Description:TECHNICAL FIELD:
The present invention generally relates to pharmaceutical sciences. Specifically, the present invention provides a pharmaceutical composition comprising the DPP-IV inhibitor. The present invention further provides the pharmaceutical composition comprising DPP IV inhibitor, optionally in combination with other antidiabetic agent wherein said composition is easy to administer, patient compliant and cost effective. The present invention further provides the process for preparation of pharmaceutical composition comprising the DPP IV inhibitor optionally in combination with other antidiabetic agents.
BACKGROUND OF THE INVENTION
Diabetes is one of the most common lifestyle disorders in India since last few decades. India has infamously been called as "diabetes capital of the world".
Diabetes mellitus, commonly known as diabetes, is a metabolic disease that causes high blood sugar. The hormone insulin moves sugar from the blood into cells to be stored or used for energy. With diabetes, body either doesn’t make enough insulin or can’t effectively use the insulin it does make. Over time, that can cause serious health problems, such as heart disease, stroke, kidney disease, eye problems, dental disease, nerve damage, foot problems.
There are three main types of diabetes: type 1, type 2, and gestational diabetes (diabetes while pregnant).
Type 1 diabetes is thought to be caused by an autoimmune reaction (the body attacks itself by mistake) that stops the body from making insulin. Approximately 5-10% of the people who have diabetes have type 1. Symptoms of type 1 diabetes often develop quickly. It’s usually diagnosed in children, teens, and young adults.
With type 2 diabetes, the body doesn’t use insulin well and can’t keep blood sugar at normal levels. About 90-95% of people with diabetes have type 2. It develops over many years and is usually diagnosed in adults (but more and more in children, teens, and young adults). There may not be any symptoms, so it’s important to get blood sugar tested if you’re at risk. Type 2 diabetes can be prevented or delayed with healthy lifestyle changes, such as losing weight, eating healthy food, and being active.
Gestational diabetes develops in pregnant women who have never had diabetes. If a pregnant woman has gestational diabetes, the baby could be at higher risk for health problems. Gestational diabetes usually goes away after the baby is born but increases the risk for type 2 diabetes later in life. Also, the baby is more likely to have obesity as a child or teen, and more likely to develop type 2 diabetes later in life too.
There are various lines of treatment of diabetes based on the type of diabetes, severity level, age of patient, responsiveness to medication, route of administration. Insulin therapy is the most common line of treatment especially for Type 1 diabetes, as Insulin is not generated in Type 1 diabetes. Injected insulin acts just like naturally occurring insulin to lower blood glucose levels. Type 2 diabetes can be managed by lifestyle changes such as diet and exercise along with Medications. The various categories of medications help to maintain the blood glucose levels. The different categories of drugs that are normally prescribed for management of type 2 diabetes are: Biguanides, DPP-4 inhibitors, Glucagon-like peptides (incretin mimetics), Meglitinides, SGLT2 inhibitors, Sulfonylureas, Thiazolidinediones, Alpha-glucosidase inhibitors, amylin analogs.
DPP-4 inhibitors are used along with diet and exercise to lower blood sugar in adults with type 2 diabetes. DPP-4 is a ubiquitous enzyme that acts on incretin hormones, mainly GLP-1 (glucagon-like peptide-1) and GIP (gastric inhibitory peptide), which maintain glucose homeostasis by increasing insulin secretion and decreasing glucagon secretion. GLP-1 is a hormone secreted by enteroendocrine L cells of the small intestine, which lowers blood glucose by stimulating insulin secretion, reducing glucagon concentrations, and delaying gastric emptying. It has a half-life of fewer than 2 minutes. GIP is a hormone secreted in the stomach and proximal small intestine by neuroendocrine K-cells. Its half-life is approximately 7 minutes in healthy individuals and 5 minutes in individuals with type 2 diabetes. These incretins are released within minutes of food intake, and DPP-4 degrades these hormones immediately due to their short half-life. By inhibiting the DPP-4 enzyme, DPP-4 inhibitors increase the levels of GLP-1 and GIP, which in turn increase beta-cell insulin secretion in the pancreas, thereby reducing postprandial and fasting hyperglycemia. DPP-4 inhibitors according to present invention is selected from group comprising but not limiting to sitagliptin, saxagliptin, linagliptin, alogliptin, vildagliptin.
There are various marketed products for the management of type 2 diabetes: Kazano®, Invokamet®, Xigduo XR®, Synjardy®, Glucovance®, Jentadueto®, Actoplus®, PrandiMet®, Avandamet®, Kombiglyze XR®, Janumet®, Januvia®, Tradjenta®, Glyxambi®, Jentadueto®, Onglyza®, Juvisync®, Nesina®, Tanzeum®, Byetta®, Victoza®, Bydureon®, Starlix®, Prandin®, Prandimet®, Farxiga®, Invokana®, Invokamet®, Jardiance®, Glyxambi®, Steglatro®.
Further, there are several products that are co-administered with one or more other antidiabetic agent.
There are several other prior art documents disclosing various compositions for the treatment of diabetes.
WO 2007/041053 relates to a tablet in which metformin is contained as intragranular component and vildagliptin is present as extragranular component. The metformin-containing granules may be prepared by wet-granulation or melt-granulation.
IN 202241025069 relates to a synergistic pharmaceutical formulation for treating diabetic mellitus comprises of characterized combination of therapeutically effective amount of Vitamin B12, Benfotiamine and Insulin along with pharmaceutically 5 acceptable carriers.
WO2017211979 relates to combinations of Linagliptin with metformin for use int he treatment of metabolic diseases in patients having chronic kidney disease.
There are several formulations available in the prior art comprising antidiabetic agents alone or in combinations of two or more different categories of drugs in single dosage form. However, there is still a need in the art to provide a single unit dosage form which comprises two antidiabetic drugs which are incompatible with each other. Further, the treatment of diabetes is for long term and patient may need to administer the drugs for lifetime. Therefore, it is very essential that the formulation comprising the antidiabetic drug is easy to administer, gives good patient experience, and cost effective. Also, it is very crucial to provide the dosage form comprising the immediate release drug and sustained release drug in a single unit dosage form.
The present inventors, however, have come up with a unique solution for various issues and provides a stable, novel pharmaceutical composition which comprises antidiabetic agent more specifically DPP IV inhibitor alone or in combination with other antidiabetic drugs, wherein the said composition is easy to administer, patient compliant and provides the immediate release and/or sustained release of drugs in a single unit dosage form. The present invention provides the composition with reduced dosing frequency and provides the good patient experience while administering the composition. Further, the composition according to the present invention can be administered by all age groups of patients, without any swallowing issue.
Further, to address the growing concern of swallowability and to overcome the “fear” of “choking/gagging” during administration of solid dosage form, current inventors have come up with an invention which makes the surface of tablet slippery upon contact with water to provide “glide” effect during oropharyngeal transit. The present invention provides the unique characteristic of coating with specialized polymer system to enable the tablet to “glide” from mouth to stomach and improve ease of swallowing by patients. The composition according to present invention demonstrates better wet-slip behavior upon contact with water & differentiates prominently from other conventional film coating systems that often tend to stick and impacts oropharyngeal transit of tablet. Thus, the composition according to the present invention can be administered by all age groups of patients, without any swallowing issue.
OBJECT OF THE INVENTION
One object of the present invention is to provide a stable pharmaceutical composition comprising antidiabetic drug.
Another object of the present invention is to provide a stable pharmaceutical composition comprising DPP-IV, optionally in the combination with other antidiabetic drugs.
Another object of the present invention is to provide a stable pharmaceutical composition in the form of bilayer tablet further comprising the combination of antidiabetic drugs.
Yet another object of the present invention is to provide the stable pharmaceutical composition in the form of bilayer tablet wherein one layer is immediate release layer and other layer is sustained release layer.
Yet another object of the present invention is to provide the process for preparation of stable pharmaceutical composition comprising the DPP-IV inhibitor.
Yet another object of the present invention is to provide the process for preparation of stable pharmaceutical composition comprising the combination of antidiabetic drugs.
Other objects of the present invention will be apparent from the description of the invention herein below.
SUMMARY OF THE INVENTION
The present invention provides a stable pharmaceutical composition comprising DPP-IV inhibitor optionally in combination with other antidiabetic agent.
In one aspect the present invention provides the stable pharmaceutical composition comprising DPP-IV inhibitor and one or more pharmaceutically acceptable excipients.
In another aspect, the present invention provides the stable pharmaceutical composition in the form of bilayer tablet comprising DPP-IV inhibitor optionally with another antidiabetic agent, wherein one layer is immediate release layer, and another layer is sustained release layer. The immediate release and sustained release layer essentially comprise two different antidiabetic agents.
In another aspect, the present invention provides the stable pharmaceutical composition in the form of bilayer tablets wherein the said formulation is easy to administer, patient compliant and can be administered by all the patient groups without any swallowing issues.
In another aspect the present invention provides the stable pharmaceutical composition in the form of bilayer tablet dosage form, wherein the said formulation comprises:
i) a sustained release layer comprising first antidiabetic agent,
ii) a immediate release layer comprising DPP-IV inhibitor,
iii) a coating layer,
iv) one or more pharmaceutically acceptable excipients.
wherein, the said composition can be easily swallowed.
In one aspect, the present invention also provides a process for the preparation of the stable pharmaceutical composition in the form of bilayer tablet dosage form comprising the sustained release layer, an immediate release layer, a coating layer and one or more pharmaceutically acceptable excipients.
DETAILED DESCRIPTION OF THE INVENTION
The invention will now be described in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully interpreted and comprehended. However, any skilled person or artisan will appreciate the extent to which such embodiments could be generalized in practice.
The term “composition” herein refers to the combination of one or more drug substances and one or more excipients, “drug product”, “pharmaceutical dosage form”, “dosage form,” “final dosage form” and the like, refer to a pharmaceutical composition and/or nutritional composition that is administered to a subject in need of treatment and generally may be in the form of tablets, capsules, tablets filled in capsule, gummies, gels, organogels, semisolid, creams, mini tablets filled in capsule, sachets containing powder or granules, pellets, liquid solutions or suspensions, patches and the like.
The term "stable" refers to a minimal change in physical and chemical properties of the composition over time relative to when it is manufactured. Stability over time may be evaluated based on pre-defined criteria including assay of active and related compounds, appearance, color, and pH.
The term “Sustained Release” herein refers to any formulation or dosage form that comprises an active drug and which is formulated to release the drug for sustained time duration and to provide a longer duration of pharmacological response after administration of the dosage form than is ordinarily not experienced after administration of a corresponding immediate release formulation comprising the same drug in the same amount.
Sustained release formulations include, inter alia, those formulations described elsewhere as “controlled release”, “delayed release”, “sustained release”, “prolonged release”, “extended release”, “programmed release”, “time release” and/or “rate controlled” formulations or dosage forms. Further for the purposes of this invention refers to release of an active pharmaceutical agent over a long period of time, such as for example over a period of 8, 12, 16 or 24 hours. By “pharmaceutically acceptable” is meant a carrier comprised of a material that is not biologically or otherwise undesirable.
The present invention discloses easy to administer, patient compliant, stable, oral composition, wherein the said composition comprises DPP-IV inhibitor and one or more pharmaceutically acceptable excipients.
In one embodiment, the pharmaceutical composition is an immediate release dosage form.
In yet another embodiment, the drug is released from the pharmaceutical composition within less than 60 minutes, preferably within less than 45 minutes, more preferably within less than 30 minutes.
In yet another embodiment, the pharmaceutical composition can be prepared by processes well known to those of skill in the art. For example, core tablets can be prepared by direct compression, wet granulation, dry granulation, melt granulation and the like.
In yet another embodiment, the pharmaceutical composition is in the form of solid oral dosage form such as tablet, capsule, granules, sachet, a tablet with or without coating, bilayer tablet, functional coated tablets or caplets, time-release tablets or caplets, floating tablets, matrices containing polymer, controlled release beads, granules, spheroids that are contained within a capsule or administered from sachet or other unit dose powder device in combination with other beneficial drugs or as a combination kit of prolonged release dosage forms for the administration in mammals.
In a preferred embodiment, the present invention provides the immediate release pharmaceutical composition comprising:
i) DPP-IV inhibitor drug;
ii) One or more pharmaceutically acceptable excipients,
wherein said composition is easily swallowable upon administration.
In another embodiment, the DPP-4 inhibitors according to present invention is selected from group comprising but not limiting to sitagliptin, Saxagliptin, linagliptin, alogliptin, vildagliptin.
In yet another embodiment the present invention comprises the immediate release pharmaceutical composition comprising:
i) Sitagliptin or pharmaceutically acceptable salts thereof;
ii) One or more pharmaceutically acceptable excipients;
wherein the said composition is easily swallowable upon administration.
In yet another embodiment, the sitagliptin or pharmaceutically acceptable salts thereof in the immediate release pharmaceutical composition is present in the amount range of 10%w/w to 50%w/w.
In yet another embodiment, the sitagliptin or pharmaceutically acceptable salts thereof in the immediate release pharmaceutical composition is present in the amount range of 15%w/w to 40 %w/w.
In yet another embodiment the pharmaceutical composition optionally comprises another antidiabetic agent.
In one feature, pharmaceutical composition optionally comprises another antidiabetic agent which are selected from but not limiting to various classes such as: Biguanides, Glucagon-like peptides (incretin mimetics), Meglitinides, SGLT2 inhibitors, Sulfonylureas, Thiazolidinediones, Alpha-glucosidase inhibitors, amylin analogs.
In another feature, the antidiabetic agent is preferably selected from Biguanide class.
Biguanides are a group of oral antihyperglycemic drugs that work by preventing the production of glucose in the liver, improving the body’s sensitivity to insulin, and reducing the amount of sugar absorbed by the intestines. Biguanides work in various ways as follows: they reduce the production of glucose during digestion by decreasing the amount of glucose absorbed from the food, they prevent the liver from converting fats and amino acids into glucose, they increase the excretion of sugar by the kidneys, they decrease the amount of sugar that the body absorbs through the stomach and intestines, in addition, they activate an enzyme (AMPK) that increases the sensitivity to insulin (a natural substance that controls the amount of glucose in the blood produced by the pancreas), helping cells to respond more effectively to insulin and use more glucose as energy, and thus reducing the concentration of glucose in the bloodstream. The biguanide according to the present invention is preferably, Metformin.
In one embodiment, the present invention provides the stable pharmaceutical composition comprising DPP-IV inhibitor, optionally another antidiabetic agent and pharmaceutically acceptable excipients, wherein the stable pharmaceutical composition is preferably bilayer tablet dosage form.
In one feature, the bilayer tablet dosage form according to present invention can be prepared by processes well known to those of skill in the art. For example, core tablets can be prepared by direct compression, wet granulation, dry granulation, melt granulation and the like.
In another feature, the present invention provides the bilayer tablet dosage form comprising at least one immediate release layer and at least one sustained release layer.
In another feature, at least one immediate release layer comprising DPP-IV inhibitor and one or more pharmaceutically acceptable excipients.
In another feature, at least one sustained release layer comprises biguanide, at least one release controlling agents, and one or more pharmaceutically acceptable excipients.
In another feature, the bilayer tablet comprising least one immediate release layer and at least one sustained release at layer is optionally coated with suitable coating agent.
In one embodiment, a bilayer tablet comprising least one immediate release layer and at least one sustained release at layer wherein the drug available in the sustained release layer is released for at least 16 hours.
In one embodiment, a bilayer tablet comprising least one immediate release layer and at least one sustained release at layer wherein the drug available in the sustained release layer is released for at least 14 hours.
In one embodiment, a bilayer tablet comprising least one immediate release layer and at least one sustained release at layer wherein the drug available in the sustained release layer is released for at least 12 hours.
In another embodiment, the present invention provides the bilayer tablet dosage form comprising:
i) an sustained release layer comprising first active pharmaceutical ingredient and one more pharmaceutically acceptable excipients;
ii) an immediate release layer comprising second active pharmaceutical ingredient and one more pharmaceutically acceptable excipients;
iii) a coating layer; and
iv) one or more pharmaceutically acceptable excipients;
wherein, said composition is easily swallowable.
In yet another embodiment, the present invention provides the bilayer tablet dosage form comprising:
i) an sustained release layer comprising first active pharmaceutical ingredient selected from biguanide and one more pharmaceutically acceptable excipients;
ii) an immediate release layer comprising second active pharmaceutical ingredient selected from DPP-IV inhibitor and one more pharmaceutically acceptable excipients;
iii) a coating layer; and
iv) one or more pharmaceutically acceptable excipients;
wherein, the said composition is easily swallowable.
In yet another embodiment, the present invention provides the bilayer tablet dosage form comprising:
i) an sustained release layer comprising metformin or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients;
ii) an immediate release layer comprising sitagliptin or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients;
iii) a coating layer; and
iv) one or more pharmaceutically acceptable excipients;
wherein, the said composition is easily swallowable.
In yet another embodiment, the metformin or pharmaceutically acceptable salts thereof in the bilayer tablet pharmaceutical composition is present in the amount range of 30%w/w to 80%w/w of the total tablet weight.
In yet another embodiment, the metformin or pharmaceutically acceptable salts thereof in the bilayer tablet pharmaceutical composition is present in the amount range of 40%w/w to 70%w/w of the total tablet weight.
In yet another embodiment, the sitagliptin or pharmaceutically acceptable salts thereof in the bilayer tablet pharmaceutical composition is present in the amount range of 1%w/w to 15%w/w of the total tablet weight.
In yet another embodiment, the present invention provides the process for preparation of bilayer tablet dosage form.
In one feature, the present invention provides the process for preparation of bilayer tablet dosage form, wherein the said bilayer tablet dosage form comprises:
i) an sustained release layer comprising metformin or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients;
ii) an immediate release layer comprising sitagliptin or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients;
iii) a coating layer; and
iv) one or more pharmaceutically acceptable excipients;
wherein, the said composition is easily swallowable.
In another feature, the present invention provides the process for preparation of bilayer tablet dosage form, wherein the said process comprises following steps:
i) preparing sustained release layer;
ii) preparing immediate release layer;
iii) compressing both layers;
iv) performing seal coating; and
v) performing film coating.

In another feature, the present invention provides the process for preparation of bilayer tablet dosage form, wherein the said process comprises following steps:
i) preparing sustained release layer comprising metformin or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients;
ii) preparing immediate release layer comprising Sitagliptin or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients;
iii) compressing both layers;
iv) performing seal coating; and
v) performing film coating
The pharmaceutical compositions according to present invention will, in general comprise of one or more excipients. Examples of pharmaceutical excipients include, but are not limited to release controlling polymer, binders, fillers or diluents, lubricants, glidants, disintegrants. A combination of excipients may also be used. The amount of excipient(s) employed will depend upon how much active agent is to be used. One excipient can perform more than one function.
In one embodiment, the release controlling polymer according to present invention include, but are not limited to, water soluble polymers such as hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropylmethyl cellulose or hypromellose, sodium carboxymethyl cellulose, vinylpyrrolidone/vinyl acetate copolymer for example marketed as Plasdone® S-630, polyvinyl alcohol, polyethylene glycol and the like, Saccharides such as monosaccharides, disaccharides, oligosaccharides, polysaccharides or sugar alcohols which include but are not limited to sucrose, xylitol, mannitol, sorbitol, glucose, fructose, galactose, maltitol, lactose, maltodextrin, Water soluble organic acids, water soluble salts of organic acids, water soluble organic bases, water soluble salts of organic bases which include but are not limited to citric acid or salts thereof, amino acids or salt thereof, inorganic salts such as sodium carbonate, sodium bicarbonate, potassium chloride and sodium chloride, polyvinyl acetate dispersion, ethyl cellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly (ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), and poly (hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly (phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), -poly (isobutyl acrylate), poly(octadecyl acrylate), waxes such as beeswax, carnauba wax, paraffin wax, microcrystalline wax, and, ozokerite; fatty alcohols such as cetostearyl alcohol, stearyl alcohol, cetyl alcohol and myristyl alcohol, and fatty acid esters such as glyceryl monostearate; glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate, and hydrogenated vegetable oils and such.
Binders include, but are not limited to, starches such as potato starch, wheat starch, corn starch; microcrystalline cellulose such as products known under the registered trademarks Avicel, Filtrak, Heweten or Pharmacel; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose (HPMC), ethyl cellulose, sodium carboxymethylcellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinylpyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth, combinations thereof and other materials known to one of ordinary skill in the art and mixtures thereof.
Fillers or diluents, which include, but are not limited to confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic or tribasic, calcium sulphate, and the like can be used.
Lubricants may be selected from, but are not limited to, those conventionally known in the art such as Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and talc.
Glidants include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium, silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one of ordinary skill in the art.
Disintegrants include, but are not limited to: alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, sodium alginate, sodium starch glycolate and starches and other materials known to one of ordinary skill in the art and combinations thereof.
EXAMPLES
The following examples represent various embodiments according to the present invention. The examples are given solely for the purpose of illustration and not to be construed as limiting the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
The following examples illustrate the preparation of stable pharmaceutical composition comprising DPP-IV inhibitors.

Example no. 1:
Table no. 01: Composition as per batch 001
INGREDIENT mg/unit
Intragranular
Sitagliptin Phosphate Monohydrate IP 128.50
Microcrystalline Cellulose (PH 101) 116.50
Croscarmellose Sodium (Ac-di-sol) 7.50
Binder
Klucel LF pharm (Hydroxy propyl cellulose) 10.00
Purified water q.s.
Extra granular
Dicalcium Phosphate Anhydrous (Granular) 120.00
Croscarmellose Sodium (Ac-di-sol) 7.50
Sodium Stearyl fumarate 6.00
Magnesium Stearate 4.00
Sub Total 400.00
Coating
Opadry II 85F570047 16.00
Purified water q.s.
Total Weight 416.00

Manufacturing Process:
1. Microcrystalline Cellulose (PH 101), Sitagliptin phosphate monohydrate and croscarmellose sodium (Ac-di-sol) were co-sifted through ASTM sieve 30#.
2. For binder preparation 300 g of water was heated upto 64ºC, klucel LF was slowly dispersed using overhead stirrer in vortex. 100 g of RT purified water was added to cooled down binder solution. Allowed to stirred for 20 min.
3. Sifted materials from step 1 loaded in 5L RMG Bowl and dry mixed at slow impeller speed for 15 min.
4. Wet granulation was performed by pouring binder solution into dry mixed at slow impeller speed and chopper off. 130 g of Extra purified water was added to formed proper wet mass. 04 minutes of kneading was performed at slow impeller and slow chopper.
5. Air drying was performed using FBD (Retsch dryer) at inlet temperature of 25ºC for 10 min. followed by drying for 30 min at inlet temperature of 55ºC.
6. Dried granules were passed through # 20 mesh screen. Retained granules were milled using Multimill of 1.5 mm screen at fast speed and Knife forward action.
7. For blending and lubrication dicalcium phosphate, granular, croscarmellose sodium, sodium stearyl fumarate are sifted through #30 sieve and added to 5L bin blender along with sized granules.
8. Blending was performed for 15 min at blending speed of 20 rpm.
9. For lubrication magnesium stearate was sifted through #60 sieve & loaded to above blend, lubrication was performed for 03 min at blending speed of 20 rpm.
10. The above lubricated blend was compressed using common blend approach at different weight setting in rotary compression machine.
11. Opadry II 85F570047/85F570007 dispersed in purified water under continuous stirring for 45 mins.

Example no. 2:
Table no. 02: Composition as per batch 002
INGREDIENT mg/unit
Intragranular
Sitagliptin Phosphate Monohydrate IP 64.25
Microcrystalline Cellulose (PH 101) 58.25
Croscarmellose Sodium (Ac-di-sol) 3.375
Binder
Klucel LF pharm (Hydroxy propyl cellulose) 5.00
Purified water q.s.
Extra granular
Dicalcium Phosphate Anhydrous (Granular) 60.00
Croscarmellose Sodium (Ac-di-sol) 3.375
Sodium Stearyl fumarate 3.00
Magnesium Stearate 2.00
Sub Total 200.0
Coating
Opadry II 85F570007 8.00
Purified water q.s.
Total Weight 208.00

Example no. 3:
Table no. 03: Composition as per batch 003 and batch 004
Batch Nos. 003 004
INGREDIENT mg/unit mg/unit
Intragranular
Sitagliptin Phosphate Monohydrate IP 128.50 64.25
Microcrystalline Cellulose (Flocel PH 101) 116.50 58.25
Croscarmellose Sodium (Ac-di-sol) 7.50 3.375
Binder
Klucel LF pharm (Hydroxy propyl cellulose) 10.00 5.00
Purified water q.s. q.s.
Extra granular
Dicalcium Phosphate Anhydrous (Granular) 120.00 60.00
Croscarmellose Sodium (Ac-di-sol) 7.50 3.375
Sodium Stearyl fumarate 6.00 3.00
Magnesium Stearate 4.00 2.00
Sub Total 400.00 200.0
Coating
Opadry II 85F570047 16.00 8.00
Purified water q.s. q.s.
Total Weight 416.00 208.00

Manufacturing Process:
1. Microcrystalline Cellulose (Flocel PH 101), Sitagliptin phosphate monohydrate and croscarmellose sodium (Ac-di-sol) were co-sifted through ASTM sieve 30#.
2. For binder preparation 300 g of water was heated upto 60ºC, klucel LF was slowly dispersed using overhead stirrer in vortex. 100 g of RT purified water was added to cooled down binder solution. Allowed to stir for 40 min.
3. Sifted materials from step 1 loaded in 6L RMG Bowl and dry mixed at slow impeller speed for 15 min.
4. Wet granulation was performed by pouring binder solution into dry mixed at slow impeller speed and chopper off. 200 g of Extra purified water was added to formed proper wet mass. 04 minutes of kneading was performed at slow impeller and slow chopper.
5. Air drying was performed using FBD (Retsch dryer) at inlet temperature of 25ºC for 10 min. followed by drying for 30 min at inlet temperature of 55ºC.
6. Dried granules were passed through # 20 mesh screen. Retained granules were milled using Multimill of 1.5 mm screen at fast speed and Knife forward action.
7. For blending and lubrication dicalcium phosphate, granular, croscarmellose sodium, sodium stearyl fumarate are sifted through #30 sieve and added to 5L bin blender along with sized granules.
8. Blending was performed for 15 min at blending speed of 20 rpm.
9. For lubrication magnesium stearate was sifted through #60 sieve & loaded to above blend, lubrication was performed for 03 min at blending speed of 20 rpm.
10. The above lubricated blend was compressed using common blend approach at different weight setting in rotary compression machine.
11. Opadry II 85F570047/85F57007 dispersed in purified water under continuous stirring for 45 mins.

Example no. 4:
Table no. 04: Composition as per batch 005 and batch 006
Batch Nos. 005 006
INGREDIENT mg/unit mg/unit
Intragranular
Sitagliptin Phosphate Monohydrate IP 128.50 64.25
Microcrystalline Cellulose (Flocel PH 101) 116.50 58.25
Croscarmellose Sodium (Ac-di-sol) 7.50 3.375
Binder
Klucel LF pharm (Hydroxy propyl cellulose) 10.00 5.00
Purified water q.s. q.s.
Extra granular
Dicalcium Phosphate Anhydrous (Granular) 120.00 60.00
Croscarmellose Sodium (Ac-di-sol) 7.50 3.375
Sodium Stearyl fumarate 6.00 3.00
Magnesium Stearate 4.00 2.00
Sub Total 400.00 200.0
Coating
Opadry II 85F570047 16.00 8.00
Purified water q.s. q.s.
Total Weight 416.00 208.00

Manufacturing Process:
1. Microcrystalline Cellulose (Flocel PH 101), Sitagliptin phosphate monohydrate and croscarmellose sodium (Ac-di-sol) were co-sifted through ASTM sieve 30#.
2. For binder preparation 3000 g of water was heated upto 65ºC, klucel LF was slowly dispersed using overhead stirrer in vortex. 1000 g of RT purified water was added to cooled down binder solution. Allowed to stir for 40 min.
3. Sifted materials from step 1 loaded in 50 L RMG Bowl and dry mixed at slow impeller speed for 15 min.
4. Sampling of dry mix was performed from different locations.
5. Wet granulation was performed by pouring binder solution into dry mixed at slow impeller speed and chopper off in 4 min 15 secs. 1000 g of Extra purified water was added to formed proper wet mass. 03 minutes of kneading was performed at slow impeller and slow chopper.
6. Drying was performed using FBD at inlet temperature of 50ºC-55 ºC and outlet temperature of 25-41 ºC in two lots.
7. Dried granules were passed through # 24 mesh screen. Retained granules were milled using Multimill of 1.5 mm screen at fast speed and Knife forward action.
8. For blending and lubrication dicalcium phosphate, granular, croscarmellose sodium, sodium stearyl fumarate are sifted through #20 sieve and added to 50L octagonal blender along with sized granules.
9. Blending was performed for 15 min at blending speed of 22 rpm. To optimized blending time Sampling were performed at stage 10 min pre-lubrication, 15 min of pre-lubrication from 10 different locations from blender.
10. For lubrication magnesium stearate was sifted through #60 sieve & loaded to above blend, lubrication was performed for 05 min at blending speed of 22 rpm, lubrication stage sampling was performed from 10 different locations from blender.
11. The above lubricated blend was compressed using common blend approach at different weight setting in rotary compression machine.
12. Opadry II 85F570047/85F570007 dispersed in purified water under continuous stirring for 45 mins.

Example no. 5:
Table no. 05: Composition as per batch 007 and batch 008
Batch Nos. 007 008
Ingredient mg/unit mg/unit
Intragranular
Sitagliptin Phosphate Monohydrate IP 128.50 64.25
Microcrystalline Cellulose (Flocel PH 101) IP 116.50 58.25
Croscarmellose Sodium (Ac-di-sol) IP 7.50 3.375
Binder
Klucel LF pharm (Hydroxy propyl cellulose) USP 10.00 5.00
Purified water q.s. q.s.
Extra granular
Dicalcium Phosphate Anhydrous (Granular) USP 120.00 60.00
Croscarmellose Sodium (Ac-di-sol) IP 7.50 3.375
Sodium Stearyl fumarate NF. PH. EUR 6.00 3.00
Magnesium Stearate IP 4.00 2.00
Sub Total 400.00 200.0
Coating
Opadry II 85F570047 Complete film coating system Beige 16.00 _
Opadry II 85F570007 Complete film coating system Beige _ 8.00
Purified water q.s. q.s.
Total Weight 416.00 208.00

Example no. 6:
Table no. 06: Composition as per batch 009, 010, 011
S. No. Ingredients Batch no. 009: 100/1000mg Batch no. 010: 50/1000mg Batch no. 011: 50/500mg
Composition of Metformin Layer
Intra-granular mg/unit mg/unit mg/unit
1 Metformin HCl 1000.00 1000.00 500.00
2 Sodium CMC (Cekol 50000P) 60.00 60.00 30.00
3 Methocel K 200 M Premium CR (a) 60.00 60.00 30.00
4 Kollidon 90F 30.00 30.00 15.00
Granulating Agent
5 Kollidon 90F 15.00 15.00 7.50
6 Isopropyl Alcohol q.s. q.s. q.s.
Extra-granular
7 Methocel K 200 M Premium CR (b) 122.00 122.00 91.00
8 Colloidal Silicon Dioxide 6.50 6.50 3.25
9 Magnesium Stearate (Ligamed MFV2) 6.50 6.50 3.25
Metformin Layer weight 1300.00 1300.00 680.00
Composition of Sitagliptin Layer
Intragranular
10 Sitagliptin Phosphate Monohydrate 128.50 64.25 64.25
11 Microcrystalline cellulose PH 101 99.00 163.25 49.50
12 Croscarmellose Sodium 4.50 4.50 2.25
Granulating Agent
13 Klucel LF 8.00 8.00 4.00
14 Isopropyl alcohol q.s. q.s. q.s.
Extra Granular
15 Dicalcium Phosphate Granular (A-Tab) 50.60 50.60 25.30
16 Croscarmellose Sodium 4.50 4.50 2.25
17 Iron oxide yellow 0.40 - 0.20
18 Iron oxide red - 0.40 -
19 Magnesium stearate 4.50 4.50 2.25
Bilayer Tablet Weight 1600.0 1600.0 830.0
Seal Coating
20 Klucel EF 15.92 15.92 8.955
21 Magnesium Stearate 0.08 0.08 0.045
22 Isopropyl alcohol q.s. q.s. q.s.
Film Coating
24 Opadry EZ easy 254U570001 beige 48.0 - -
25 Opadry EZ easy 254U520024 yellow - 48.00 -
26 Opadry EZ easy 254U505022 blue - - 26
27 Purified Water q.s. q.s. q.s.
Total Tablet Weight 1664.0 1664.0 865.0

Manufacturing Process:
I) Manufacturing of Metformin Hydrochloride Sustained Release part:
1. Metformin Hydrochloride was milled in RMG at fast speed of impeller and chopper for 15 minutes. The milled Metformin was sifted through sieve #20 using vibratory sifter.
2. Methocel K200M Premium CR, Sodium CMC (Cekol 50,000P) and Povidone (Kollidon 90F) was shifted through sieve #20 mesh.
3. Povidone K90 (Kollidon 90F) was dissolved in Isopropyl Alcohol in SS container with stirring to get transparent and lump free binder solution.
4. The sifted Metformin Hydrochloride, Sodium CMC (Cekol 50,000P), Methocel 200M Premium CR and Povidone 90 (Kollidon 90F) was transferred to RMG and dry mixed for 15 minutes at slow speed of impeller and chopper off.
5. The wet granulation was performed by addition of binder prepared in step 3 over dry mix in a thin stream for about 13 minutes at slow speed of impeller and switch on the chopper at slow speed after 7 minute of binder addition. Kneading was performed for 3 minute 30 seconds at fast speed of impeller and slow speed of chopper.
6. Dry the wet mass in fluid bed dryer initially through air drying for 10 minutes at 30°C followed by further drying at around 55°C to achieve the required loss on drying (LOD) of 0.7 - 1.2% w/w for 05 minutes at 105°C.
7. The dried granules were passed through sieve 20# mesh. The retained granules were milled through multimill using screen of 1.0 mm with knives at forward orientation & fast speed.
8. Sized granules, Methocel K 200 M Premium CR and Colloidal Silicon dioxide was transferred to blender and blended for 15 minutes at 20 RPM.
9. Then Magnesium stearate was sifted through sieve 60# and added to above blend and blended for 5 minutes at 20 RPM.

II) Manufacturing of Sitagliptin Immediate Release part
1. Microcrystalline Cellulose PH 101, Sitagliptin phosphate monohydrate and Croscarmellose sodium (Ac-di-sol) was co-sifted through ASTM sieve 30#.
2. Binder was prepared by dispersing Klucel LF in Isopropyl Alcohol using overhead stirrer.
3. Sifted materials from step 1 loaded in RMG Bowl and dry mixed at slow impeller speed for 15 min and chopper off.
4. Wet granulation was performed by pouring binder solution into dry mixed at slow impeller speed and chopper off for around 4 minutes. Kneading was performed with additional IPA at slow speed of impeller and slow speed of chopper for around 3 minutes to achieve granulation end point.
5. Air drying was performed using FBD at inlet temperature of around 30ºC for 10 minutes followed by drying at inlet temperature of around 50ºC to achieve the LOD of around 3 %w/w.
6. Dried granules were passed through sieve # 20 mesh. Retained granules were milled using Multimill of 1.5 mm screen at fast speed and knife forward direction and passed through sieve #20 mesh
7. Iron oxide red was sifted through sieve #100 mesh and premixed with granules. Dicalcium phosphate Anhydrous (A-TAB), Croscarmellose sodium was sifted through #20 mesh and transferred to 10L Bin blender and blended for 15 minutes at 20 rpm.
8. Magnesium stearate was sifted through #60 sieve & added to above blend and blended performed for 05 minute at 20 rpm.
9. The above lubricated blend was compressed in bilayer rotary compression machine using 21.00 mm x 10.50 mm punch.

III) Bilayer Compression
10. Compress the Metformin sustained release blend and Sitagliptin blend on rotary bilayer compression machine using suitable punches to produce bilayer tablets having one layer as Metformin Sustained Release and other as Sitagliptin immediate release.

IV) Seal Coating:
11. Take Isopropyl alcohol and keep under stirring at suitable speed. Create a vortex by sufficiently increasing the stirring speed and disperse the Klucel EF to the vortex followed by Magnesium stearate. If required increase the speed of stirrer to maintain the vortex during addition of Klucel EF as polymer start hydrating and viscosity is built up. After complete addition of Klucel EF and Magnesium Stearate, reduce the speed of stirrer nearly to eliminate the vortex and continue the agitation for 45 minutes. Ensure that all the material is dispersed completely, and no lump is formed.
12. The seal coating dispersion is used for coating the bilayer tablets in auto-coater.

v) Film Coating:
13. Prepare the of Coating dispersion by dispersing coating material in purified water followed by stirring for 45 min.
14. The seal coated tablets are then coated using Film coating dispersion in auto-coater.

IN VITRO DRUG RELEASE PROFILE:
Table no. 07: Comparative Release Profile of Metformin from batch no 009 on Stability
Time in hour Initial 3M, 40/75 3M, 30/75
0.5 20 19 19
2 50 50 49
4 72 72 71
8 94 94 92
12 101 102 101

Table 08: Comparative Release profile of Metformin from Batch no 009 with marketed formulations:
Time in Hour Batch 009 Gluformin XL 1000 mg (GXB8013) Janumet XR 100/1000 mg (Combi Pack)
0.5 20 25 24
2 50 51 50
4 72 69 70
8 94 89 91
12 101 98 101

Table 09: Comparative Release profile of Metformin from batch no 011 with Marketed formulation:
Time in Hour Batch 011 Gluformin XL 500 (GXA8019)
0.5 23 30
1 38 42
2 60 60
3 75 71
4 86 81
6 97 93
8 100 99
10 101 102
12 102 104 , Claims:1) A stable oral pharmaceutical composition comprising:
i) Sitagliptin or pharmaceutically acceptable salts thereof;
ii) optionally one or more other antidiabetic agent; and
iii) one or more pharmaceutically acceptable excipients;
wherein the said composition is easily swallowable upon administration.
2) The composition as claimed in claim 1, wherein the antidiabetic agent is selected from biguanides, glucagon-like peptides (incretin mimetics), meglitinides, sglt2 inhibitors, Sulfonylureas, Thiazolidinediones, Alpha-glucosidase inhibitors, amylin analogs.
3) The composition as claimed in claim 1, wherein the antidiabetic agent is metformin or pharmaceutically acceptable salts thereof.
4) The composition as claimed in claim 1, wherein the stable oral composition is selected from tablet, granules, bilayer tablet, capsules.
5) The composition as claimed in claim 1, wherein the stable oral composition is in the form of immediate release tablet.
6) The composition as claimed in claim 1, wherein the stable oral composition is in the form of bilayer tablet.
7) The composition as claimed in claim 6, wherein the bilayer tablet comprises immediate release layer and sustained release layer.
8) The composition as claimed in claim 7, wherein the immediate release layer comprises Sitagliptin or pharmaceutically acceptable salts thereof.
9) The composition as claimed in claim 7. wherein the sustained release layer comprises Metformin or pharmaceutically acceptable salts thereof.
10) The process for preparation of bilayer tablet dosage form as claimed in claims 1-9, wherein the said process comprises following steps:
i) preparing sustained release layer comprising Metformin or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients;
ii) preparing immediate release layer comprising Sitagliptin or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients;
iii) compressing both the layers;
iv) performing seal coating; and
v) performing film coating