to provide improved formulations of the metformin HCl portion of the pharmaceutical compositions according to this disclosure.

For the metformin HCl part a high drug load is advantageous to be achieved as a pre-requisite for a reasonable small tablet size.

Thus, it has been found that drug load of metformin HCl and compactability (compression force-crushing strength profile) of the tablets of this disclosure can be improved by surface treatment of metformin HCl with a water-soluble polymer, particularly copolyvidone.

Several water-soluble polymers including polyvinyl alcohol (PVA), hypromellose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose (MC), Povidone (PVP) and copolyvidone may be tested to improve compactability (compression force-crushing strength profile). As the results, PVA shows the best effect in terms of compactability but the manufacturability can be poor due to sticking problem during fluid-bed granulation. Further on, PVA may be not finally selected because of its negative impact on the stability of certain DPP-<NUM> inhibitors of this disclosure.

Formulation optimization studies have identified a composition with over <NUM>% drug load of metformin HCl and improved crushing strength by surface-treatment of metformin HCl with the water-soluble polymer copolyvidone.

Therefore, finally, copolyvidone is selected and the amount can be optimized, advantageously resulting in stable formulations and the viscosity of the granulating solution is enough low to prepare the aqueous solution and operate spraying by a fluid-bed granulator.

In optional addition, it has been found that heating/drying of metformin HCl drug substance is effective to improve the stability of certain DPP-<NUM> inhibitors of this disclosure in combination with metformin HCl. The pre-treatment for metformin HCl needs to be conducted before starting of granulation with the DPP-<NUM> inhibitor. The heating/drying at <NUM> with a fluid-bed granulator may be helpful to reduce an excessive amount of volatile impurities (which might be urea) in the metformin HCl.

The present disclosure is not to be limited in scope by the specific embodiments described herein. Various modifications of the disclosure in addition to those described herein may become apparent to those skilled in the art from the present disclosure.

Further embodiments, features and advantages of the present disclosure may become apparent from the following examples. The following examples serve to illustrate, by way of example, the principles of the disclosure without restricting it.

The composition of mono-layer tablets for a DPP-<NUM> inhibitor of this disclosure (Bl <NUM>) + metformin HCl FDC (Film-coated Tablets) is shown in Table <NUM>.

DPP-<NUM> inhibitor of this disclosure (e.g. BI <NUM>) + metformin HCl FDC mono-layer tablets are produced by a fluid-bed granulation process and a conventional tableting process with a rotary press. Optionally, metformin HCl and corn starch may be pre-treated by heating in a chamber of fluid-bed granulator to remove excessive HCl and/or impurity products before mixing with the active DPP-<NUM> inhibitor ingredient. After the optional pre-treatment of metformin HCl and corn starch, the DPP-<NUM> inhibitor is either added as powder and premixed before fluid-bed granulation is conducted by spraying of "Granulation Liquid" composed of copolyvidon (Kollidon VA64), L-arginine and purified water, or directly dispersed in the "granulation liquid". After finishing of fluid-bed granulation, the granulate is sieved with a suitable screen. The sieved granulate is blended with colloidal anhydrous silica (Aerosil <NUM>) 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, containing hypromellose as film-forming agent, propylene glycol as plasticizer, talc as glidant and the pigments yellow iron oxide and/or red iron oxide and titanium dioxide.

Narrative more specific description of the preferred manufacturing process for the mono-layer tablets:.

Narrative more specific description of an alternative manufacturing process for the mono-layer tablets:.

The composition of bi-layer tablets for a DPP-<NUM> inhibitor of this disclosure (Bl <NUM>) + metformin HCl FDC (Film-coated Tablets) is shown in Table <NUM>.

DPP-<NUM> inhibitor of this disclosure (e.g. BI <NUM>) + metformin HCl FDC bi-layer tablets are produced by a high-shear wet granulation process (for DPP-<NUM> inhibitor-granulate), a fluid-bed granulation process (for metformin HCl-granulate), and bi-layer tableting process with a multilayer rotary press.

DPP-<NUM> inhibitor-granulate: By using a high-shear granulator the active DPP-<NUM> inhibitor ingredient is pre-mixed with the diluents D-mannitol and pregelatinized starch. The mixture is moistened with granulating liquid, containing purified water and copovidone as a binder. After further mixing, drying and sieving, the dried granulate is blended with magnesium stearate as a lubricant.

Narrative more specific description of the manufacturing process for the BI <NUM>-granulate:.

Metformin HCl-granulate: Metformin HCl and corn starch are pre-treated by heating in a chamber of fluid-bed granulator to remove excessive HCl and/or impurity products. After the pre-treatment of metformin HCl and corn starch, fluid-bed granulation is conducted by spraying of "Granulation Liquid" composed of copolyvidon (Kollidon VA64) and purified water. After finishing of fluid-bed granulation, the granulate is sieved with a suitable screen. The sieved granulate is blended with colloidal anhydrous silica (Aerosil <NUM>) and magnesium stearate as a lubricant.

Narrative more specific description of the manufacturing process for the Metformin HCl-granulate:.

The "Final Blend A" and "Final Blend B" are compressed into bi-layer tablets using a multilayer rotary press. The tablet cores may be film-coated by an aqueous film-coating suspension, containing hypromellose as film-forming agent, propylene glycol as plasticizer, talc as glidant and the pigments yellow iron oxide and/or red iron oxide and titanium dioxide.

Narrative more specific description of the manufacturing process for the film-coating:.

The composition of Tablet-in-Tablet or Bull's eye tablets for a DPP-<NUM> inhibitor of this disclosure (Bl <NUM>) + metformin HCl FDC (Film-coated Tablets) is shown in Table <NUM>.

DPP-<NUM> inhibitor of this disclosure (e.g. BI <NUM>) + metformin HCl FDC Tablet-in-Tablet or Bull's eye tablets are produced by a high-shear wet granulation process (for DPP-<NUM> inhibitor-granulate), a rotary press (for DPP-<NUM> inhibitor core-tablet), a fluid-bed granulation process (for metformin HCI-granulate), and press-coating process with a press-coater.

Narrative more specific description of the manufacturing process for the BI <NUM> core-tablets:.

The "DPP-<NUM> inhibitor core-tablets" and "Metformin HCl-granulate" are compressed into Tablet-in-Tablet or Bull's eye tablets using a press-coater. The difference between the Tablet-in-Tablet and Bull's eye tablet is the position of the core tablet.

Narrative more specific description of the manufacturing process for the Tablet-in-Tablet:.

Narrative more specific description of the manufacturing process for the Bull's eye tablets:.

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

The composition of a DPP-<NUM> inhibitor of this disclosure (Bl <NUM>) + metformin HCl FDC (Film-coated Tablets) which are prepared by drug loading by film-coating on the Metformin HCl Tablet is shown in Table <NUM>.

DPP-<NUM> inhibitor (e.g. BI <NUM>) + metformin HCl FDC with drug coating is produced by a fluid-bed granulation process, a conventional tableting process, and film-coating process with three steps: seal-coating, drug-loading and over-coating. The over-coating may be able to be skipped by combining with the drug-loading, if the stability is acceptable.

Metformin HCl Tablets: Metformin HCl and corn starch are pre-treated by heating in a chamber of fluid-bed granulator to remove excessive HCl and/or impurity products. After the pre-treatment of metformin HCl and corn starch, fluid-bed granulation is conducted by spraying of "Granulation Liquid" composed of copolyvidon (Kollidon VA64) and purified water. After finishing of fluid-bed granulation, the granulate is sieved with a suitable screen. The sieved granulate is blended with colloidal anhydrous silica (Aerosil <NUM>) and magnesium stearate as a lubricant. The final blend is compressed into the tablets with a conventional rotary press.

Film-coating: The tablets are film-coated by (<NUM>) seal-coating: by an aqueous film-coating suspension, containing hypromellose as film-forming agent, propylene glycol as plasticizer, talc as glidant and the pigments yellow iron oxide and/or red iron oxide and titanium dioxide, (<NUM>) drug-loading: by an aqueous film-coating suspension, containing hypromellose as film-forming agent, propylene glycol as plasticizer, BI <NUM> as drug substance, and L-arginine as stabilizer, and (<NUM>) over-coating: by an aqueous film-coating suspension, containing hypromellose as film-forming agent, propylene glycol as plasticizer, talc as glidant and the pigments yellow iron oxide and/or red iron oxide and titanium dioxide,.

Narrative more specific description of the manufacturing process for the film-coating with a coating machine:.

The product description of BI <NUM> + Metformin HCl FDC mono-layer tablets (tablet core and film-coated tablets) is shown in Table <NUM> and Table <NUM>, respectively.

Stability data of BI <NUM> + Metformin HCl FDC mono-layer tablets (tablet core) with or without L-arginine is shown in the following tables (over <NUM> weeks, <NUM> month and <NUM> months):.

Claim 1:
A pharmaceutical composition comprising or made from a DPP-<NUM> inhibitor which is <NUM>-[(<NUM>-methyl-quinazolin-<NUM>-yl)methyl]-<NUM>-methyl-<NUM>-(<NUM>-butyn-<NUM>-yl)-<NUM>-(<NUM>-(R)-amino-piperidin-<NUM>-yl)-xanthine free base, a partner drug which is metformin hydrochloride, and one or more pharmaceutical excipients, and a nucleophilic and/or basic agent for stabilizing said DPP-<NUM> inhibitor against degradation,
wherein the nucleophilic and/or basic agent is a basic amino acid having an intramolecular amino group and alkaline characteristics, which is L-arginine,
wherein the pharmaceutical composition is in the dosage form of a mono-layer tablet which comprises or is obtainable from a mixture comprising any one of the following amounts (<NUM>), (<NUM>) or (<NUM>) of active ingredients and L-arginine:
(<NUM>) <NUM> of <NUM>-[(<NUM>-methyl-quinazolin-<NUM>-yl)methyl]-<NUM>-methyl-<NUM>-(<NUM>-butyn-<NUM>-yl)-<NUM>-(<NUM>-(R)-amino-piperidin-<NUM>-yl)-xanthine free base, <NUM> metformin hydrochloride, and <NUM> L-arginine;
(<NUM>) <NUM> of <NUM>-[(<NUM>-methyl-quinazolin-<NUM>-yl)methyl]-<NUM>-methyl-<NUM>-(<NUM>-butyn-<NUM>-yl)-<NUM>-(<NUM>-(R)-aminopiperidin-<NUM>-yl)-xanthine free base, <NUM> metformin hydrochloride, and <NUM> L-arginine;
(<NUM>) <NUM> of <NUM>-[(<NUM>-methyl-quinazolin-<NUM>-yl)methyl]-<NUM>-methyl-<NUM>-(<NUM>-butyn-<NUM>-yl)-<NUM>-(<NUM>-(R)-aminopiperidin-<NUM>-yl)-xanthine free base, <NUM> metformin hydrochloride, and <NUM> L-arginine;
with the disclaimer that the mono-layer tablet does not comprise a film coat.