A tablet of linagliptin and metformin

Abstract

A single-layer tablet comprising linagliptin, or a pharmaceutically acceptable salt thereof, metformin hydrochloride, a diluent, a glidant and a lubricant, wherein the tablet is produced by direct compression.

Description

[0001] A TABLET OF LINAGLIPTIN AND METFORMIN

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a tablet composition comprising linagliptin and metformin hydrochloride and to the process for the preparation of the said composition. The composition of linagliptin and metformin hydrochloride is indicated in adults with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control.

[0004] BACKGROUND OF THE INVENTION

[0005] Linagliptin is a dipeptidyl peptidase IV (DPP-IV) inhibitor with the chemical name 1 - [(4-methyl-quinazolin-2-yl)- methyl]-3-methyl-7-(2-butyn-l -yl)-8-(3-(R)- aminopiperidin-1-yl)-xanthine. Linagliptin is marketed as Trajenta®. Linagliptin is also marketed in combination with metformin hydrochloride. Metformin has the chemical name N,N-dimethylbiguanide and belongs to the biguanide class of compounds. The combination of linagliptin with metformin has the brand name Jentadueto® and it is indicated in adults with type 2 diabetes mellitus. Tablets of Jentadueto® are available in different strengths of linagliptin and metformin hydrochloride such as 2.5mg / 500 mg, 2.5mg / 850 mg and 2.5mg / 1000 mg.

[0006] Compositions containing DPP-IV inhibitors are challenging as DPP-IV inhibitors with a primary or secondary amino group show incompatibilities with several standard excipients. The amino group appears to react with reducing sugars and with other reactive groups such as carbonyl or carboxylic acid functional groups of certain excipients.

[0007] Though the DPP-IV inhibitors themselves are very stable, they may react with incompatible antidiabetic compounds or their impurity products while preparing fixed combinations. The DPP-IV inhibitors may also react with many excipients used in solid dosage forms and with impurities of excipients, especially when in tight contact provided in tablets and at high excipient / drug ratios. These unforeseen difficulties are primarily observed in low dosage ranges of the DPP- 4 inhibitor used, in view of its high potency, and / or high dosage ranges of the incompatible antidiabetic compounds used. Thus, formulation development of a combination of linagliptin and metformin requires formulators to solve these technical problems, which may be associated with high potency of linagliptin.

[0008] European patent application EP2285410 discloses a pharmaceutical composition comprising linagliptin, metformin and one or more pharmaceutical excipients, and a nucleophilic and / or basic agents for stabilizing said DPP-IV inhibitor, linagliptin, against degradation.

[0009] EP’410 exemplifies use of a basic amino acid, L-arginine, to overcome the incompatibility issues and poor stability, which may be caused by reaction of linagliptin when combined with metformin hydrochloride, or its impurity product and / or a pharmaceutical excipient having incompatible functional groups. Using a suitable nucleophilic and / or basic agent (e.g., a buffering and / or pH modifying agent) in pharmaceutical compositions helps in protecting the decomposition and degradation of linagliptin.

[0010] PCT application WO2015 / 107536 discloses a combination of linagliptin and metformin HCI without any basic amino acid or stabilizer. The ‘536 application exemplifies fixed combination of linagliptin and metformin hydrochloride using copovidone leading however to higher amounts of total impurities of linagliptin.

[0011] European patent application 3456319 discloses a combination of linagliptin and metformin HCI in intimate admixture with a stearate.

[0012] The inventors of the present invention surprisingly found a chemically stable tablet composition comprising a combination of linagliptin and metformin HCI that overcomes the above-mentioned problems.

[0013] SUMMARY OF THE INVENTION

[0014] The present invention provides a single-layer tablet comprising

[0015] (a) metformin hydrochloride; (b) linagliptin, or a pharmaceutically acceptable thereof; and

[0016] (c) a pharmaceutically acceptable diluent, a pharmaceutically acceptable glidant and a pharmaceutically acceptable lubricant, wherein the tablet is produced by a direct compression process.

[0017] The direct compression process for the preparation of the tablet of the present invention comprises the following steps: i) obtaining metformin hydrochloride particles comprising from 1.5 wt% to 3.0 wt% water, ii) mixing linagliptin, or a pharmaceutically acceptable salt thereof with at least one of the diluent, the glidant, and the lubricant, iii) mixing metformin hydrochloride particles obtained in i) with the mixture obtained in ii), iv) optionally, adding to the mixture obtained in iii) a pharmaceutically acceptable excipient, and v) compressing into a tablet.

[0018] The tablet of the present invention exhibits excellent stability of both active ingredients. Furthermore, the tablet of the present invention exhibits fast dissolution of both active ingredients from the tablet.

[0019] DETAILED DESCRIPTION OF THE INVENTION

[0020] The present invention provides a single-layer tablet of linagliptin and metformin hydrochloride.

[0021] Specifically, the present invention provides a tablet of linagliptin and metformin hydrochloride which does not have to contain stabilizers of the active ingredients, such as those disclosed in the prior art.

[0022] More specifically, the present invention provides a tablet of linagliptin and metformin hydrochloride which does not have to comprise a basic amino acid, a stabilizer of the active ingredients and / or a binder selected from povidone and copovidone.

[0023] Thus, the present invention provides a single-layer tablet comprising (a) metformin hydrochloride;

[0024] (b) linagliptin or a pharmaceutically acceptable thereof; and

[0025] (c) a pharmaceutically acceptable diluent, a pharmaceutically acceptable glidant and a pharmaceutically acceptable lubricant, wherein the tablet is produced by a direct compression process comprising i) obtaining metformin hydrochloride particles comprising from 1.5 wt.% to 3.0 wt.% water, ii) mixing linagliptin, or a pharmaceutically acceptable salt thereof with at least one of a pharmaceutically acceptable diluent, a pharmaceutically acceptable glidant and a pharmaceutically acceptable lubricant, iii) mixing metformin hydrochloride particles obtained in i) with the mixture obtained in ii), iv) optionally, adding to the mixture obtained in iii) a pharmaceutically acceptable excipient and v) compressing into a tablet.

[0026] The present inventors have found that a tablet which comprises linagliptin, or a pharmaceutically acceptable salt thereof and metformin hydrochloride and is produced by direct compression, exhibits excellent physical properties and stability of the both ingredients and fast dissolution of both active ingredients from the tablet.

[0027] Furthermore, the present inventors have found that the water content of metformin hydrochloride which is used for the manufacture of the tablet affects significantly the physical properties of both the powder blend before the compression and the produced tablet. For example, it was found that when metformin hydrochloride which is used for the preparation of the tablet comprises from 1 .5 wt % to 3.0 wt % water, the flowability and compressibility of the blend before the compression are better than when the water content of metformin hydrochloride which is used for the preparation of the tablet is outside the above range. It was also found that the properties of the produced tablet are significantly better than when the water content of metformin hydrochloride which is used for the preparation of the tablet is outside the above range.

[0028] According to the present invention, when the initial water content of metformin hydrochloride is lower than 1.5 wt %, metformin hydrochloride is mixed with water in order to achieve water content from 1.5 wt % to 3.0 wt %. When the initial water content of metformin hydrochloride is higher than 3.0 wt %, water is removed, for example, by drying, in order to achieve water content from 1 .5 wt % to 3.0 wt %. After the desired water content is obtained, metformin hydrochloride is used in the preparation of the tablet of the present invention.

[0029] Preferably, metformin hydrochloride which is used for the preparation of the tablet comprises form 1 .8 wt % to 2.5 wt % water.

[0030] The water content can be determined by methods well known in the art. For example, the water content can be determined by the Karl Fischer method.

[0031] Preferably, mixing of linagliptin, or a pharmaceutically acceptable salt thereof, with one or more of a diluent, a glidant and a lubricant, i.e., step ii) of the process of the present invention, is carried out by performing a geometric dilution. Preferably, mixing of metformin hydrochloride with the mixture of linagliptin, or a pharmaceutically acceptable salt thereof with at least one of a diluent, a glidant and a lubricant, i.e., step iii) of the process of the present invention, is carried out by performing a geometric dilution. More preferably, both step ii) and step iii) of the process of the present invention are carried out by performing a geometric dilution. Geometric dilution leads to improved uniformity of the resulting blend.

[0032] Preferably, in step ii) of the process of the present invention, linagliptin, or a pharmaceutically acceptable salt thereof, is mixed with a diluent and a glidant.

[0033] Preferably, the tablet of the present invention is film coated. In such a case, after the compression of step iv) of the above process, the tablet is coated. When coating is present, it is preferably non-functional.

[0034] Linagliptin, or a pharmaceutically acceptable salt thereof, may be used in crystalline or amorphous form. Preferably, the tablet of the present invention comprises linagliptin form A, or linagliptin form B, or a mixture of form A and form B. Linagliptin form A and linagliptin form B are disclosed in European patent application No. EP2016079 A1. The D90 by volume of linagliptin, or of a pharmaceutically acceptable salt thereof which is used in the preparation of the tablet of the present invention is preferably less than 200 pm (microns), more preferably, less than 50 microns, as measured by laser light diffraction as described in European Pharmacopoeia (EP) 11thEdition 2.9.31.

[0035] Metformin hydrochloride may be used in crystalline or amorphous form. The D90 by volume of metformin hydrochloride which is used in the preparation of the tablet of the present invention is preferably less than 400 microns, as measured by laser light diffraction as described in EP 11thEdition 2.9.31.

[0036] The term “D90 by volume” means that 90% of the volume of the particles have a diameter which is less than the specified diameter.

[0037] The weight ratio of metformin hydrochloride to linagliptin, or to a pharmaceutically acceptable salt thereof, in the tablet is preferably from 100:1 to 500:1.

[0038] Specific embodiments of tablet of linagliptin and metformin hydrochloride according to the present invention may be as follows -

[0039] (1) 2.5 mg of linagliptin and 500 mg metformin hydrochloride;

[0040] (2) 2.5 mg of linagliptin and 850 mg metformin hydrochloride;

[0041] (3) 2.5 mg of linagliptin and 1000 mg metformin hydrochloride.

[0042] The tablet of linagliptin and metformin hydrochloride of the present invention may be administered once or twice daily to the patient, preferably twice daily.

[0043] Examples of pharmaceutically acceptable diluents which can be used in the tablet of the present invention include calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose anhydrous, lactose monohydrate, lactose dihydrate, lactose trihydrate, mannitol sorbitol, starch, pregelatinized starch, sucrose, talc, xylitol, maltose maltodextrin and maltitol.

[0044] Examples of pharmaceutically acceptable glidants which can be used in the tablet of the present invention include calcium silicate, powdered cellulose, starch, talc, colloidal silicon dioxide and magnesium trisilicate. Examples of pharmaceutically acceptable lubricants which can be used in the tablet of the present invention include magnesium stearate, stearic acid, sodium stearyl fumarate, magnesium lauryl sulphate, talc, polyethylene glycol and glyceryl behenate.

[0045] The tablet of the present invention may include one or more additional pharmaceutically acceptable excipients, such as fillers binders, disintegrants, sweeteners, antioxidants, anti-adherents, plasticizers, colouring agents, flavouring agents, or one or more surfactants.

[0046] Suitable fillers may be selected, for example, from at starch derivatives, such as corn starch, potato starch or rice starch; polysaccharides such as dextrins, maltodextrins, dextrates, microcrystalline cellulose, powdered cellulose, mixtures of microcrystalline cellulose and guar gum, co-processed blends of microcrystalline cellulose; and polyhydric alcohols, such as xylitol and sorbitol.

[0047] Suitable binders may be selected, for example, from acacia, alginic acid, carbomer, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, sodium alginate, starch paste, pregelatinized starch, sucrose, tragacanth, low-substituted hydroxypropyl cellulose, glucose and sorbitol.

[0048] Suitable disintegrants may be selected, for example, from alginic acid, carbon dioxide, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, croscarmelose sodium, crospovidone, sodium docusate, guar gum, hydroxypropyl cellulose, methylcellulose, polacrilin potassium, poloxamer, sodium alginate, sodium glycine carbonate, sodium starch glycolate, starch, pregelatinized starch and low-substituted hydroxypropyl cellulose.

[0049] Suitable sweeteners may be selected, for example, from sugars, such as sucrose and glucose; cyclamate and salts thereof; saccharin and salts thereof; and aspartame.

[0050] Suitable flavouring agents may be selected, for example, from natural or synthetic flavours such as strawberry flavour, wild cherry flavour, green apple flavour, spearmint flavour, and peppermint flavour. Suitable colouring agents may be selected, for example, from dyes such as: FD&C red #4, FD&C yellow #5; pigments such as: iron oxides (red, yellow, etc), Titanium dioxide, calcium carbonate; Lakes such as indigo, Aluminum Lakes and the like.

[0051] Suitable surfactants may be selected, for example, from sodium lauryl sulfate, copolymers of poly(ethylene oxide) and polypropylene oxide) (commercially called Poloxamers or Poloxamines), Polysorbates such as Tween® 20, Tween® 80 and the like.

[0052] Suitable stabilizers may be selected, for example, from antioxidants, ascorbic acid, citric acid, phosphoric acid, BHT, BHA and the like.

[0053] Suitable plasticizers may be selected, for example, from polysorbate 80, polyethylene glycol, propylene glycol, hydroxypropyl cellulose and the like.

[0054] Suitable anti-adherents may be selected, for example, from talc, polyethylene glycol, hydrogenated castor oil, glyceryl behenate and the like.

[0055] Preferably, the tablet of the present invention is free of a basic amino acid, a stabilizer of the active ingredients and a binder selected from povidone and copovidone.

[0056] The tablet of the present invention exhibits fast dissolution of both active ingredients. Thus, the dissolution of both metformin and linagliptin from the tablet of the present invention is preferably at least 50% after 30 minutes, when the tablet is subjected to dissolution tests at pH range from 1.2 to 6.8 at 37° C ± 0.5°C using a USPII paddle apparatus with stirring speed of 50 rpm. More preferably, the dissolution of both metformin and linagliptin from the tablet of the present invention is at least 80% after 30 minutes, when the tablet is subjected to dissolution tests at pH range from 1.2to 6.8 at 37° C ± 0.5°C using a USPII paddle apparatus with stirring speed of 50 rpm. Even more preferably, the dissolution of both metformin and linagliptin from the tablet of the present invention is at least 90% after 30 minutes, when the tablet is subjected to dissolution tests at pH range from 1.2to 6.8 at 37° C ± 0.5°C using a USPII paddle apparatus with stirring speed of 50 rpm. Furthermore, the tablet of the present invention exhibits excellent stability of both active ingredients. Furthermore, the tablet of the present invention exhibits excellent physical properties, such as friability.

[0057] EXAMPLES

[0058] EXAMPLE 1

[0059] Tablet 1 is a tablet according to the present invention.

[0060] Tablets 2-4 are comparative examples in which the water content of metformin hydrochloride which was used in the preparation of the tablets lies outside the claimed range. The water content of metformin hydrochloride that was used in the preparation of the tablets was determined by the Karl Fischer method described in EP, 11thedition, section 2.5.12. The Loss on drying (LOD) was determined by the method described in EP, 11thedition, section 2.2.32 (d), by using a Thermo balance.

[0061] The above tablets were prepared using the following process: Step 1 : Metformin hydrocloride is processed to achieve the desired water content.

[0062] Step 2: Linagliptin, MCC 102 and Colloidal silicon dioxide (Aerosil 200) is mixed with the blend obtained from Step 1 as described in detail in the following Example 3. Step 3: Lubrication: Sieving of Magnesium Stearate (#60mesh) and mixing.

[0063] Step 4: Compression.

[0064] Step 5: Coating.

[0065] EXAMPLE 2

[0066] This example shows the physical attributes of the tablets of Example 1 and the physical attributes of the corresponding powders

[0067] Flowability refers to the flowability of the mixture subjected to compression.

[0068] ** Compressibility was evaluated with Hausner Ratio

[0069] The above results show that in Tablets 2 & 3 with lower water content values (< 1.5%), although the powders exhibit good flowability behavior, during the compression runtime, capping appears at the tablets. Furthermore, the tablets of Examples 2 & 3 failed the friability test. On the other hand, the powder of Tablet 4 with higher water content value (>3%) exhibits bad flowability and “rat holing” in the funnel during compression.

[0070] EXAMPLE 3

[0071] This example shows the geometric dilution used in the preparation of the tablets of Example 1 . Mixing I

[0072] (a) MCC 102 & Aerosil (Mixture A) are sifted and then mixed for 2-5 min,

[0073] (b) Add Linagliptin (optionally sieved) with equal quantity of above Mixture A. (i.e., weight ratio of linagliptin to Mixture A 1 :1) in three steps in the following manner: i) Linagliptin is combined with equal weight of Mixture A and the mixture is mixed for 5 minutes. ii) The resulting mixture of i) is combined with equal weight of Mixture A and the mixture is mixed for 5 minutes. iii) The resulting mixture of ii) is combined with equal weight of Mixture A and the mixture is mixed for 5 minutes.

[0074] Mixing II

[0075] (c) The remaining amount of Mixture A is added to Metformin [Mixture B],

[0076] (d) Mixture B is sifted and then mixed for 10 min,

[0077] (e) The resulting mixture of Mixing I (Linagliptin + ~5% of MCC 102 / Aerosil) is mixed with geometric dilution as described below with Mixture B (remaining mixture A (-95%) + Metformin) (initial weight ratio 1 :10, repeat 3 times): i) Mixing I is combined 10-fold amount of Mixture B after sieving and the mixture is mixed for 5-10 minutes, ii) The resulting mixture of step i) is combined with 2-fold quantity of Mixture B after sieving and the mixture is mixed for 5-10 min, iii) The resulting mixture of step ii) is combined with the remaining amount of Mixture B after sieving and the mixture is sieved for 120 min.

[0078] The content uniformity of the resulting blend falls well within the limits of 90% - 110%. The blend was subjected to lubrication and compression as described in Example 1. When all the ingredients of the tablets of Example 1 are sifted and mixed without geometric dilution, the content uniformity of the resulting lies outside the range of 90% - 110%, even after 120 minutes of mixing.

[0079] The above results show that when geometric dilution is used for mixing linagliptin with a pharmaceutical excipient, as well as for mixing of metformin with the linagliptin / excipient mixture, the content uniformity of the resulting blend is better, compared to the content uniformity of a blend which is obtained by mixing the same ingredients without geometric dilution. EXAMPLE 4

[0080] This example shows the dissolution of the two active ingredients from Tablet 1 of Example 1 (a tablet of the present invention) and from the Reference Listed Drug (RLD), which is the commercially available Jentadueto® tablet in various media. The qualitative composition of Jentadueto® tablet is shown in the table below.

[0081] Dissolution profiles in comparison with the reference listed drug (RLD) in the different media are shown in the tables below.

[0082] HCI 0.1 N = pH 1.2 pH 4.5 pH 6.8

[0083] The above results show that the tablet of the present invention exhibits excellent dissolution of both active ingredients in a wide pH range. EXAMPLE 5

[0084] This example shows the stability of the two active ingredients in Tablet 1 of Example 1 (a tablet of the present invention) and in the Reference Listed Drug (RLD), which is the commercially available Jentadueto® tablet. The qualitative composition of Jentadueto® tablet is shown in Example 4.

[0085] LIMITS

[0086] METFORMIN

[0087] Known impurities < 0.15 % highest individual unspecified impurity < 0.10 %

[0088] LINAGLIPTIN

[0089] Known impurities < 1.00 % highest individual unspecified impurity < 0.40 %

[0090] Total impurities < 3.0 % (TBD)

[0091] The table below shows the dissolution profile of Tablet 1 of Example 1 after storage of 3 months at 40 °C and 75% relative humidity (RH).

[0092] The above results show that tablet of the present invention is stable for 3 months at 40 °C I 75% RH. The % maximum known and unknown impurities of linagliptin and metformin hydrochloride are well below the standard limits. Furthermore, the stability of the tablet of the present invention is better than the stability of Jentadueto® tablet.

Claims

CLAIMS1. A single-layer tablet comprising(a) metformin hydrochloride;(b) linagliptin or a pharmaceutically acceptable thereof; and(c) a pharmaceutically acceptable diluent, a pharmaceutically acceptable glidant and a pharmaceutically acceptable lubricant, wherein the tablet is produced by a direct compression process comprising i) obtaining metformin hydrochloride particles comprising from 1.5 wt.% to 3.0 wt.% water, ii) mixing linagliptin, or a pharmaceutically acceptable salt thereof with at least one of the diluent, the glidant and the lubricant, iii) mixing metformin hydrochloride particles obtained in i) with the mixture obtained in ii), iv) optionally, adding to the mixture obtained in iii) a pharmaceutically acceptable excipient and v) compressing into a tablet.

2. The single-layer tablet according to claim 1, wherein metformin hydrochloride comprises from 1.8 wt % to 2.5 wt % water.

3. The single-layer tablet according to claim 1 or 2, wherein the mixing in step ii) is performed with a geometric dilution.

4. The single-layer tablet according to any one of the preceding claims, wherein the mixing in step iii) is performed with a geometric dilution.

5. The single-layer tablet according to any one of the preceding claims, wherein the mixing in step ii) and the mixing in step iii) is performed with a geometric dilution.

6. The-single layer tablet according to any one of the preceding claims, wherein the weight ratio of metformin hydrochloride to linagliptin, or to a pharmaceutically acceptable salt thereof, in the tablet ranges from 100:1 to 500:1.

7. The single-layer tablet according to any one of the preceding claims, wherein the tablet comprises500 mg metformin hydrochloride and 2.5 mg of linagliptin, or 850 mg metformin hydrochloride and 2.5 mg of linagliptin, or 1000 mg metformin hydrochloride and 2.5 mg of linagliptin.

8. The single-layer tablet according to any one of the preceding claims, wherein the D90 by volume of metformin hydrochloride which is used in the preparation of the tablet is less than 400 pm, as measured by laser light diffraction as described in European Pharmacopoeia, 11th Edition, 2.9.31.

9. The single-layer tablet according to any one of the preceding claims, wherein the D90 by volume of linagliptin, or a pharmaceutically acceptable salt thereof, which is used in the preparation of the tablet is less than 200 pm, preferably less than 50 pm, as measured by laser light diffraction as described in European Pharmacopoeia, 11th Edition, 2.9.31.

10. The single-layer tablet according to any one of the preceding claims, wherein the tablet exhibits dissolution properties such that at least 80% of metformin and at least 80% of linagliptin are released from the tablet within 30 minutes; and wherein the dissolution test is performed at pH range from 1.2 to 6.8, at 37.0°C ± 0.5°C, using USP II paddle apparatus at stirring speed of 50 rpm.11 . The single-layer tablet according to any one of the preceding claims, wherein in step ii) linagliptin, or a pharmaceutically acceptable salt thereof, is mixed with a diluent and a glidant.

12. The single-layer tablet according to claim 11 , wherein the diluent is microcrystalline cellulose and the glidant is colloidal silicon dioxide.

13. The single-layer tablet according to claim 11 or 12, wherein the tablet further comprises magnesium stearate as lubricant.

14. The single-layer tablet according to any one of the preceding claims, wherein after step iv) the tablet is film coated.

15. The single-layer tablet according to any one of the preceding claims, wherein the tablet is free of a basic amino acid, free of a stabilizer of metformin or linagliptin and free of a binder selected from povidone and copovidone.

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