FIELD OF INVENTION

The invention relates to oral solid pharmaceutical compositions comprising a combination of Dipeptidyl Peptidase Inhibitor and Biguanide.

More particularly, the invention relates to oral solid pharmaceutical compositions comprising a combination of sitagliptin and metformin.

The present invention also relates to a process for preparation of oral solid pharmaceutical compositions comprising a combination of sitagliptin and metformin.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ART

Sitagliptin belongs to a class of dipeptidyl peptidase-4 (DPP-4) inhibitor, which is basically used as an oral antihyperglycemic agent. Chemically, it is (i?)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine and is disclosed in U.S. Patent No. 6,699,871.

Sitagliptin is commercially available under the trade name Januvia in the form of oral tablet in the U.S.

Metformin, chemically known as N,N-dimethylimidodicarbonimidic diamide and is disclosed in U.S. Patent No. 3,174,901. It is used as a first-line drug for the treatment of Type 2 diabetes. It is basically marketed in high strength such as 500, 750, 850 and 1000 mg strengths and used once or twice daily due to its short half-life. It can be marketed in single as well as in combination with other antidiabetic drugs for the treatment of type 2 diabetes.

Metformin is commercially available under the trade name Glucophage in the form of oral tablet as well as Glumetza™ in the form of extended release tablet in the U.S.

A combination of sitagliptin and metformin is commercially marketed under the trade name Janumet™ as an oral tablet having dose strength of (50+500)mg and (50+1000)mg in order to provide improved medication in the treatment of Type 2 diabetes.

Commercially available Janumet™ tablet contains microcrystalline cellulose, polyvinylpyrrolidone, sodiumlauryl sulfate, and sodium stearyl fumarate. In addition, the film coating contains the following inactive ingredients such as polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, red iron oxide and black iron oxide.

There are several prior arts, as discussed below, which disclose and cover various compositions and processes for preparation of said combination of sitagliptin and metformin.

U.S. 7,125,873 discloses a composition comprising sitagliptin and other anti diabetic agent such as biguanides.

U.S. 2009/0105265 disclose a composition comprising: (a) about 3 to 20% by weight of a dipeptidyl peptidase-4 (DPP-4) inhibitor or a pharmaceutically acceptable salt thereof (b) about 25 to 94% by weight of metformin hydrochloride (c) about 0.1 to 10% by weight of a lubricant; and (d) about 0 to 35% by weight of a binding agent. Further, this patent publication discloses that the composition is prepared by means of wet granulation.

U.S. 2008/0064701, U.S. 2007/0172525 and U.S. 2010/074950 discloses a composition comprising a slow release biguanide and a dipeptidyl peptidase IV inhibitor wherein the composition comprises: a) a slow release core comprising an anti-diabetic metformin or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipients, and b) an immediate release coat comprising a dipeptidyl peptidase IV inhibitor and also the method of treating diabetes.

U.S. 2008/0227825 disclose a composition comprising: i) between 1.5 to 35% of a DPP-IV inhibitor, or a pharmaceutically acceptable salt thereof, ii) between 65 to 98.5% of metformin or a pharmaceutically acceptable salt thereof, wherein metformin is in the form of granules and wherein the composition comprises between 1 to 25% of a binder. This patent publication preferably discloses the composition comprising vildagliptin and metformin.

U.S. 2010/216800 discloses the use of a combination of a DPIV inhibitor and metformin or a thiazolidinedione as first-line combination therapy for treatment of type 2 diabetes.

WO 2009/111200 discloses a composition comprising an inner core tablet comprising metformin hydrochloride coated with sustained-release polymer which further coated with an immediate-release composition of sitagliptin, or a pharmaceutically acceptable salt thereof, and an immediate- release polymer.

WO 2009/099734 discloses a tablet composition comprising an inner core matrix comprising metformin hydrochloride and an extended-release excipient; and further coated with an outer coat immediate-release composition comprising sitagliptin, or a pharmaceutically acceptable salt thereof, and at least one excipient.
The above prior art references disclose various combination composition comprising sitagliptin and metformin in the form of either immediate or extended release form but still there exists a need to develop improved pharmaceutical composition comprising sitagliptin and metformin.

The inventors of the present invention during their continuous effort to develop an improved composition comprising sitagliptin and metformin found that the composition comprising sitagliptin, metformin and one or more pharmaceutically acceptable excipients being devoid of any lubricant and prepared by either melt granulation or wet granulation, is effective to produce an improved composition and at the same time being comparable to marketed dosage form, in terms of drug release profile and stability.

SUMMARY AND OBJECTIVES OF THE INVENTION

The invention relates to solid pharmaceutical compositions comprising a combination of sitagliptin and metformin.

Particularly, the invention relates to solid pharmaceutical compositions comprising sitagliptin, metformin and one or more pharmaceutically acceptable excipients, wherein said composition is devoid of any lubricant.

More particularly, the invention relates to solid pharmaceutical compositions comprising sitagliptin, optionally metformin and one or more pharmaceutically acceptable excipients, wherein said composition being devoid of any lubricant is prepared by melt granulation or by wet granulation.

The invention also relates to a process for preparing solid pharmaceutical compositions comprising sitagliptin, metformin and one or more pharmaceutically acceptable excipients, wherein said composition is devoid of any lubricant.

The invention also relates to a solid pharmaceutical compositions comprising a combination of sitagliptin and metformin in such a way that it will comply with the reference product Janumet™ in terms of in vitro parameters like dissolution and stability.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

The invention relates to solid pharmaceutical compositions comprising a combination of sitagliptin and metformin.

Sitagliptin as used in the invention include sitagliptin base and its pharmaceutically acceptable salts or its combinations thereof. Preferably sitagliptin according to the invention is used in form of sitagliptin phosphate.

Metformin as used in the invention include metfomin base and its pharmaceutically acceptable salts and its combinations thereof.

Preferably metformin according to the invention is used in form of metformin hydrochloride.

In particular, the invention relates to solid pharmaceutical compositions comprising sitagliptin phosphate, metformin hydrochloride and one or more pharmaceutically acceptable excipient, wherein said composition is devoid of any lubricant.

In an embodiment, the invention also relates to solid pharmaceutical compositions comprising sitagliptin, and one or more pharmaceutically acceptable excipient, wherein said composition is devoid of any lubricant.

In another embodiment, the invention relates to solid pharmaceutical compositions comprising sitagliptin, optionally metformin and one or more pharmaceutically acceptable excipients, wherein said composition being devoid of any lubricant, is prepared by melt granulation or wet granulation.

Yet in another embodiment, the invention also relates to a process for preparing solid pharmaceutical compositions comprising sitagliptin and one or more pharmaceutically acceptable excipients, wherein said composition is devoid of any lubricant.

The invention also provides a process for preparing solid pharmaceutical compositions comprising sitagliptin, metformin and one or more pharmaceutically acceptable excipients, wherein said composition is devoid of any lubricant.

"Pharmaceutical composition" as described herein, includes dosage forms such as tablets, mini-tablets, layered tablets, inlay tablets, coated tablets, capsules, pellets, beads, pills, powders, granules and the like.

"Composition devoid of any lubricant" as used herein, refers that the composition according to the invention does not contain lubricant which are generally used by a person skilled in the art, for the preparation of solid oral pharmaceutical composition, such as magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, fumaric acid and the like or combinations thereof.

Pharmaceutically acceptable excipient according to the invention include diluents, binders, disintegrants, surfactants and the like or combinations thereof.

Diluents according to the invention are selected from a group comprising mannitol, sorbitol, dibasic calcium phosphate dihydrate, microcrystalline cellulose, powdered cellulose and the like or combinations thereof.

Binders according to the invention may be either hydrophilic or hydrophobic binders which are having melting point is in the range of about 40°-250°C.

The hydrophilic binders are selected from a group comprising Gelucire™ 50/13, Poloxamer™ 188, polyethylene glycol 2000, polyethylene glycol 3000, polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000, and polyethylene glycol 20000 aand the like or combinations thereof.

The hydrophobic binders are selected from a group comprising beeswax, carnauba wax, cetyl palmitate, glyceryl behenate, glyceryl monostearate, stearic alcohol and the like or combinations thereof.

In addition to the above, binders may also be selected from a group comprising hydroxypropylcellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, pre-gelatinized starch, povidone, co-povidone, gelatin and the like or combinations thereof.

Disintegrants according to the invention are selected from a group comprising modified starches, modified cellulose polymers, or polycarboxylic acids, such as croscarmellose sodium, crospovidone, sodium starch glycollate, polacrillin potassium, carboxymethylcellulose calcium, pre-gelatinized starch and the like or combinations thereof.

Surfactants according to the invention are selected from a group comprising sodium lauryl sulfate, sodium dodecane sulfonate, sodium oleyl sulfate, benzalkonium chlorides and alkyltrimethylammonium bromides, glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters, polyvinyl alcohol, sorbitan esters and the like or combinations thereof.

In yet another embodiment, sitagliptin phosphate is present in a range of about 3-20% w/w and metformin hydrochloride is present in a range of about 50-90% w/w of the tablet.

The tablet dosage form of the present invention may also be coated with film coating materials which are prepared with a mixture of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyethylene glycol, polyvinyl alcohol, titanium dioxide and coloring agent such as iron oxides, dyes and lakes.

In another embodiment, the invention relates to a process for preparing solid pharmaceutical compositions comprising sitagliptin and one or more pharmaceutically acceptable excipients, and being devoid of any lubricant, involves the steps of:

1. Preparing a homogeneous melt by mixing sitagliptin with a suitable binder;

2. Cooling the melt from step 1 and milling and sizing to obtain desired granules;

3. Blending the granules from step 2 with one or more pharmaceutically acceptable excipients

4. Compressing the blend from step 3 to obtain tablets and

5. Coating the tablets from step 4 using film coating material.

In another embodiment, the invention relates to a process for preparing solid pharmaceutical compositions comprising sitagliptin, metformin and one or more pharmaceutically acceptable excipients, and being devoid of any lubricant, involves the steps of:

1. Preparing a homogeneous melt of metformin with a suitable binder;

2. Cooling the melt from step 1 to get metformin granules;

3. Blending the granules from step 2 with sitagliptin and one or more pharmaceutically acceptable excipients;

4. Compressing the blend from step 3 to obtain tablets; and

5. Coating the tablets from step 4 using film coating material.

Yet in another embodiment, the invention also relates to a process for preparing solid pharmaceutical compositions comprising sitagliptin, optionally metformin, and being devoid of any lubricant, is prepared by wet granulation, involves the steps of:

1. Mixing sitagliptin, optionally metformin, and one or more pharmaceutically acceptable excipients in a suitable mixer;

2. Granulating the mixture from step 1 using a binder solution followed by drying to get dry granules;

3. Blending granules from step 2 with extra-granular excipients to form a blend;

4. Compressing the blend from step 3 to obtain tablets; and

5. Coating the tablets from step 4 using a film coating material.

In a preferred embodiment, the invention relates to a solid pharmaceutical compositions comprising 3-20%w/w of sitagliptin phosphate and 50-90%w/w of metformin hydrochloride and one or more pharmaceutically acceptable excipients such as binders selected from a group comprising polyethylene glycol, poloxamer, pregelatinized starch or combinations thereof; disintegrants selected from a group comprising crospovidone, croscarmellose sodium or combinations thereof, surfactants selected from a group comprising sodium lauryl sulfate, benzalkonium chlorides or combinations thereof, wherein said composition is devoid of any lubricant and is prepared by melt granulation or wet granulation.

The following examples illustrate specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.

Example 1

Ingredient mg/unit
Sitagliptin Phosphate 62.03
Polyethylene glycol 150.97
Crosspovidone 80.00
Sodium lauryl sulphate 7.00
Total weight 300.00

Brief Manufacturing Process:

1. Sitagliptin phosphate and a part of polyethylene glycol were mixed to form a homogeneous mixture followed by melting.

2. The melted mass from step 1 was cooled to room temperature to get the granules which further passes through sieve to obtain desired granules.

3. The granules from step 2 were blended with extra granular crospovidone, sodium lauryl sulfate and remaining part of polyethylene glycol.

4. The blend from step 3 was compressed by using suitable tooling to obtain tablets and

5. Coating the tablets from step 4 using a film coating material.

Example 2

Ingredient mg/unit
Metformin Hydrochloride 1000
Sitagliptin Phosphate 62.03
Polyethylene glycol 150.97
Crosspovidone 80.00
Sodium lauryl sulphate 7.00
Total weight 1300.00

Brief Manufacturing Process:

1. Metformin hydrochloride and a part of polyethylene glycol were mixed to form a homogeneous mixture.

2. The mixture from step 1 was heated to form a melt of metformin hydrochloride and polyethylene glycol.

3. The melted mass from step 2 was cooled to room temperature to form granules followed by passing through a suitable sieve.

4. The granules from step 3 were blended with extra-granular sitagliptin phosphate, crospovidone, sodium lauryl sulfate and remaining part of polyethylene glycol.

5. The blend from step 4 was compressed using a suitable tooling to form tablets and

6. Tablets from step 5 were coated using a film coating material.

The compositions given in examples 3 to 6 were prepared by using similar procedure as described in example 2.

Example 3

Ingredient mg/unit
Metformin Hydrochloride 1000.00
Sitagliptin Phosphate 62.03
Poloxamer 188 77.97
Crosspovidone 50.00
Sodium lauryl sulphate 10.00
Total weight 1200.00
Example 4
Ingredient mg/unit
Metformin Hydrochloride 1000.00
Sitagliptin Phosphate 62.03
Gelucire 50/13 47.97
Crosspovidone 80.00
Sodium lauryl sulphate 10.00
Total weight 1200.00

Example 5

Ingredient mg/unit
Metformin Hydrochloride 1000.00
Sitagliptin Phosphate 62.03
Polyethylene glycol 257.97
Crospovidone 70.00
Sodium lauryl sulphate 10.00
Total weight 1400.00

Example 6

Ingredient mg/unit
Metformin Hydrochloride 1000.00
Sitagliptin Phosphate 62.03
Polyethylene glycol 157.97
Crospovidone 70.00
Sodium lauryl sulphate 10.00
Total weight 1300.00

Example 7

Ingredient mg/unit
Sitagliptin Phosphate 62.03
Polyethylene glycol 237.97
Microcrystalline cellulose 70.00
Crospovidone 70.00
Sodium lauryl sulphate 10.00
Total weight 450.00

Brief Manufacturing Process:

1. Sitagliptin phosphate, a part of polyethylene glycol and microcrystalline cellulose were blended to form a homogeneous mixture.

2. The binder solution was prepared by dissolving sodium lauryl sulphate and polyethylene glycol in purified water.

3. The mixture obtained in step 1 was granulated using the binder solution prepared in step 2 to form granules.

4. The granules obtained in step 3 were passed through a suitable sieve and blended with extra granular excipients such as crospovidone, sodium lauryl sulphate and remaining part of polyethylene glycol.

5. The blend of step 4 was compressed by using suitable tooling to form tablets and

6. The tablets were coated with a film coating material.

Example 8

Ingredient mg/unit
Metformin Hydrochloride 1000.00
Sitagliptin Phosphate 62.03
Polyethylene glycol 237.97
Microcrystalline cellulose 70.00
Crospovidone 70.00
Sodium lauryl sulphate 10.00
Total weight 1450.00

Brief Manufacturing Process:

1. Sitagliptin phosphate, metformin hydrochloride, a part of polyethylene glycol and microcrystalline cellulose were blended to form a homogeneous mixture.

2. The binder solution was prepared by dissolving sodium lauryl sulphate and polyethylene glycol in purified water.

3. The mixture obtained in step 1 was granulated using the binder solution prepared in step 2 to form granules.

4. The granules obtained in step 3 were passed through a suitable sieve and blended with extra granular excipients such as crospovidone, sodium lauryl sulphate and remaining part of polyethylene glycol.

5. The blend of step 4 was compressed by using suitable tooling to form tablets and

6. The tablets were coated with a film coating material.

The compositions given in example 9 to 12 were prepared by using similar procedure as described in example 8.

Example 9

Ingredient mg/unit
Metformin Hydrochloride 1000.00
Sitagliptin Phosphate 62.03
Pre-gelatinized starch 257.97
Microcrystalline cellulose 70.00
Sodium lauryl sulphate 10.00
Total weight 1400.00

Example 10

Ingredient mg/unit
Metformin Hydrochloride 1000.00
Sitagliptin Phosphate 62.03
Pre-gelatinized starch 557.97
Microcrystalline cellulose 70.00
Sodium lauryl sulphate 10.00
Total weight 1700.00

Example 11

Ingredient mg/unit
Metformin Hydrochloride 1000.00
Sitagliptin Phosphate 62.03
Pre-gelatinized starch 497.97
Croscarmellose sodium 90.00
Sodium lauryl sulphate 10.00
Total weight 1300.00

Example 12

Ingredient mg/unit
Metformin Hydrochloride 1000.00
Sitagliptin Phosphate 62.03
Pre-gelatinized starch 497.97
Croscarmellose sodium 90.00
Sodium lauryl sulphate 10.00
Total weight 1300.00

Stability Studies

The tablet prepared according to the example 8 and example 10 of the invention was subjected to accelerated conditions [40°C/75% RH] for 4 weeks and 12 weeks and parameters such as assay, related substances, impurities, dissolution were analyzed.

Samples were analyzed using an HPLC method and results are summarized in Table 1 and 2.

Table 1

S. No. I Parameters Example 8 Janumet™ (567 lOOOmg)
Initial 4 week Initial 12 week
Sitagliptin Metformin Sitagliptin Metformin Sitagliptin Metformin Sitagliptin Metformin
Phosphate HC1 Phosphate HC1 Phosphate HC1 Phosphate HC1
1 Assay 99.5 99.2 99.3 99.4 101.0 101.1 101.1 99.4
2 Related substance (%w/w)
Maximum unknown 0.03 0.01 0.07 0.01 0.08 0.01 0.099 0.02
impurity
Total impurities 0.06 0.02 0.11 0.04 0.18 0.03 0.28 0.04
3 | Water content 1 2.92 3.16 2.48 2.47

Table 2

S.No Parameters Example 10 Janumet™ (SO / l000mg)
Initial 12 week Initial 12 week
Sitagliptin Metformin Sitagliptin Metformin Sitagliptin Metformin Sitagliptin Metformin
Phosphate HC1 Phosphate HC1 Phosphate HC1 Phosphate HC1
1 Assay 99.3 101.2 98.7 100.5 101.0 101.1 101.1 99.4
2 Related substance (%w/w)
Maximum unknown 0.03 0.02 0.05 0.04 0.08 0.01 0.09 0.02
impurity
Total impurities 0.13 0.05 0.31 0.07 0.18 0.03 0.28 0.04
3 Water content 3.12 3.23 2.48 2.47
4 Dissolution (Min) Medium: 0.025M NaCl / Paddle 75 RPM & 900ml
% of drug release
10 68 71 66 69 75 77 70 74
15 82 88 84 87 92 95 90 92
20 94 96 93 95 97 KX) 97 98
30 98 98 99 100 98 100 98 99
45 100 99 99 100 - - -

WE CLAIM:

1. A solid pharmaceutical composition comprising sitagliptin and one or more pharmaceutically acceptable excipients, wherein said composition is devoid of any lubricant.

2. A solid pharmaceutical composition comprising sitagliptin, metformin and one or more pharmaceutically acceptable excipients, wherein said composition is devoid of any lubricant.

3. A solid pharmaceutical composition comprising sitagliptin, optionally metformin and one or more pharmaceutically acceptable excipients, wherein said composition being devoid of any lubricant is prepared by melt granulation or wet granulation.

4. The solid pharmaceutical composition according to any of the preceding claims, wherein said excipients are selected from a group comprising diluents, binders, disintegrants, surfactants or combinations thereof.

5. A process for preparing a solid pharmaceutical composition comprising sitagliptin and one or more pharmaceutically acceptable excipients, and being devoid of any lubricant, involves the following steps of:

(a) Preparing a homogeneous melt by mixing sitagliptin with suitable binder;

(b) Cooling the melt from step(a), milling and sizing to obtain granules;

(c) Blending the granules from step(b) with one or more pharmaceutically acceptable excipients;

(d) Compressing the blend from step(c) to obtain tablets; and optionally

(e) Coating the tablets.

6. A solid pharmaceutical composition comprising sitagliptin, optionally metformin and one or more pharmaceutically acceptable excipients, and being devoid of any lubricant, involves the following steps of:

(a) Preparing a homogeneous melt of metformin and a binder;

(b) Cooling the melt from step(a), milling and sizing to get metformin granules;

(c) Blending the granules from step(b) with sitagliptin and one or more pharmaceutically acceptable excipients;

(d) Compressing the blend from step(c) to obtain tablets; and optionally

(e) Coating the tablets.

7. A process for preparing a solid pharmaceutical composition comprising sitagliptin, optionally metformin and one or more pharmaceutically acceptable excipients, and being devoid of any lubricant, involves the
following steps of:

(a) Mixing sitagliptin, optionally metformin and one or more pharmaceutically acceptable excipients in a suitable mixer;

(b) Granulating the mixture from step(a) using a binder solution followed by drying to get dry granules;

(c) Blending granules from step(b) with extra granular excipients to form a blend;

(d) Compressing the blend from step(c) to obtain tablets; and optionally

(e) Coating the tablets.

8. The solid pharmaceutical composition according to any of the preceding claims, wherein sitagliptin is selected from sitagliptin phosphate or other pharmaceutical acceptable salts thereof.

9. The solid pharmaceutical composition according to any of the preceding claims, wherein metformin is selected form metformin hydrochloride or other pharmaceutical acceptable salts thereof.

10. A solid pharmaceutical compositions comprising 3-20%w/w of sitagliptin phosphate; 50-90%w/w of metformin hydrochloride; one or more pharmaceutically acceptable excipients, such as binders selected from a group comprising polyethylene glycol, poloxamer, pregelatinized starch or combinations thereof; disintegrants selected from a group comprising crospovidone, croscarmellose sodium or combinations thereof, surfactants selected from a group comprising sodium lauryl sulfate, benzalkonium chlorides or combinations thereof, wherein said composition is devoid of any lubricant.