FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
AND
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. TITLE OF THE INVENTION
"Extended release oral composition of metformin and DPP4 inhibitor"
2. APPLICANT
(a) NAME: VerGo Pharma Research Laboratories Pvt. Ltd.
(b) NATIONALITY: An Indian Company
(c) ADDRESS: Plot No. B5, Phase 1A, Verna Industrial Estate, Verna, Salcette, Goa 403722
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of the Invention
The present invention relates, in general, to the field of pharmaceutical compositions and in particular, to pharmaceutical compositions designed for immediate release delivery of sitagliptin phosphate and controlled release delivery of metformin HCI.
Background of the Invention
Sitagliptin, chemically described as (3R)-3-amino-1-[9-(trifluoromethyl)-1, 4, 7, 8-tetrazabicyclo-[4.3.0] nona-6, 8-dien-4-yl]-4-(2, 4, 5-trifluorophenyl) butan-1-one, belongs to dipeptidyl peptidase IV inhibitor class of drugs and is a hypoglycemic agent having the following structure:

Metformin is biguanide antihyperglycemic agent indicated for the treatment of type 2 diabetes. The US Food and Drug Administration (FDA) approved the immediate release combination product of sitagliptin and metformin under the brand name Janmet®. Merck further announced that the FDA approved Janmet® XR, or sitagliptin and metformin hydrochloride extended-release, tablets. The extended-release formulation of Janumet® is an investigational treatment for type 2 diabetes that combines a DPP-4 inhibitor such as Sitagliptin, which is the active component of Januvia® (sitagliptin) with metformin extended release, a commonly-prescribed medication for type 2 diabetes, into a single tablet.
Combination product is indicated, as an adjunct to diet and exercise, to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both sitagliptin and metformin is appropriate. Sitagliptin and metformin combination should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Fixed-dose combinations of immediate-release sitagliptin and immediate-release metformin are disclosed in the WO 2007/078726.
US20100330177 discloses pharmaceutical compositions of a fixed-dose of an extended-release form of metformin coated with an immediate release form of sitagliptin which are prepared by wet or dry processing methods.

There is a need of a simple manufacturing process for the pharmaceutical compositions comprising a immediate release sitagliptin phosphate and a slow release metformin.
Summary of the Invention
The present invention provides provides method of manufacturing of pharmaceutical compositions comprising sitagliptin and a slow release metformin in the form of a single tablet by various design such as tablet in tablet, bilayer tablet of immediate release and extended release layer, extended release matrix tablet of metformin and gradient layering of immediate release sitagliptin, another aspect is osomotic sustained delivery of metformin with immediate release of sitagliptin from a single tablet.
The present invention is designed for once-a-day adminsitration of an oral dosage form to deliver metformin hydrochloride for more than 85% at about 8 to 14 hours by using metformin hydrochloride and deliver more than 85% of sitagliptin phosphate within 1 to 2 hours. This approximately 8 to 14 hours of release is at a substantially ascending rate of release from the tablet with 95% delivery occurring at about 24 hours.
The present invention provides for a substantially high drug release rate of sitagliptin from immediate release portion by using sitagliptin phosphate monohydrate salt form and slow, continuous, non-pulsatile and ascending type drug release rate of metformin hydrochloride from extended release portion. It has been further discovered that the drug release rate and release profile from extended release composition of metformin hydrochloride can be modified by using different release rate controlling polymer.
The present invention provides ascending type release, the dosage form utilizes wet granulation by rapid mixer granulator and/or top spray granulation of the metformin hydrochloride by using release rate controlling polymer(s) and this coated metformin hydrochloride granules are to be use in the sustained release matrix core of a tablet along with the immediate release portion of Sitagliptin or pharmaceutically equivalent salt form having particles size greater than 10 micrometer or alternatively d90 greater than 10 micron.

The present invention is designed for a once-a-day dosage form that is therapeutically effective while providing stability using or without using moisture barrier coating stabilizer.
The present invention provides a dosage form comprising a immediate release layer of sitagliptin and an extended release layer of core made up of hydrophilic or hydrophobic substances including swellable or gell forming or soluble or insoluble ingredients.
The present invention provides a dosage form comprising a immediate release layer of Sitagliptin and an extended release layer of core made up of sustained release microspheres of metformin hydrochloride coated with hydrophobic substances including swellable or gell forming or insoluble ingredients.
The present invention provides is designed to achieve controlled release of metformin hydrochloride for 14 hrs and immediate release of sitagliptin within 2 hrs.
The present invention provides comprises a sustained release dosage form adapted to release over a prolonged period of time at a substantially ascending rate of release using extended release core and extended release coat approach for the compound metformin hydrochloride. The drug release profile of the extended release pharmaceutical preparations of metformin hydrochloride is preferably as not more than 40% in 2 hours, not more than 70% in 4 hours, not more than 95% in 10 hours and not less than 95% in 14 hours.
The present invention provides a method of treating diabetes in a subject responsive to administration of Metformin hydrochloride and Sitagliptin or a pharmaceutically acceptable salt thereof, which comprises orally administering to the subject a osmotic or non osmotic oral controlled release dosage form adapted to release the compound at a substantially ascending rate of release over a prolonged period of time. Most preferably, the dosage form is administered orally with once a day frequency.
The present invention provides use known polymers to modify the release from the core as required to achieve the desired ascending release.
Brief Description of Drawings
Fig 01: Dissolution profile of metformin HCI

Fig 02: Dissolution profile of sitagliptin Fig 03: Dissolution profile of metformin HCI Fig 04: Dissolution profile of sitagliptin Fig 05: Dissolution profile of metformin HCI Fig 06: Dissolution profile of sitagliptin Fig 07: Dissolution profile of metformin HCI Fig 08; Dissolution profile of sitagliptin Fig 09: Dissolution profile of- metformin HCI Fig 10: Dissolution profile of sitagliptin Fig 11: Dissolution profile of metformin HO Fig 12: Dissolution profile of sitagliptin Fig 13: Dissolution profile of metformin HCI Fig 14: Dissolution profile of sitagliptin Fig 15: Dissolution profile of metformin HCI Fig 16: Dissolution profile of sitagliptin Fig 17: Dissolution profile of metformin HCI Fig 18: Dissolution profile of sitagliptin Fig 19: Dissolution profile of metformin HCI Fig 20: Dissolution profile of sitagliptin
Detailed Description of the Invention
The present invention provides immediate release sitagliptin and extended release metformin hydrochloride pharmaceutical drug compositions of therapeutically effective doses of at least 50 mg and 100 mg of sitagliptin along with 500 mg and 1000 mg of metformin hydrochloride {50/500 mg, 50/1000 mg and 100/1000 mg) or their pharmaceutically acceptable salts, solvates, enantiomers , recimates or mixtures thereof, the processes for preparing the same and methods of use and treatment for patients with clinical symptom to treat with combination drug products.
The following disclosure describes the pharmaceutical composition which constitutes the invention. The invention is not limited to the specific composition described herein, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention.

It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural references unless the context clearly dictates otherwise.
Unless defined otherwise, all technical and scientific terms as used herein have the ordinary meaning as understood by those skilled in the art to which this invention belongs.
In a preferred embodiment, the invention provides bilayer pharmaceutical compositions of sitagliptin and metformin hydrochloride with release rate controlling hydrophilic polymer and metformin hydrochloride inside the core matrix are prepared to form extended release formulations and layered with immediate release composition of sitagliptin or pharmaceutically accepted salt form.
In another preferred embodiment, the invention provides pharmaceutical compositions of sitagliptin and metformin hydrochloride with release rate controlling hydrophilic polymer and metformin hydrochloride inside the core matrix are prepared to form extended release formulations and coated with immediate release composition of sitagliptin or pharmaceutically accepted salt form.
In still another preferred embodiment, the invention provides stable pharmaceutical compositions of metformin hydrochloride with hydrophilic and hydrophobic or either of one was prepared either by aqueous or non aqueous granulation or direct compression or roller compaction to form a extended release core embedded with immediate release mini-tablet of sitagliptin.
In still another preferred embodiment, the invention provides osmotic pharmaceutical compositions of sitagliptin and metformin hydrochloride with release rate controlling hydrophilic polymer, metformin hydrochloride and at least one osmotic agent inside the core matrix are prepared to form extended release core and layered with immediate release composition of sitagliptin or pharmaceutically accepted salt form, finally coated with sustained release polymer along with a orifice at the sitagliptin layer.
In yet another preferred embodiment, the invention provides stable pharmaceutica! compositions of sitagliptin and metformin hydrochloride with extended release

polymer or substance coated metformin hydrochloride along with sustain released polymer in core with immediate release composition of sitagliptin.
Various pharmaceutically acceptable excipients that may form a part of extended release substances can either hydrophilic or hydrophobic. Hydrophilic or water soluble excipients include but are not limited to celluloses such as carboxymethy! cellulose, hydroxypropyl methylcellulose, carboxymethylamide; potassium methacrylate/divinylbenzene copolymers; polyvinylpyrrolidone; polyethylene oxide; gums such as agrose, gum arabic, gum ghatti, gum karaya, gum tragacanth; hydrophilic colloids such as alginates; other substances such as arbinoglactan, pectin, amyiopectin, and the like. Hydrophobic or water-insolubie substances or combinations thereof used in various ratios are exemplified by but are not limited to fatty acid esters such as glyceryl monostearate, glycerol distearate, glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax, carnauba wax, glyceryl palmitostearate, Stearic acid, hydrogenated vegetable oil, hydrogenated castor oil and glyceryl behenate; celluloses such as ethyl cellulose, low substituted hydroxypropyl cellulose (L-HPC), cellulose acetates and their derivatives; phthalates such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate; cellulose acylate, cellulose diacylate and cellulose triacylate; cellulose acetate, cellulose diacetate and cellulose triacetate; mono-, di- and tri-cellulose alkanylates, mono-, di-, and tri-cellulose arylates and mono-, di- and tri-cellulose alkenylartes; polyacrylic acid, polymethacrylic acid based polymers and copolymers such as those sold using the trademark EUDRAGIT (RL, RS and NE-30D); polyvinyl acetate (PVA) copolymers of the above polymers or mixtures of any two or more in various ratios and proportions as required are within the scope of this invention without limitation.
Common diluents that can be used so as to add bulk to the core tablet of the invention includes microcrystalline cellulose (MCC), silicified MCC (e.g. Prosolv™ HD 90), micro fine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, and the like.
In one of the preferred embodiment of the present invention, a suitable solvent system such as aqueous or alcoholic or hydro-alcoholic or organic may be used in wet granulation along with extended release polymer or waxy material for preparing

the metformin hydrochloride core tablets in combination with immediate release composition of sitagliptin.
The extended release metformin hydrochloride and immediate release sitagliptin compositions comprising metformin hydrochloride and rate controlling polymer as a blend and sitagliptin with or without pharmaceutically acceptable excipients in another composition may be in the form of coated tablets, bilayer tablets, tablet in tablet, inlay tablets, Osmotic tablets. The invention includes all pharmaceutically acceptable metformin and sitagliptin with their pharmaceutically acceptable salts or esters.
Binders can include in the pharmaceutical compositions of the present invention to help hold tablets together after compression. Some typical binders are acacia, guar gum, alginic acid, dextrin, maltodextrin, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. KLUCEL®), hydroxypropyl methylcellulose (e.g. METHOCEL®), carboxymethylcellulose sodium, povidone (e.g. Povidone K -90 D, KOLLIDON®, PLASDONE®) and starch. Pharmaceutical compositions may further include but are not limited to pharmaceutically acceptable glidants, lubricants, opacifiers, colorants and other commonly used excipients.
The compositions for tabletting may further include additional pharmaceutically acceptable excipients, including one or more of glidants, lubricants, surfactants and other commonly used excipients.
The process for manufacturing the formulation of present invention is not limited to the processes described in the application and the formulation can be prepared by using any of the processes known to one skilled in the art. The active ingredient can be microencapsulated or granulated by wet granulation or dry granulation with or without excipients. The granules of active(s) are prepared by sifting the actives and excipients through the desired mesh size sieve and then are mixed using a rapid mixer granulator or planetary mixer or mass mixer or ribbon mixer or fluid bed processor or any other suitable device. The blend can be granulated, such as by adding a solution of a binder whether aqueous or alcoholic or hydro-alcoholic in a low or high shear mixer, fluidized bed granulator and the like. The granulate can be dried using a tray drier or fluid bed drier or rotary cone vacuum drier and the like. The sizing of the granules can be done using an oscillating granulator or comminuting mill or any other conventional equipment equipped with a suitable screen. Alternatively,

granules can be prepared by extrusion and spheronization, or roller compaction. The dried granulate particles are sieved, and then mixed with lubricants.
Alternatively the manufacture of granules may be done by direct compression by mixing the directly compressible excipients with active(s). The blend so obtained can either be compressed using a suitable device, such as a multi-station rotary machine to form compressed slugs or by roller compaction to form slugs, which are passed through a multimill, fluid energy mill, ball mill, colloid mill, roller mill, hammer mill, or the like, equipped with a suitable screen. The milled slugs are then mixed with lubricants and compressed into tablets.
In another aspect of the invention, the inlay tablets can be made of various sizes and shapes, as desired. The techniques and processes known to a person skilled in the art of making inlay tablets fall within the scope of this invention. The small tablet is formed by compression and then placed into a cavity, into which the granulated or powdered mixture that will comprise the larger tablet is added and the larger tablet will be compressed around the smaller tablet. Exposure of a surface of the smaller tablet is achieved by contact of that surface with the surface of a compression die, and placing granulate or powder mixture over the smaller tablet before the final compression step. Sitagliptin can be present as a small tablet placed within a large tablet that is containing Metformin hydrochloride and hydrophilic or hydrophobic polymers. The tablets can further be optionally film coated or enteric coated or coated with control release polymers. The coating can be done by techniques known to one skilled in the art such as spray coating, dip coating, fluidized bed coating and the like,
In one of the embodiments of the present invention, a suitable solvent system such as aqueous or alcoholic or hydro-alcoholic or organic may be used in the granulation or coating. In another embodiment of the present invention a suitable solvent system comprises solvents such as purified water, ethanol, isopropyl alcohol, acetone, methylene chloride and the like.
The following examples will further illustrate certain aspects of the invention in greater detail and are not intended to limit the scope of the invention.

Unless otherwise specified this invention is directed towards achieving the ascending type release of metformin hydrochloride from extended release tablets using sustain released polymers.
In one of the embodiment of this invention the core of the tablet is of osmotic or non osmotic type and release is governed by hydrophilic and hydrophobic polymers within the core. The ascending type of drug release is modulated by using a typical coating composition containing hydrophilic and hydrophobic polymers along with typical combination of polymers in core tablet.
The particle size of the sitagliptin phosphate monohydrate in a pharmaceutical composition or dosage form of the present invention is below 200 microns. Preferably, more than 90% of the particles have a particle size between 10 to 500 microns. The particle size of 90% of the metformin hydrochloride is below 1000 microns.
Dosage forms include, but are not limited to tablets, capsules, chewing gum and lozenges. The dosage forms also include immediate release, controlled, extended, sustained and delayed release. Most preferably the dosage forms are extended release tablets or capsules.
Following are the non limiting examples for making the double layer tablet with extended release core tablets with rate controlling polymers to achieve the desired ascending type release and an immediate release portion on the second layer.
Example 1
Extended release core matrix composition using combination of different hydrophilic
and hydrophobic substances

Ingredients B4 B5 B6 B8 B10
Extended Release layer % w/w
Metformin HCI 55.56 55.56 55.56 55.56 55.56
Microcrystalline cellulose 3.89 6.94 6.94 3.89 3.89
HPMC 2208 22.22 17.22 5.56 17.22 12.22
Polyacrylic acid -- 5.00 — 5.00 „
Xanthan gum 3.06 — — 3.06 3.06
Sodium alginate — — 16.67 ~ —
Stearic acid — — — ~ 10.00
Silicon dioxide 0.56 0.56 0.56 0.56 0.56
Magnesium stearate 0.83 0.83 0.83 0.83 0.83

Weight of ER layer 86.11 86.11 86.11 86.11 86.11
Immediate Release layer % w/w
Sitagliptin phosphate monohydrate 7.14 7.14 7.14 7.14 7.14
Microcrystalline cellulose 1.19 1.19 1.19 1.19 1.19
Croscarmellose sodium 1.39 1.39 1.39 1.39 1.39
Starch 1.11 1.11 1.11 1.11 1.11
Lactose 2.72 2.72 2.72 2.72 2.72
Silicon dioxide 0.14 0.14 0.14 0.14 0.14
Sodium stearyl Fumarate 0.14 0.14 0.14 0.14 0.14
FD&C Yellow #6 0.06 0.06 0.06 0.06 0.06
Weight of IR layer 13.89 13.89 13.89 13.89 13.89
Total weight% 100.00 100.00 100.00 100.00 100.00
Tabel
Dissolution profiles of Metformin hydrochloride tablet with extended release core matrix in dissolution water with 900 ml media volume at 100 rpm speed by using USP Type II apparatus (with sinker) with respect to Janumet XR 100/1000mg tablet.

Time in
Hrs. Janumet XR B4 B5 B6 B8 B10

% w/w Metformin hydroc ;hloride Released
0 0 0 0 0 0 0
2 42 47 45 52 45 50
4 64 68 65 73 65 70
6 78 81 78 87 78 84
10 95 96 93 100 94 97
14 100 101 98 102 100 101
% w/w Sitagliptin released
0 0 0 0 0 0 0
15 62 72 70 75 68 78
30 95 98 99 98 99 97
45 100 99 100 99 100 99
60 101 100 100 100 100 100
Table 2
Manufacturing Process
1. Metformin hydrochloride was sifted together with rate controlling excipients except lubricants through ASTM # 40 mesh and can be used directly for direct compression with extra granular lubricants

2. Lubricants sifted through ASTM # 60 mesh and dry mix of step 1 were lubricated for 5 mins.
3. Sitagliptin phosphate monohydrate was sifted together with other excipients except lubricants through ASTM # 40 mesh and can be used directly for direct compression with extra granular lubricants.
4. Lubricants sifted through ASTM # 60 mesh and dry mix of step 1 were blended for 5 mins.
5. FDC yellow # 6 color was passed through ASTM # 100 mesh and mixed geometrically with the sitagliptin blend of step 3.
6. Final lubricated blend of step 2 (as extended release layer) and step 5 (as immediate release layer) was compressed into Bilayer tablet for performing dissolution test.
7. Dissolution test was performed in water with 900 ml media volume at 100 rpm speed by using USP Type II apparatus (with sinker) with respect to Janumet XR 100/1000mg tablet.
Example 2
Extended release core matrix composition using hydrophobic substance in wet
granulation

Ingredients B11 B12 B13 B14
Extended Release layer % w/w
Metformin HCI 54.05 54.05 54.05 54.05
Ethyl cellulose 2.70 2.70 2.70 2.70
HPMC 2208 24.60 21.62 21.62 24.60
HPMC 2208 — 2.98 — —
Xanthan Gum — — 2.98 —
Microcrystalline cellulose 3.41 3.41 3.41 3.41
Silicon dioxide 0.86 0.86 0.86 0.86
Magnesium stearate 0.86 0.86 0.86 0.86
Total 86.49 86.49 86.49 86.49
Immediate Release layer % w/v t
Sitagliptin phosphate monohydrate 6.95 6.95 6.95 6.95
Microcrystalline cellulose 1.16 1.16 1.16 1.16
Crosscarmellose sodium (Ac-di-sol) 1.35 1.35 1.35 1.35
Starch 1.08 1.08 1.08 1.08
Lactose 2.65 2.65 2.65 2.65
Silicon dioxide 0.14 0.14 0.14 0.14
Sodium stearyl fumarate 0.14 0.14 0.14 0.14
FD&C Yellow #6 0.05 0.05 0.05 0.05
Weight of IR layer 13.51 13.51 13.51 13.51
Total weight% 100.00 100.00 100.00 100.00
Table 3

Dissolution Profile

Time in hrs. Janumet XR 100/1000 B11 B12 B13 B14
% w/w Metformin hydrochloride releasec
0 0 0 0 0 0
2 42 45 48 51 47
4 64 64 68 61 64
6 78 77 81 71 77
10 95 94 97 84 92
14 100 101 103 99 98
% w/w Sitagliptin released
0 0 0 0 0 0
15 62 77 68 71 79
30 95 98 99 100 99
45 100 99 100 101 100
60 101 100 100 101 100
Table 4
Manufacturing Process
1. Metformin hydrochloride was sifted and granulated with ethyl cellulose solution in iso-propyl alcohol, then dried granules were mixed together with rate controlling excipients except lubricants through ASTM # 40 mesh and can be used directly for direct compression with extra granular lubricants
2. Lubricants sifted through ASTM # 60 mesh and dry mix of step 1 were lubricated for 5 mins.
3. Sitagliptin phosphate monohydrate was sifted together with other excipients except lubricants through ASTM # 40 mesh and can be used directly for direct compression with extra granular lubricants.
4. Lubricants sifted through ASTM # 60 mesh and dry mix of step 1 were blended for 5 mins.
5. FDC yellow # 6 color was passed through ASTM # 100 mesh and mixed geometrically with the Sitagliptin blend of step 3.
6. Final lubricated blend of step 2 (as extended release layer) and step 5 (as immediate release layer) was compressed into bilayer tablet for performing dissolution test.
7. Dissolution test was performed in water with 900 ml media volume at 100 rpm speed by using USP Type !! apparatus (with sinker) with respect to Janumet XR 100mg/1000mg tablet.

Example 3
Extended release core composition with wax granulated API and hydrophilic
polymers

Ingredients
B15 B16
Extended Release layer % w/w
Metformin HCI 54.05 54.05
HPMC 2208 21.62 21.62
HPMC 2208 1.89 1.69
Cetostearyl Alcohol 3.78 —
Glyceryl Behenate — 3.24
Microcrystalline cellulose 3.41 3.95
Silicon dioxide 0.86 0.86
Magnesium stearate 0.86 0.86
Total 86.49 86.49
Immediate Release layer % w/w
Sitagliptin phosphate monohydrate 6.95 6.95
Microcrystalline cellulose 1.16 1.16
Croscarmellose sodium 1.35 1.35
Starch 1.08 1.08
Lactose 2.65 2.65
Silicon dioxide 0.14 0.14
Sodium stearyl fumarate 0.14 0.14
FD&C Yellow #6 0.05 0.05
Weight of/R layer 13.51 13.51
Total weight% 100.00 100.00

Table 5
Dissoluti
on Profile Table 6

Time (Hr.) Janumet XR 100/1000 B15 B16
% Metformin Rele ased
0 0 0 0
2 42 48 45
4 64 67 64
6 78 80 77
10 95 95 94
14 100 101 100
% Sitagliptin Rele< ased
Time (Min) JanumetXR 100/1000 B15 B16
0 0 0 0
15 62 71 65
30 95 98 96
45 100 100 99
60 101 100 100
Manufacturing Process

1. Metformin hydrochloride API was sifted and granulated with wax solution in ethyl alcohol, then dried granules were mixed together with rate controlling excipients except lubricants through ASTM # 40 mesh.
2. Lubricants sifted through ASTM # 60 mesh and dry mix of step 1 were lubricated for 5 mins.
3. Sitagliptin phosphate monohydrate API was sifted together with other excipients except lubricants through ASTM # 40 mesh and can be used directly for direct compression with extra granular lubricants.
4. Lubricants sifted through ASTM # 60 mesh and dry mix of step 1 was blended for 5 mins.
5. FDC yellow # 6 color was passed through ASTM # 100 mesh and mixed geometrically with the Sitagliptin blend of step 3.
6. Final lubricated blend of step 2 (as extended release layer) and step 5 (as immediate release layer) was compressed into bilayer tablet for performing dissolution test.
7. Dissolution test was performed in water with 900 ml media volume at 100 rpm speed by using USP Type II apparatus (with sinker) with respect to Janumet XRl00mg/1000mg tablet.
Example 4
Extended release core composition with hydrophobic granulated API and polymers

Ingredients B18 B19 B20
Extended Release Layer % ) W/W
Metformin HCI 54.05 54.05 54.05
Ethyl Cellulose 5.41
Stearic acid — 5.41 5.41
HPMC 2208 21.62 21.62 16.76
HPMC 2208 1.89 1.89 1.89
Polyacrylic acid — ~ 4.86
Microcrystalline cellulose 1.83 1.83 1.83
Silicon dioxide 0.86 0.86 0.86
Magnesium stearate 0.86 0.86 0.83
Total 86.49 86.49 86.49
Immediate Release Layer % 'W/W
Sitagliptin phosphate monohydrate 6.95 6.95 6.95
Microcrystalline cellulose 1.16 1.16 1.16
CrosearmeIlose sodium 1.35 1.35 1.35
Starch 1.08 1.08 1.08
Lactose 2.65 2.65 2.65
Silicon dioxide 0.14 0.14 0.14
Sodium stearyl Fumarate 0.14 0.14 0.14
FD&C Yellow #6 0.05 0.05 0.05
Weight of IR layer 13.51 13.51 13.51

Total weight% 100.00 I 100.00 100.00
Table 7 Dissolution Profile

Time (Hr) Janumet XR 100/1000 B18 B19 B20
% Metformin Released
0 0 0 0 0
2 42 46 42 43
4 64 64 59 61
6 78 76 73 74
10 95 92 90 90
14 100 99 98 99
% Sitagliptin Released
Time (Min) Janumet XR 100/1000 B18 B19 B20
0 0 0 0 0'
15 62 69 70 68
30 95 98 97 99
45 100 99 100 100
60 101 100 100 100
Table 8
Manufacturing Process
1. Metformin hydrochloride was sifted and granulated with ethyl cellulose solution in iso-propyl alcohol or Stearic acid solution in ethyl alcohol, then dried granules of each composition were mixed separately with rate controlling excipients except lubricants through ASTM # 40 mesh and can be used directly for direct compression with extra granular lubricants
2. Lubricants sifted through ASTM # 60 mesh and dry mix of step 1 were lubricated for 5 mins.
3. Sitagliptin phosphate monohydrate was sifted together with other excipients except lubricants through ASTM # 40 mesh and can be used directly for direct compression with extra granular lubricants.
4. Lubricants sifted through ASTM # 60 mesh and dry mix of step 1 were blended for 5 mins.
5. FDC yellow # 6 color was passed through ASTM # 100 mesh and mixed geometrically with the Sitagliptin blend of step 3.

6. Final lubricated blend of step 2 (as extended release layer) and step 5 (as immediate release layer) was compressed into bilayer tablet for performing dissolution test.
7. Dissolution test was performed in water with 900 ml media volume at 100 rpm speed by using USP Type II apparatus (with sinker) with respect to Janumet XR 100mg/1000mg tablet.
Example 5
Extended release core composition with Cellulose acetate granulated API and
sustained release polymers

Table 9 Dissolution Profile

Ingredients B22 B23 B24
Extended Release Layer % w/w
Metformin HCI 54.05 51.28 51.28
Cellulose acetate 5.41 5.13 5.13
HPMC 2208 21.62 20.51 20.51
HPMC 2208 — — 4.62
Polyacrylic acid — 4.62 —
HPMC 2910 2.81 2.67 2.67
Microcrystalline cellulose 1.73 2.10 2.10
Silicon dioxide 0.43 0.44 0.44
Magnesium Stearate 0.43 0.44 0.44
Weight of ER layer 86.49 87.18 87.18
Immediate Release Layer 0.00 0.00 0.00
Sitagliptin phosphate monohydrate 6.95 6.59 6.59
Microcrystalline cellulose 1.16 1.10 1.10
Croscarmellose sodium 1.35 1.28 1.28
Starch 1.08 1.03 1.03
Lactose 2.65 2.51 2.51
Silicon dioxide 0.14 0.13 0.13
Sodium steryl Fumarate 0.14 0.13 0.13
FD&C Yellow #6 0.05 0.05 0.05
Weight of IR layer 13.51 12.82 12.82
Total weight% 100.00 100.00 100.00

Time (Hr) Janumet XR 100/1000 B22 B23 B24
% Metformin Released
0 0 0 0 0
2 42 46 43 48
4 64 65 61 67
6 78 78 73 80
10 95 94 89 97
14 100 101 97 104
% Sitagliptin Released

Time (Min) Janumet XR 100/1000 B22 B23 B24
0 0 0 0 0
15 62 68 65 67
30 95 96 97 99
45 100 99 100 100
60 101 100 100 100
Table 10
Example 6
Extended release core composition with pH dependent polymer granulated API and
polymers

t able 11 Dissolution Profile

Ingredients B25 B26 B27
Extended Release Layer % w/w
Metformin HCI 48.78 48.78 50.00
Cellulose acetate 4.88 4.88 5.00
HPMC 2208 19.51 19.51 20.00
HPMC 2208 4.39 —
Polyacrylic acid — 4.39 4.50
HPMC 2208 2.54 2.54 2.60
Xanthan Gum 5.07 5.07 —
Kollidon SR — — 2.30
Sodium Alginate — — —
MCC 200 1.76 1.76 2.20
Aerosil 0.44 0.44 0.45
Magnesium Stearate 0.44 0.44 0.45
Weight of ER layer 87.80 87.80 87.50
Immediate Release Layer 0.00 0.00 0.00
Sitagliptin phosphate monohydrate 6.95 6.59 6.59
Microcrystalline cellulose 1.16 1.10 1.10
Croscarmellose sodium 1.35 1.28 1.28
Starch 1.08 1.03 1.03
Lactose 2.65 2.51 2.51
Silicon dioxide 0.14 0.13 0.13
Sodium steryl Fumarate 0.14 0.13 0.13
FD&C Yellow #6 0.05 0.05 0.05
Weight of IR layer 12.20 12.20 12.20
Total weight% 100.00 100.00 100.00

Time (Hr) Janumet XR 100/1000 B25 B26 B27
% Metformin Released
0 0 0 0 0
2 42 44 41 44
4 64 61 58 62

6
78 73 70 74
10 95 89 86 91
14 100 99 96 99
% Sitagliptin Released
Time
(Min) Janumet XR 100/1000 B25 B26 B27
0 0 0 0 0
15 62 69 66 61
30 95 96 97 99
45 100 99 100 100
60 101 100 100 100
Tablet 12
Example 7
Extended release core matrix composition using Spray dried Metformin hydrochloride
with pH dependent and pH independent polymers

Ingredients B29A B29B B30A B30B B31 A B31 B

%w/w %w/w %w/w %w/w %w/w %w/w
Ext ended Rel ease Layer
Metformin HCI 51.28 51.28 51.28 51.28 51.28 51.28
HPMCP 55 15.38 15.38 0 0 0 0
Cellulose Acetate 0 0 15.38 15.38 0 0
Ethyl cellulose 0 0 0 0 15.38 15.38
HPMC 2208 15.38 10.77 15.38 10.77 15.38 10.77
HPMC 2208 2.56 2.56 2.56 2.56 2.56 2.56
Carbopol 4.62 4.62 4.62
Microcrystalline cellulose 1.74 1.74 1.74 1.74 1.74 1.74
Silicon dioxide 0.41 0.41 0.41 0.41 0.41 0.41
Magnesium Stearate 0.41 0.41 0.41 0.41 0.41 0.41
Weight of ER layer 87.18 87.18 87.18 87.18 87.18 87.18
Immedia te Release Layer
Sitagliptin phosphate mono hydrate 6.59 6.59 6.59 6.27 6.59 6.59
Microcrystalline cellulose 1.1 1.1 1.1 1.05 1.1 1.1
Croscarmellose sodium 1.28 1.28 1.28 1.22 1.28 1.28
Starch 1.02 1.02 1.02 0.97 1.02 1.02

Table 13 Dissolution Profile
Lactose 2.51 2.51 2.51 2.39 2.51 2.51
Silicon dioxide 0.13 0.13 0.13 0.13 0.13 0.13
Sodium stearyl Fumarate 0.13 0.13 0.13 0.13 0.13 0.13
FD&C Yellow #6 0.05 0.05 0.05 0.05 0.05 0.05
Weight of IR layer 12.83 12.83 12.83 12.2 12.83 12.83
Total weight 100 100 100 100 100 100

Time in Hrs B29A B29B B 30A B 30B B31 A B31 B
% w/w Metformin hydrochloride released
0 0 0 0 0 0 0
2 43 46 44 43 44 45
4 63 63 63 60 61 62
6 75 74 76 72 73 73
10 90 88 93 87 88 88
14 97 93 103 96 96 95
% w/w Sitagliptin released
0 0 0 0 0 0 0
15 min 70 66 60 65 63 70
30 min 96 97 95 98 96 98
45 min 99 100 99 100 99 100
60 min 100 100 100 100 100 100
Table 14
Example 8
Extended release core matrix composition by using hydrophilic gel forming polymer

Ingredients B36
Extended Release Layer %w/w
Metformin HCI 55.56
HPMC 2208 25.00
Microcrystalline cellulose 3.89
Silicon dioxide 0.83
Sodium stearyl Fumarate 0.83
Weight of ER layer 86.10
Immediate Release Layer 0.00
Sitagliptin phosphate monohydrate 7.14
Microcrystalline cellulose 1.19
Croscarmellose sodium 1.39
Starch 1.11
Lactose 2.72
Silicon dioxide 0.14

Total 100.0
Table 15 Dissolution Profile

Time (Hr) Janumet XR B36
% Metformin Released
0 0 0
2 42 45
4 64 65
6 78 79
10 95 95
14 100 100
% Sitagliptin Released
Time (Min) Janumet XR B36
0 0 0
15 62 65
30 95 96
45 100 99
60 101 100
Table 16
Manufacturing Process
1. Metformin hydrochloride was sifted together with rate controlling excipients except lubricants through ASTM # 40 mesh and can be used directly for direct compression with extra granular lubricants
2. Lubricants sifted through ASTM # 60 mesh and dry mix of step 1 were lubricated for 5 mins.
3. Sitagliptin phosphate monohydrate was sifted together with other excipients except lubricants through ASTM # 40 mesh and can be used directly for direct compression with extra granular lubricants.
4. Lubricants sifted through ASTM # 60 mesh and dry mix of step 1 were blended for 5 mins.
5. FDC yellow # 6 color was passed through ASTM # 100 mesh and mixed geometrically with the Sitagliptin blend of step 3.
6. Final lubricated blend of step 2 (as extended release layer) and step 5 (as immediate release layer) was compressed into Bilayer tablet for performing dissolution test.

7. Dissolution test was performed in water with 900 ml media volume at 100 rpm speed by using USP Type II apparatus (with sinker) with respect to Janumet XR 100/1000 mg tablet.
Example 9
Extended release core matrix composition by using a cross linking gel forming
polymer.

Table
17
Dissol ution
Profile

Ingredients B38 B39
Extended Release layer % w/w
Metformin HCI 51.28 51.28
Microcrystalline cellulose 2.21 2.21
HPMC 2208 20.51 20.51
Sodium Alginate 7.69 7.69
Calcium Chloride 3.85 —
Calcium Silicate — 3.85
Aerosil 200 0.82 0.82
Magnesium stearate 0.82 0.82
Total 87.18 87.18
Immediate Release layer % w/w
Sitagliptin phosphate monohydrate 6.95 6.95
Microcrystalline cellulose 1.16 1.16
Crosscarmellose sodium (Ac-di-sol) 1.35 1.35
Starch 1.08 1.08
Lactose 2.65 2.65
Silicon dioxide 0.14 0.14
Sodium stearyl fumarate 0.14 0.14
FD&C Yellow #6 0.05 0.05
Weight of IR layer 12.82 12.82
Total weight% 100.00 100.00

Time (Hr) Janumet XR 100/1000 B38 B39
% Metformin Re eased
0 0 0 0
2 42 47 40
4 64 66 56
6 78 79 67
10 95 92 81
14 100 95 88
% Sitagliptin Re eased
Time {Min) Janumet XR 100/1000 B38 B39
0 0 0 0
15 62 66 70
30 95 96 98
45 100 99 99
60 101 100 100
Table 18

Example 10
Extended release core matrix composition by using a cross linking gel forming
polymer in combination with HMPC 2208

Table 19 Dissolution profile

Ingredients B40 B41 B42 B44 B45

%w/w %w/w %w/w %w/w %w/w
Extended Release Layer
Metformin HCi 53.33 48.78 49.38 50.00 50.00
Hydrogenated vagetable oil — — — 12.50 12.50
Dicalcium Phosphate 2.29 2.10 2.12 0.90 3.40
HPMC 2208 21.33 19.51 19.75 15.00 20.00
HPMC 2208 8.00 7.32 3.70 7.50 —
Sodium Alginate 4.88 7.41 —
Calcium Silicate 3.66 — — —
Calcium Chloride 0.00 0.00 3.70 0.00 0.00
Aerosil 200 0.85 0.78 0.79 0.80 0.80
Magnesium stearate 0.85 0.78 0.79 0.80 0.80
Weight of ER layer 87.17 87. 17 87.17 87.17 87.17
mmediate Re lease Layer
Sitagliptin phosphate monohydrate 6.59 6.59 6.59 6.27 6.59
Microcrystalline cellulose 1.1 1.1 1.1 1.05 1.1
Croscarmellose sodium 1.28 1.28 1.28 1.22 1.28
Starch 1.02 1.02 1.02 0.97 1.02
Lactose 2.51 2.51 2.51 2.39 2.51
Silicon dioxide 0.13 0.13 0.13 0.13 0.13
Sodium steryl Fumarate 0.13 0.13 0.13 0.13 0.13
FD&C Yellow #6 0.05 0.05 0.05 0.05 0.05
Weight of IR layer 12.83 12.83 12.83 12.2 12.83
Total weight% 100 100 100 100 100

Time (Hr) Janumet XR 100/1000 B40 B41 B42 B44 B45
% Metr ormin Re eased
0 0 0 0 0 0 0
2 42 44 40 45 46 47
4 64 62 55 64 63 64
6 78 74 66 77 75 76

10 95 90 82 91 90 91
14 100 97 91 97 96 96
% Sitagliptin Released
Time (Min) Janumet XR 100/1000 B40 B41 B42 B44 B45
0 0 0 0 0 0 0
15 62 64 71 69 73 65
30 95 96 98 95 97 98
45 100 99 100 99 100 100
60 101 100 100 100 100 100
Table 20
AN patent and non-patent publications cited in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.
Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims
1. A bilayer pharmaceutical composition comprising a core matrix containing metformin hydrochloride and a release rate controlling polymer, and an immediate release layer composition containing sitagliptin phosphate monohydrate surrounding the core matrix.
2. The bilayer pharmaceutical composition of claim 1, wherein the core matrix is prepared by aqueous or non-aqueous granulation.
3. The bilayer pharmaceutical composition of claim 1, wherein the core matrix is prepared by direct compression.
4. The bilayer pharmaceutical composition of claim 1, wherein the core matrix is prepared by roller compaction.
5. The bilayer pharmaceutical composition of claim 1, wherein the core matrix is prepared by spray dried technique.
6. The bilayer pharmaceutical composition of claim 1, wherein the release rate controlling polymer is selected from the group consisting of hydrophilic, hydrophobic or mixtures thereof.
7. The bilayer pharmaceutical composition of claim 1, wherein sitagliptin phosphate monohydrate is having d90 particle size between 10 to 500 microns.
8. The bilayer pharmaceutical composition of claim 1, wherein metformin HCI is having d90 particle size below 1000 microns.