TECHNICAL FIELD OF INVENTION

The invention relates to pharmaceutical compositions comprising sitagliptin and simvastatin.

BACKGROUND OF THE INVENTION

Sitagliptin phosphate is an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme indicated as an adjunct to diet and exercise to improve glycemic control in adults with type II diabetes mellitus. Sitagliptin was introduced into the market under the brand name of Januvia® and is currently available in 25, 50, and 100mg dosage strengths. Sitagliptin phosphate monohydrate is described chemically as 7-[(3R)-3-amino- 1 -oxo-4-(2,4,5- trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3 -(trifluoromethyl)- 1 ,2,4-triazolo[4,3-a] pyrazine phosphate (1:1) monohydrate.

Simvastatin is a lipid-lowering agent that is derived synthetically from a fermentation product of Aspergillus terreus. After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed to the corresponding 3-hydroxyacid form. This is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (11MG- CoA) reductase.

This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol. Simvastatin was introduced into the market under the brand name of Zocor® and is currently available in 5, 10, 20, 40 and 80 mg dosage strengths. Simvastatin is chemically designated as butanoic acid, 2,2-dimethyl-, 1,2,3 ,7,8,8a- hexahydro-3 ,7-dimethyl-8- [2-(tetrahydro-4hydroxy-6-oxo-2H-pyran-2-yl)-ethyl] - 1 -naphthalenyl ester, [1 S-[ 1 a,3a,7p,8f3(2S*,4S*),8af3]].

Recently, US Food & Drug Administration has approved the combination dosage form (tablet) containing sitagliptin and simvastatin for the treatment of patient’s having type-TI diabetes along with high cholesterol level under the brand name JuvisyncTM. The new tablet, JuvisyncTM, is an FDC (fixed-dose combination) of the two medications and available in (sitagliptinlsimvastatin) dosages – 100 mg/10 mg, 5OmgIlOmg, 100 mgI2O mg, 5OmgI2Omg, 100 mg/40 mg and 50mg140.

As per the approved prescription information literature said JuvisyncTM is a bilayer tablet, wherein each tablet contains 128.5 mg or 64.25 mg of sitagliptin phosphate monohydrate, which is equivalent to 100 mg or 50 mg of free base, respectively, either 10 mg, 20 mg, or 40 mg of simvastatin, and the following inactive ingredients: anhydrous dibasic calcium phosphate, microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, magnesium stearate, ascorbic acid, citric acid monohydrate, lactose monohydrate, and pre-gelatinized corn starch.

In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, red iron oxide, yellow iron oxide, and black iron oxide. butylated hydroxyanisole (BHA) is added as a preservative.
PCT Application No. W02003/055467 discloses that simvastatin is a lactone prodrug that is converted in-vivo to the corresponding active, ring open, hydroxy acid form. The lactone ring and hydroxy acid forms of simvastatin may exist in equilibrium.

In general, it is believed that the lactone form of simvastatin predominantly exists under acidic conditions, while the hydroxy acid form is preferably formed under alkaline conditions. Presumably the presence of ascorbic and citric acids in the commercially available Zocor® tablets ensures that the microenvironment pH is acidic, thereby stabilizing simvastatin in the preferred lactone form.

These acids, along with butylated hydroxyanisole (BHA), a weak acid, also serve as antioxidants and thus may also be present to ensure that the double bonds in the ring structure do not react; i.e. do not form epoxides.

PCT Application No. W02010/000469 discloses that sitagliptin salts are prone to hydrolysis causing degradation.

PCT Application No. W0201 1/098483 discloses pharmaceutical compositions comprising a combination of metformin and sitagliptin in the form of multilayer tablet preferably bilayer tablet, wherein metformin and sitagliptin are present in two separate compartments or layers. It also discloses that it has been unexpectedly found that changes in sitagliptin polymorphism can be avoided if the use of any solvents like water or organic solvents is omitted during formulation.

The omitting of solvents prevents the crystalline sitagliptin to change its polymorphic form or turn into an amorphous form, thus reducing the hydrolytic degradation. The sitagliptin layer in the bilayer tablet is prepared by direct compression thereby omitting the use of water and organic solvents.

Thus, from the above mentioned prior arts it is clear that it is difficult to formulate sitagliptin and simvastatin in a single layer monolithic tablet dosage form due to physicochemical incompatibility and different stability requirements of these two drugs and that is one of the primary reasons why the Brand has chosen to prepare a bilayer tablet.

Bilayer tablets are mainly prepared to avoid chemical incompatibilities between two or more drugs by physical separation into two separate layers. In the last few years, interest in developing bilayer tablets comprising two or more drugs has increased in the pharmaceutical industry for the treatment of co-morbidity i.e. either the presence of one or more disorders (or diseases) in addition to a primary disease or disorder such as diabetes with hyperlipidemia, diabetes with hypertension, or obesity with hyperlipidemia etc.

Thus, bilayer tablets comprising fixed dose combination of two or more drugs can reduce the number of pills to be taken by the patients and improve the patient’s compliance. But the bilayer tablet compression technology has several disadvantages -viz, it requires a bilayer tablet compression machine; which has a low yield; and a high cost of production, when compared to conventional single layer tablets compression machine.

It also faces many practical difficulties such as cross-contamination between the layers, capping and separation of the two individual layers due to elastic and hardness variation, and weight ratio variation within each layer and so on and so forth.

Thus, in case of fixed dose combinations, there is constant need in the art for developing single monolithic layer tablet, comprising two or more physicochemically incompatible drugs, which will reduce the overall cost of production and overcome the practical difficulties associated with bilayer tablets. The present inventors have successfully developed a single layer monolithic tablet comprising sitagliptin and simvastatin

SUMMARY AND OBJECTIVES OF THE INVENTION

The invention relates to pharmaceutical composition comprising sitagliptin, simvastatin and optionally one or more pharmaceutically acceptable excipient(s). More specifically, it relates to a single layer monolithic tablet comprising sitagliptin, simvastatin and optionally one or more pharmaceutically acceptable excipient(s) and processes for preparing the same.

An objective of the invention is to prepare a single layer monolithic tablet comprising sitagliptin, simvastatin and optionally one or more pharmaceutically acceptable excipient(s).

Another objective of the invention relates to processes for preparing a single layer monolithic tablet comprising sitagliptin, simvastatin and optionally one or more pharmaceutically acceptable excipient(s).

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION
As discussed in the background of the invention bilayer tablet compression technology has several disadvantages; such as it requires bilayer tablet compression machine, it has low yield, thereby resulting in high cost of production compared to conventional single layer monolithic tablets.

Further it also faces many practical difficulties such as cross-contamination between the layers, capping and separation of the two layers due to elastic and hardness variation between said two layers, and layer weight ratio variation etc.

Thus, the invention focuses on developing single layer monolithic tablets comprising sitagliptin and simvastatin and the processes for preparing the same, which is aimed at reducing the overall cost of production and as well overcome the practical difficulties associated with tablet formulation containing two or more chemically incompatible drugs in a bilayer tablet. More particularly, the invention relates to a single layer monolithic tablet comprising sitagliptin, simvastatin and optionally one or more pharmaceutically acceptable excipient(s).

According to the invention, if the first drug is sitagliptin, then the second drug would be simvastatin and vice-versa. According to an embodiment of the invention, sitagliptin may be present in the amorphous or crystalline form. As used herein, the term “sitagliptin “ is intended to include the active agent itself, as well as its pharmaceutically acceptable salts or derivatives thereof.

According to an embodiment of the invention, simvastatin may be present in the amorphous or crystalline form. As used herein, the term “simvastatin” is intended to include the active agent itself, as well as its pharmaceutically acceptable salts or derivatives thereof.

As used herein, the term, “monolithic” when used in connection with the term “tablet” refers to a tablet comprised of one continuous block of solid. According to an embodiment of the invention the term “simvastatin granules” as used herein, is intended to include granules comprising simvastatin and optionally one or more pharmaceutically acceptable excipient(s), prepared by employing wet granulation, dry granulation, melt granulation method.

According to an embodiment of the invention the term “separating layer” as used herein, is intended to include an inert layer which separates sitagliptin portion from simvastatin portion within the single layer monolithic tablet.
According to an embodiment of the invention the term “inert layer” as used herein, is intended to include a film layer comprising film forming polymer optionally containing one or more pharmaceutically acceptable excipient(s), which is devoid of either sitagliptin and! or simvastatin.

According to an embodiment of the invention the term “coated simvastatin particles” as used herein, is intended to include simvastatin drug particles coated with film forming polymer solution optionally containing plasticizer and/or antioxidant.
According to an embodiment of the invention, the term “solid dispersion” as used herein, is intended to include a dispersion of one or more active ingredient(s) in an inert carrier or matrix at solid state.

According to an embodiment of the invention, the physical separation of sitagliptin and simvastatin in a single layer monolithic tablet can be achieved by:

(a) formulating sitagliptin and simvastatin in two different physical form selected from coated drug particles, powder form, granules, pellets, beads, mini-tablets, and

(b) then formulating the two different physical form comprising sitagliptin and simvastatin in to a single layer monolithic tablet dosage form, wherein

(i) coated drug particles may be prepared by coating the drug particles with film polymer solution, optionally containing a plasticizer, by employing suitable coating technique;

(ii) powder form may be prepared by mixing the drug optionally with one or more pharmaceutically acceptable excipients;

(iii) granules may be prepared by wet granulation or by dry granulation method;

(iv) pellets or beads may be prepared by extrusion spheronization; and/or drug layer techniques; and

(v) mini-tablets and tablets may be prepared by using wet granulation or dry granulation or by direct compression method.

According to an embodiment of the invention, the physical separation of sitagliptin and simvastatin in a single layer monolithic tablet can also be achieved by:

(a) formulating the first drug in the form of coated drug particles, powder form, granules, pellets, beads, mini-tablets;

(b) second drug in the form of a solid dispersion; and

(c) then formulating the two different physical form comprising two different drugs in to a single layer monolithic tablet dosage form, wherein

(i) coated drug particles may be prepared by coating the drug particles with film polymer
solution, optionally containing a plasticizer, by employing suitable coating technique;

(ii) powder form may be prepared by mixing, the drug optionally with one or more pharmaceutically acceptable excipients;

(iii) granules may be prepared by wet granulation or by dry granulation method;

(iv) pellets or beads may be prepared by extrusion spheronization; and/or drug layer techniques;

(v) mini-tablets and tablets may be prepared by using wet granulation or dry granulation or by direct compression method; and

(vi) solid dispersion may be prepared by solvent evaporation method. According to an embodiment of the invention, the physical separation of sitagliptin and simvastatin in a single monolithic layer tablet can also be achieved by:

(a) formulating first drug in the form of coated drug particles, powder form, granules, pellets, beads, mini-tablets;

(b) optionally providing a separating layer coating; (c) finally coating with the second drug; and

(d) then formulating into single layer monolithic tablet dosage form, wherein:

(i) coated drug particles may be prepared by coating the drug particles with polymer solution optionally containing a plasticizer, employing suitable coating technique;

(ii) powder form may be prepared by mixing, optionally the drug with one or more pharmaceutically acceptable excipients;

(iii) granules may be prepared by wet granulation or by dry granulation method;

(iv) pellets or beads may be prepared by extrusion spheronization, and/or drug layer technique;

(v) mini-tablets and tablets may be prepared by using wet granulation or dry granulation or by direct compression; and

(vi) second drug layer coating over the tablet core /bead/granules etc comprises of drug solution or dispersion containing suitable film forming polymer and optionally a plasticizer.

According to an embodiment of the invention, the physical separation of sitagliptin and simvastatin in a single layer monolithic tablet can also be achieved by:

(a) formulating first drug in the form of tablet, and

(b) coating the tablet with second drug layer, optionally providing a separating layer coating between the tablet containing first drug and second drug layer, wherein:

(1) the tablets may be prepared by using wet granulation or dry granulation or by direct compression, and

(ii) second drug layer coating comprises of drug solution or dispersion containing suitable film forming polymer and optionally a plasticizer. According to an embodiment of the invention, the drug particle coating may be done by employing the Wurster-coater and the solid dispersion may be prepared by solvent evaporation technique using spray drying technique.

The tablet dosage form according to an embodiment of the invention may be prepared by using optionally one or more pharmaceutically acceptable excipient(s) selected from a group consisting of diluents, surfactants, wetting agents, surface stabilizers, binders, disintegrants, super-disintegrants, antioxidants, acidifying agents, basifying agents, glidants, and! or lubricants.

Suitable diluents according to the invention include, but are not limited to, copovidone, mannitol, xylitol, sorbitol, lactose, sucrose, cellulose, microcrystalline cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, calcium phosphate dibasic anhydrous, calcium phosphate dibasic dihydrate, calcium phosphate tribasic, starch, calcium trisilicate, magnesium trisilicate, cellulose acetate, dextrose, or combinations thereof.

Suitable binders according to the invention include, but are not limited to povidone, copovidone, pregelatinized starch, polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), starch, hyclroxyethyl cellulose (HEC), ethyl cellulose (EC), chitosan, guar gum, methyl cellulose (MC), carbomer, acacia, sodium alginate, calcium alginate or combinations thereof.

Suitable glidants and lubricants according to the invention include, but are not limited to, colloidal silicon dioxide, talc, magnesium stearate, sodium stearyl fumarate, calcium stearate or combinations thereof.

Suitable disintegrants according to the invention include, but are not limited to starch, microcrystalline cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, polacrilin potassium or combinations thereof.

Suitable superdisintegrants according to the invention include, but are not limited to crospovidone, croscarmellose sodium, and sodium starch glycolate, low-substituted hydroxypropyl cellulose (L-HPC), pregelatinised starch or combinations thereof.

Suitable surfactants, wetting agents, surface stabilizers according to the invention include, but are not limited to, anionic surfactants such as potassium laurate, triethanolamine stearate, sodium lauryl sulfate, cationic surfactants include quatemary ammonium compounds, benzalkonium chloride, cetyltrimethylammonium bromide; nonionic surfactants include glycerol monostearate, cetyl alcohol, cetostearyl alcohol, and. polyoxyethylene glycol sorbitan alkyl esters (polysorbate), sorbitan alkyl esters (span), poloxamer or combinations thereof.

Suitable antioxidants according to the invention include, but are not limited to, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite, ascorbic acid, propyl gallate, sodium ascorbate, sodium bisulfite, monothioglycerol or combinations thereof.

Suitable acidifying agents according to the invention include citric acid, ascorbic acid, fumaric acid, malic acid, tartaric acid, or combinations thereof. Suitable basifying agents according to the invention include metal oxides, inorganic bases, organic bases such as meglumine, dibasic calcium phosphate, calcium phosphate dibasic anhydrous, magnesium oxide, magnesium hydroxide, aluminum hydroxide, aluminum oxide, calcium carbonate, calcium phosphate dibasic dihydrate, calcium phosphate tribasic, calcium trisilicate, magnesium trisilicate or combinations thereof.

According to an embodiment of the invention, drug particle coating or the separating layer coating comprises of film polymers, and optionally plasticizer and/or antioxidants.
According to the invention, film coating excipients may be selected from a group consisting of film formers, plasticizers, opacifiers, and coloring agents, etc.

Suitable film formers according to the invention include, but are not limited to, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl acetate (PVAc), methyl cellulose (MC) and ethyl cellulose (EC), hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methacrylic acid copolymer, cellulose acetate phthalate, cellulose phthalate, hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate, and natural gums and resins such as zein, gelatin, shellac and acacia or combinations thereof.

Suitable plasticizers according to the invention include, but are not limited to, castor oil, polyethylene glycol, propylene glycol, glycerin, triacetin, polysorbates, phthalate esters, dibutyl sebacate, citrate esters, and monoglycerides or combinations thereof.
Suitable opacifiers according to the invention include, but are not limited to, titanium dioxide, and talc or combinations thereof.

Suitable coloring agents according to the invention include, but are not limited to, FDA approved dyes and lakes such as sunset yellow, tartrazine, erythrosine, iron oxide yellow, and natural colors such as carmine or combinations thereof.

According to the invention, ready-to-use film coating systems such as Opadry TM, InstacoatTM may also be used for film coating, separating layer coating or for drug particle coating.

The invention is described in the following examples, but the examples are illustrative and do not limit the scope of this invention.

EXAMPLE 1: Tablet comprising intragranular simvastatin and extragranular sitagliptin, prepared by wet granulation method.

Unit Composition:

Ingredients

jg/tablet

Intra-granular

Simvastatin

40.00

Starch pregelatinised

100.00

Citric acid monohydrate

5.00

Ascorbic acid

10.00

Granulating solution

Butylated hydroxy anisole

0.05

Isopropyl alcohol

g.s

Purified Water

g.s

Extra-granular

Sitagliptin phosphate

124.06

Anhydrous dibasic calcium phosphate

20.00

Croscarmellose sodium

12.00

Microcrystalline cellulose

97.89

Sodium stearyl fumarate

15.00

Magnesium stearate

6.00

Core Tablet Weight

430.00

Film Coating

OpadrylM

10.750

Purified water

g.s

Coated Tablet Weight

440.750

Brief manufacturing process:

1. Sift simvastatin, starch pregelatinised, citric acid monohydrate and ascorbic acid through suitable sieve and mix well.

2. Dissolve butylated hydroxy anisole in isopropyl alcohol and add purified water to it under stirring.

3. Granulate the blend of step (1) with granulating solution obtained in step (2) to get wet mass.

4. Dry the wet mass and mill to get granules of suitable size.

5. Sift sitagliptin phosphate, anhydrous dibasic calcium phosphate, croscarmellose sodium, microcrystalline cellulose through suitable sieve and mix with the granules obtained in step (4).

6. Sift sodium stearyl fumarate and magnesium stearate through suitable sieve and mix with the blend obtained in step (5).

7. Compress the lubricated blend of step (6) into tablets.

8. Film coat the tablets obtained in step (7) using aqueous dispersion of Opadry.

Dissolution Data:

Tablets prepared according to the Example 1 and the marketed JuvisyncTM tablets (sitagliptin 100mg and simvastatin 40 mg) were subjected to in-vitro dissolution test in 900ml of pH 7.0 phosphate buffer containing 0.5% sodium lauryl sulphate, USP type I (Basket) dissolution apparatus at 100 rpm and the resultant data is compiled in Table 1.

Table 1

Time

(Mm)

Cumulative % Drug Dissolved

JuvisyncTM Tablet

Example 1 Tablets

InitiaJ

Initial

After 24 weeks

(40°C and 75% RH)

Sita

gliptin

Simva

statin

Sita

gliptin

Simva

statin

Sita

gliptin

Simva

statin

5

69

13

97

74

96

57

10

92

55

100

82

98

73

15

98

77

99

83

98

79

20

98

84

99

85

99

83

30

99

88

100

88

98

85

45

99

89

100

88

98

88

60

99

89

100

88

98

90

Stability Data:

The tablets prepared according to Example 1 were subjected to accelerated stability study at 40°C/75%RH for 24 weeks. The results of the accelerated stability study are tabulated in Table 2.

EXAMPLE 2: Tablet comprising intragranular simvastatin and extragranular sitagliptin, prepared by wet granulation method.

Unit Composition:

Brief manufacturing process:

1. Sift simvastatin, lactose monohydrate, starch pregelatinised, citric acid monohydrate, and ascorbic acid through suitable sieve and mix well.

2. Dissolve butylated hydroxy anisole in isopropyl alcohol and add purified water to it under stirring.

3. Granulate the blend of step (1) with granulating solution obtained in step (2) to get wet mass.

4. Dry the wet mass and mill to get granules of suitable size.

5. Sift sitagliptin phosphate, anhydrous dibasic calcium phosphate, croscarmellose sodium, microcrystalline cellulose through suitable sieve and mix with the granules obtained in step (4).

6. Sift sodium stearyl fumarate and magnesium stearate through suitable sieve and mix with the blend obtained in step (5).

7. Compress the lubricated blend of step (6) into tablets.

8. Film coat the tablets obtained in step (7) using aqueous dispersion of OpadryTM.

Dissolution Data:

Tablets prepared according to the Example 2 and the marketed JuvisyncTM tablets (sitagliptin 100mg and simvastatin 40 mg) were subjected to in-vitro dissolution test in 900ml of pH 7.0 phosphate buffer containing 0.5% sodium lauryl sulphate, USP type I (Basket) dissolution apparatus at 100 rpm and the resultant data is compiled in Table 3.
Stability Data:

The tablets prepared according to Example 2 were subjected to accelerated stability study at 40°C/75%RFI for 24 weeks. The results of the accelerated stability study are tabulated in Table 4.

EXAMPLE 3: Tablet comprising core containing sitagliptin and coating comprising simvastatin, prepared by direct compression method.

Unit Composition:

Ingredients

mg/tablet

Intra-granular

Sitagliptin phosphate

124.06

Anhydrous dibasic calcium phosphate

20.00

Croscarmellose sodium

12.00

Microcrystalline cellulose

109.94

Sodium stearyl fumarate

7.50

Magnesium stearate

2.50

Separating layer Opadry

8.00

Purified water

g.s

Simvastatin Coating

Simvastatin

40.00

Hydroxypropylmethyl cellulose

10.00

Polyethylene glycol 6000

0.92

Butylated hydroxy anisole

0.08

Isopropyl alcohol

g.s

Purified water

g.s

Film Coating

Opadry

10.00

Purified water

g.s

Total weight

345.00

Brief manufacturing process:

1. Sift sitagliptin phosphate, anhydrous calcium phosphate, croscarmellose sodium, microcrystalline cellulose through suitable sieve and mix well.

2. Sift sodium stearyl fumarate and magnesium stearate through suitable sieve and mix with the blend obtained in step (1).

3. Compress the lubricated blend of step (2) into tablets

4. Coat the tablets obtained in the step (3) with OpadryTM as separating layer.

5. Dissolve hydroxypropylmethyl cellulose and polyethylene glycol 6000 in purified water.

6. Dissolve butylated hydroxy anisole in isopropyl alcohol.

7. Add solution obtained in step (6) to step (5) drop wise under stirring, and then add simvastatin with continuous stirring to get uniform dispersion.

8. Coat the separating layer coated tablets obtained in step (4) with the dispersion obtained in step (7).

9. Finally film coat the simvastatin coated tablets of step (8) with OpadryTM dispersion in purified water.

EXAMPLE 4: Tablet comprising core containing coated simvastatin particles and uncoated sitagliptin, prepared by direct compression method.

Unit Composition:

Ingredients

mg/tablet

Intra-granular

Simvastatin

40.00

Coating solution

Hydroxypropylmethyl cellulose

10.00

Polyethylene glycol 6000

0.92

Butylated hydroxy anisole

0.08

Isopropyl alcohol

g.s

Purified Water

g.s

Extra-granular

Sitagliptin phosphate

124.06

Anhydrous dibasic calcium phosphate

20.00

Croscarmellose sodium

12.00

Microcrystalline cellulose

96.94

Starch pregelatinised

30.00

Citric acid monohydrate

5.00

Ascorbic acid

10.00

Sodium stearyl fumarate

15.00

Magnesium stearate

6.00

Total weight

370.00

Brief manufacturing process:

1. Dissolve hydroxypropylmethyl cellulose and polyethylene glycol 6000 in purified water.

2. Dissolve butylated hydroxy anisole in isopropyl alcohol.

3. Add solution of step (2) to step (1) drop wise under stirring.

4. Coat simvastatin in fluid bed granulator using coating solution obtained in step (3) and
dry the coated simvastatin.

5. Sift coated simvastatin obtained in step (4), sitagliptin phosphate, anhydrous dibasic calcium phosphate, croscarmellose sodium, microcrystalline cellulose, starch pregelatinised, citric acid monohydrate, ascorbic acid through suitable sieve and mix well.

6. Sift sodium stearyl fumarate and magnesium stearate through suitable sieve and mix with the blend obtained in step (5).

7. Compress the lubricated blend of step (6) into tablets.

EXAMPLE 5: Tablet comprising core containing intragranularly a solid dispersion of simvastatin and sitagliptin extragranularly, prepared by direct compression method.

Unit Composition:

Ingredients

mg/tablet

Solid dispersion

Simvastatin

40.00

Polyvinylpyrrolidone

40.00

Colloidal silicon dioxide

40.00

Dichioromethane

g.s

Extra-granular

Sitagliptin phosphate

124.06

Anhydrous dibasic calcium phosphate

20.00

Croscarmellose sodium

12.00

Microcrystalline cellulose

97.94
Starch pregelatinised

Citric acid monohydrate

—

5.00

Ascorbic acid
1

0.00

Sodium stearyl fumarate

15.00

Magnesium stearate

6.00

Total weight

440.00

Brief manufa cturing process:

1. Disperse simvastatin, polyvinylpyrrolidone and colloidal silicon dioxide in dichloromethane.

2. Spray dry dispersion obtained in step (1) using a spray drier to get solid dispersion of simvastatin.

3. Sift solid dispersion of simvastatin obtained in step (2), sitagliptin phosphate, anhydrous dibasic calcium phosphate, croscarmellose sodium, microcrystalline cellulose, starch pregelatinised, citric acid monohydrate, ascorbic acid through suitable sieve and mix well.

4. Sift sodium stearyl fumarate and magnesium stearate through suitable sieve and mix with the blend obtained in step (3)

5. Compress the lubricated blend of step (4) into tablets.
EXAMPLE 6: Tablet comprising intragranular simvastatin and extragranular sitagliptin, prepared by wet granulation method.

Unit Composition:

Ingredients

mg/tablet

Intra-granular

Simvastatin

40.00

Starch pregelatinised

30.00

Anhydrous Lactose

239.95

Citric acid monohydrate

5.00

Ascorbic acid

10.00

Microcrystalline cellulose

40.00

Binder solution

Butylated hydroxy anisole

0.05

Isopropyl alcohol

g.s

Purified Water

g.s

Extra-granular

Sitagliptin phosphate

124.06

Microcrystalline cellulose

159.94

Magnesium stearate

6.00

Core Tablet Weight

655.00

Film Coating

Opadry

16.370

Purified water

g.s

Coated Tablet Weight

67 1.370

Brief manufacturing process:

1. Sift simvastatin, anhydrous lactose, starch pregelatinised, citric acid monohydrate, and ascorbic acid through suitable sieve and mix well.

2. Dissolve butylated hydroxy anisole in isopropyl alcohol and add purified water to it under stirring.

3. Granulate the blend of step (1) with granulating solution obtained in step (2) to get wet mass.

4. Dry the wet mass and mill to get granules of suitable size.

5. Sift microcrystalline cellulose and mix with step (4).

6. Sift sitagliptin phosphate, microcrystalline cellulose through suitable sieve and mix with step (5).

7. Sift magnesium stearate through suitable sieve and mix with the blend obtained in step (6).

8. Compress the lubricated blend of step (7) into tablets.

9. Film coat the tablets obtained in step (8) using aqueous dispersion of OpadryTM.

Dissolution Data:

Tablets prepared according to the Example 6 and the marketed JuvisyncTM tablets (sitagliptin 100mg and simvastatin 40 mg) were subjected to in-vitro dissolution test in 900m1 of pH 7.0 phosphate buffer containing 0.5% sodium lauryl sulphate, USP type I (Basket) dissolution apparatus at 100 rpm and the resultant data is compiled in Table 5.
Stability Data:

The tablets prepared according to Example 6 were subjected to accelerated stability study at 40°C/75%RH for 24 weeks. The results of the accelerated stability study are tabulated in Table 6.

Table 6

Tests

Initial

After 24 weeks

(40°C and 75% RB)

Assay (%) Sitagliptin

Simvastatin

97.7

97.6

96.7

94.5

Water By KF (%)

2.69

2.496

Butylated Hydroxy Anisole Content(mglTablet)

0.03

0.03

Citric Acid Content (mg/Tablet)

4.99

4.00

Ascorbic acid content (mg/Tablet)

9.79

7.35

Related Substances (%)

Simvastatin Hydroxy acid

0.185

0.701

Acetate ester

NR*

0.000

Lovastatin

0.002

0.004
Anhydro-simvastatin

0.158

0.467

Simvastatin dimer

0.056

0.065

*NR - Not Reported

From the above examples, it is clear that the single layer monolithic tablets comprising sitagliptin and simvastatin in two different physical forms or physically separated can be prepared successfully.

WE CLAIM:
1. A single layer monolithic tablet comprising sitagliptin, simvastatin and optionally one or more pharmaceutically acceptable excipient(s).

2. A single layer monolithic tablet comprising:

(a) simvastatin granules;
(
b) sitagliptin; and

(c) optionally one or more pharmaceutically acceptable excipient(s).

3. A single layer monolithic tablet comprising:

(a) a tablet core comprising sitagliptin;

(b) optionally a separating layer over said tablet core; and

(c) a simvastatin layer over said separating layer.

4. A single layer monolithic tablet comprising:

(a) coated simvastatin particles;

(b) sitagliptin; and

(c) optionally one or more pharmaceutically acceptable excipient(s).

5. A single layer monolithic tablet comprising:

(a) solid dispersion of simvastatin;

(b) sitagliptin; and

(c) optionally one or more pharmaceutically acceptable excipient(s).

6. A single layer monolithic tablet comprising sitagliptin and simvastatin according to
claim 1, 2, 4 and 5, wherein the pharmaceutically acceptable excipient(s) are selected from a group comprising of diluents, surfactants, wetting agents, surface stabilizers, binders, disintegrants, super-disintegrants, antioxidants, acidifying agents, basifying agents, glidants, and! or lubricants.

7. A single layer monolithic tablet comprising sitagliptin and simvastatin having the following unit composition:

Ingredients

mg/tablet

Intra-granular

Simvastatin

40.00

Starch pregelatinised

100.00

Citric acid monohydrate

5.00

Ascorbic acid

10.00

Granulating solution

Butylated hydroxy anisole

0.05

Isopropyl alcohol

g.s

Purified Water

q.s

Extra-granular

Sitagliptin phosphate

124.06

Anhydrous dibasic calcium phosphate

20.00

Croscarmellose sodium

12.00

Microcrystalline cellulose

97.89

Sodium stearyl fumarate

15.00

Magnesium stearate

6.00

Core Tablet Weight

430.00

Film Coating

Opadry

10.750

Purified water

g.s

Coated Tablet Weight

440.750

8. A single layer monolithic tablet comprising sitagliptin and simvastatin having the
following unit composition:

Ingredients

mg/tablet

Intra-granular

Simvastatin

40.00

Lactose monohydrate

240.00

Starch pregelatinised

30.00

Citric acid monohydrate

5.00

Ascorbic acid

10.00

Granulating solution

Butylated hydroxy anisole

0.05

Isopropyl alcohol

g.s

Purified Water

g.s

Extra-granular

Sitagliptin phosphate

124.06

Anhydrous dibasic calcium phosphate

20.00

Croscarmellose sodium

12.00

Microcrystalline cellulose

97.89

Sodium stearyl fumarate

15.00

Magnesium stearate

6.00

Core Tablet Weight

600.00

Film Coating

Opadry’

15.000

Purified water

g.s

Coated Tablet Weight

665.00

9. A single layer monolithic tablet comprising sitagliptin and simvastatin having the following unit composition:

Ingredients

mg/tablet

Intra-granular

Simvastatin

40.00

Starch pregelatinised

30.00

Anhydrous Lactose

239.95

Citric acid monohydrate

5.00

Ascorbic acid

10.00

Microcrystalline cellulose

40.00

Binder solution

Butylated hydroxy anisole

0.05

Isopropyl alcohol

g.s

Purified Water

g.s

Extra-granular

Sitagliptin phosphate

124.06

Microcrystalline cellulose

159.94

Magnesium stearate

6.00

Core Tablet Weight

655.00

Film Coating

Opadry

16.370

Purified water

g.s

Coated Tablet Weight

67 1.370

10. A single layer monolithic tablet comprising sitagliptin, simvastatin and optionally one or more pharmaceutically acceptable excipient(s) as herein described and exemplified.