Description:FIELD OF THE INVENTION
The present invention relates to a fixed dose pharmaceutical composition comprising a combination of sitagliptin, metformin and glimepiride or their pharmaceutically acceptable salt thereof. In particular, the invention relates to a fixed dose pharmaceutical composition comprising a combination of 50mg of sitagliptin or its pharmaceutically acceptable salt thereof, 500mg or 1000mg of metformin, and 1mg or 2mg of glimepiride, wherein the composition does not show any hypoglycemic effect when administered to a diabetic patient. The invention also includes process of preparing such compositions and use of such compositions for the treatment of diabetes.
BACKGROUND OF THE INVENTION
Diabetes mellitus (DM), commonly referred to as diabetes, is a group of metabolic disorders in which there are high blood sugar levels over a prolonged period. Type 2 diabetes is a chronic and progressive disease arising from a complex pathophysiology involving the dual endocrine defects of insulin resistance and impaired insulin secretion. The treatment of Type 2 diabetes typically begins with diet and exercise, followed by oral ant-idiabetic monotherapy. The haemoglobin A1c (HbA1c) goal for patients with type 2 diabetes mellitus (T2DM) – especially in those patients who have a longer duration of the disease – is often difficult to achieve. Exemplary drugs useful for managing type II diabetes and its precursor syndromes such as insulin resistance include classes of compounds, such as, biguanides, glitazones, sulfonylureas, thiazolidinediones a-glycosidase inhibitors, meglitinides and dipeptidyl peptidase IV inhibitors (DPP4 inhibitors).
Presently, dipeptidyl peptidase IV inhibitors, biguanides, glitazones and sulfonylureas are commercially available in the form of tablets of the individual drugs, either in immediate release (IR) formulations or in controlled release (CR) formulations.
For many patients, monotherapy do not sufficiently control glycaemia during long-term treatment, leading to a requirement for combination therapy within several years following diagnosis with complimentary mechanisms of action. However, this may result in treatment regimens that are complex and difficult for many patients to follow. Lack of adherence to the multidrug therapy, possibly due to greater number of pills, higher administration frequency and poor tolerability, may lead to deficiency in the clinical outcomes. One way of addressing these problems is through a use of fixed-dose combinations. Fixed-dose combinations (FDCs) offer an alternative to separately dispensed, individual medications the advantages that directly contribute to improved medication concordance are:
• the number of medications and the dosing/timing schedule may be simplified, which reduces the frequency of missed doses.
• The lower doses of two or more agents in fixed combinations may offer greater efficacy in combination than that achieved with a higher or maximal dose of a single agent.
• The glycaemic goals are obtained utilizing lower doses of agents in combination, the risk of adverse events that are more likely to occur with the higher doses of monotherapy can be avoided.
• A fixed combinations are typically less costly than free combination of the two or more agents and should offer a financial advantage for patients, since the cost of fixed combination often is no more than the cost of one of the included monotherapies.
Examples of marketed combination tablets include GlucovanceTM (metformin and glyburide), Janumet® (sitagliptin and metformin), Avandaryl® (rosiglitazone/glimepiride); Dapanorm Trio® (dapagliflozin, sitagliptin and metformin) AvandameTM (metformin and rosiglitazone), and MetaglipTM (metformin and glipizide).
Sitagliptin phosphate and metformin hydrochloride are two anti-hyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes mellitus: sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor which is believed to exert its actions by slowing the inactivation of incretin hormones, and metformin hydrochloride is a member of the biguanide class which decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Their combination is marketed as Janumet® (sitagliptin and metformin). Glimepiride primarily lowers blood glucose by stimulating the release of insulin from pancreatic ß cells. Combining glimepiride with Janumet® may further provide a rapid lowering of Hb1AC achieving HbA1C <7.0%. However, the dosage combination of dipeptidyl peptidase-4 (DPP-4) inhibitors and sulphonylureas have shown to increase the risk of hypoglycaemia. Salvo et al, BMJ. 2016 May 3; 353: i2231 discloses risk of hypoglycaemia associated with the concomitant use of dipeptidyl peptidase-4 (DPP-4) inhibitors and sulphonylureas and disclosed that a ddition of DPP-4 inhibitors to sulphonylurea to treat people with type 2 diabetes is associated with a 50% increased risk of hypoglycaemia. The present invention provides a fixed dose composition comprising Sitagliptin, Metformin and Glimepiride or their pharmaceutically acceptable salt thereof at a specific dose that does not show any hypoglycemic effect when administered to a diabetic patient.
However, formulating a novel fixed dose composition comprising two or more drugs is challenging. A balance must be struck between stability and release characteristics such that the composition is both stable and has acceptable dissolution and pharmacokinetic properties. Accordingly, there is a need to develop stable and effective pharmaceutical compositions that allow for a novel fixed dose composition of sitagliptin, metformin and glimepiride that have improved, desirable PK and release properties. The present disclosure overcomes difficulties associated with co-formulating these three drugs together.

SUMMARY OF THE INVENTION
The present invention provides oral fixed dose pharmaceutical composition comprising:
a) sitagliptin or its pharmaceutically acceptable salt thereof,
b) metformin or its pharmaceutically acceptable salt thereof,
c) glimepiride, and
d) one or more pharmaceutically acceptable excipient.
In one aspect, the present invention provides oral fixed dose pharmaceutical composition comprising:
a) sitagliptin or a pharmaceutically acceptable salt thereof, equivalent to 50mg of sitagliptin base
b) 1000mg of metformin or a pharmaceutically acceptable salt thereof,
c) 1mg of glimepiride, and
d) one or more pharmaceutically acceptable excipient,
which when administered twice daily for a period of at least 16 weeks to a diabetic patient having a HbA1c = 8% - = 11% and results into a reduced HbA1c = 7 % without showing any hypoglycemic effect
In another aspect of the invention the pharmaceutical fixed dose composition is a tablet, capsule, powder, pellets, suspension, solution.
In a another aspect of the invention the pharmaceutical fixed dose compositon is in the form of a tablet composition, wherein the tablet is an bilayer tablet.
In one of the aspect of the invention a fixed dose bilayer tablet composition comprising,
a) one layer comprises of glimepiride and one or more pharmaceutically acceptable excipient.
b) another layer comprises of sitagliptin and metformin or its pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipient
In another aspect of the invention provides a fixed dose bilayer tablet composition comprising,
a) one layer comprises of 1 mg og glimepiride and one or more pharmaceutically acceptable excipient.
b) another layer comprises of
i. sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50mg of sitagliptin base and
ii. 500mg or 100mg of metformin hydrochloride, and
iii. one or more pharmaceutically acceptable excipient
In another aspect of the invention provides a fixed dose bilayer tablet composition comprising,
a) one layer comprises of 1 mg og glimepiride and one or more pharmaceutically acceptable excipient.
b) another layer comprises of
i. sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50mg of sitagliptin base and
ii. 500mg or 100mg of metformin hydrochloride, and
iii. one or more pharmaceutically acceptable excipient
which when administered twice daily for a period of at least 16 weeks to a diabetic patient having a HbA1c = 8% - = 11% and results into a reduced HbA1c = 7 % without showing any hypoglycemic effect.
In a preferred aspect of the invention, the pharmaceutically acceptable salt of sitagliptin comprises of phosphate monohydrate, phosphate anhydrate or fumarate
In one of the aspect of the invention, the bilayer pharmaceutical composition is prepared by wet granulation
In one of the aspect of the invention a pharmaceutical bilayer composition comprises of
a) one layer comprises of, glimepiride and one or more pharmaceutically acceptable excipient,
b) another layer comprises of metformin hydrochloride and sitagliptin phosphate monohydrate; and one or more pharmaceutically acceptable excipient,
wherein, the compositon when tested for dissolution in a phosphate buffer at a pH 7.8 exhibits at least 90% release of glimepiride in 180 mins.
In yet another aspect of the invention, the pharmaceutical bilayer compositon when tested for dissolution in a phosphate buffer at a pH 7.8 exhibits at least 85% release of glimepiride in 45 mins
In another aspect of the inventon, the pharmaceutical bilayer compositon when tested for dissolution in a phosphate buffer at a pH 7.8 exhibits at least 85% release of glimepiride in 30 mins.
In another aspect of the an oral fixed dose pharmaceutical composition comprising
a) sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50 mg of sitagliptin base;
b) 1000mg of metformin hydrochloride, and
c) glimepiride
wherein the composition is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin reference formulation and an equal dose of an immediate-release glimepiride reference formulation with the Cmax T/R ratio falling within 80% -125% range when administered to human subjects.
In a preferred aspect of the invention an oral fixed dose pharmaceutical composition comprising
a) sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50 mg of sitagliptin base;
b) 1000mg of metformin hydrochloride, and
c) glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100ng/ml to about 300ng/ml, a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin reference formulations with the Cmax T/R ratio falling within 80% -125% range when administered to human subjects.
In a preferable aspect, the present invention provides an oral fixed dose pharmaceutical composition comprising
a) sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50 mg of sitagliptin base;
b) 1000 mg of metformin hydrochloride, and
c) 2mg of glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100ng/ml to about 200ng/ml, a a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml and a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin, and immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range.
In a more preferable aspect, the present invention provides a fixed dose pharmaceutical composition comprising
a) sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50 mg of sitagliptin base;
b) 1000 mg of metformin hydrochloride, and
c) glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100ng/ml to about 200ng/ml, a a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin reference formulations with the Cmax T/R ratio falling within 80% -125% range when administered to human subjects.
In a more preferable aspect, the present invention provides a fixed dose pharmaceutical composition comprising
a) sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50 mg of sitagliptin base;
b) 1000 mg of metformin hydrochloride, and
c) 2 mg of glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to human.
In yet another aspect, the present invention provides a fixed dose bilayer tablet composition comprising:
a) one layer comprising 2mg of glimepiride.
b) another layer comprising 1000 mg of metformin hydrochloride and sitagliptin or its salt thereof, equivalent to 50mg of sitagliptin base;
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100 ng/ml to about 300ng/ml, a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml and a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin, and immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to human.
In yet another aspect, the present invention provides a fixed dose bilayer tablet composition comprising:
a) one layer comprising glimepiride.
b) another layer comprising 1000mg of metformin hydrochloride and sitagliptin or its salt thereof, equivalent to 50mg of sitagliptin base;
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100 ng/ml to about 300ng/ml, a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to human
In yet another aspect, the present invention provides a fixed dose bilayer tablet composition comprising:
a) one layer comprising 2mg of glimepiride.
b) another layer comprising 1000mg of metformin hydrochloride and sitagliptin or its salt thereof, equivalent to 50mg of sitagliptin base;
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to humans.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 A illustrates the Linear plot of Mean Plasma of Sitagliptin Concentration v/s Time (hr)

Figure 1 B illustrates the Linear plot of Mean Plasma of Metformin Concentration v/s Time (hr)
Figure 1 C illustrates the Linear plot of Mean Plasma of Glimeperide Concentration v/s Time (hr)
Figure 2 illustrates the outline of the clinical studies of example 5

DETAILED DESCRITPTION OF THE INVENTION
It should be noted that, the singular forms “a,” “an,” and, “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an excipient” includes reference to one or more of such excipients, and reference to “the carrier” includes reference to one or more of such carriers.

As used herein, “drug,” “active agent,”, “pharmaceutically active agent,” “therapeutically active agent” and “pharmaceutical,” may be used interchangeably to refer to an agent or substance that has measurable specified or selected physiologic activity when administered to a subject in a significant or effective amount. These terms of art are well-known in the pharmaceutical and medicinal arts.

As used herein, the term “treatment” when used in conjunction with the administration of progesterone, refers to the administration of progesterone to subjects who are either asymptomatic or symptomatic. In other words, “treatment” can be to reduce, ameliorate, or eliminate symptoms associated with a condition or it can be prophylactic treatment, i.e. to prevent or reduce the occurrence or severity of the symptoms.

As used herein, the terms “formulation” and “composition” are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules. When any of the above terms is modified by the term “oral” such terms refer to compositions, formulations, or dosage forms formulated and intended for oral administration to subjects.

As used herein, “subject” refers to a mammal that may benefit from the administration of a drug composition or method of this invention. In one specific aspect, a subject is a human. In another aspect, the subject is a female. In one embodiment, the subject can be a non-pregnant female or woman.

The term “oral administration” represents any method of administration in which an active agent can be administered by swallowing, chewing, or sucking or drinking an oral dosage form.

A used herein connection with numerical values, the terms “approximately” and “about” mean ±10% of the indicated value, including the indicated value.
The present disclosure provides a fixed dose pharmaceutical composition comprising:
a) sitagliptin or its pharmaceutically acceptable salt thereof,
b) metformin or its pharmaceutically acceotable salt thereof,
c) glimepiride, and
d) one or more pharmaceutically acceptable excipient.
In one embodiment, the present disclosure provides a fixed dose pharmaceutical composition comprising:
a) sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50mg of sitagliptin base.
b) 500mg or 1000mg of metformin or its pharmaceutically acceptable salt thereof, and
c) 1mg or 2mg of glimepiride
d) one or more pharmaceutically acceptable excipient,
The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include ferric, ferrous, lithium, magnesium, aluminum, copper, ammonium, calcium, copper, manganous, zinc, sodium, potassium, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, substituted amines such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylene-diamine, N-ethyl-morpholine, N-ethylpiperidine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, glucamine, glucosamine, histidine, methylglucamine, morpholine, piperazine, piperidine, hydrabamine, isopropylamine, lysine, , polyamine resins, procaine, purines, tripropylamine, tromethamine, theobromine, triethylamine, trimethylamine, , and the like. When the compound is basic, salts may be prepared from pharmaceutically acceptable acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, lactic, maleic, malic, mandelic ethanesulfonic, fumaric, gluconic, glutamic, pamoic, pantothenic, phosphoric, succinic, sulfuric hydrobromic, hydrochloric, isethionic, , methanesulfonic, mucic, nitric, , tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are hydrochloric, and phosphoric acids.
Sitagliptin or its pharmaceutically acceptable salt may be present in the fixed-dose pharmaceutical composition of the present disclosure in an amount of 25mg, 50mg, 75mg, 100mg, 150mg, or 200mg, equivalent to sitagliptin base. Preferably, sitagliptin may be present in the form of its pharmaceutically acceptable salt, for example phosphateor fumarate. These salts may be in the form of anhydtate or monohydrate. More preferably, sitagliptin may be present in the form of sitagliptin phosphate monohydrate. An equivalent amount of Sitagliptin phosphate monohydrate to the Sitagliptin base may be present in the fixed-dose pharmaceutical composition of the invention in an amount of 32.13mg, 64.25mg, 96.38mg, 128.5mg, 192.75mg, and 257mg, respectively.

Metformin or its pharmaceutically acceptable salt may be present in the fixed-dose pharmaceutical composition of the present disclosure in an amount of 250mg, 500mg, 625mg, 750mg, 850mg, and 1000mg. Preferably, metformin is present in the form of metformin hydrochloride in an amount of 250mg, 500mg, 625mg, 750mg, 850mg, and 1000mg.

Glimepiride may be present in the fixed-dose pharmaceutical composition of the present disclosure in an amount of 1mg to 10mg. More preferably, in an amount of 1mg, 2mg, 3mg ot 4mg.

In yet another embodiment, the present disclosure provides a fixed dose pharmaceutical composition comprising
a) sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50mg of sitagliptin base,
b) 500mg or 1000mg of metformin hydrochloride,
c) 1mg or 2mg of glimepiride and
d) one or more pharmaceutically acceptable excipient
Preferably, sitaglitptin is in the form of sitagliptin phosphate monohydrate.
In one of embodiment of the invention the fixed dose composition is in the form of oral dosage form which is tablet, capsule, powder, pellets, suspension, solution, sachets.
As used herein, “pharmaceutically acceptable excipients” or “carrier” or “pharmaceutically acceptable carrier” refers to a substance with which a drug may be combined to achieve a specific dosage formulation or oral dosage form for delivery to a subject.

In one embodiment of the present disclosure, the fixed-dose pharmaceutical composition of the present disclosure may comprise one or more pharmaceutically acceptable excipients to improve performance, handling, or processing. Non-limiting examples include binders, surfactants, diluents, film forming agents, disintegrants, fillers, lubricants, glidants, and combinations thereof.

In one aspect of the embodiment, diluents, or fillers, may be added to increase the bulk to make the composition in a practical size for compression. Examples of diluents useful in composition is selected from the group consisting of but not limited to, lactose monohydrate, dibasic calcium phosphate anhydrous, dibasic calcium phosphate dihydrate, calcium sulfate, dicalcium phosphate, tricalcium phosphate, lactose, cellulose including microcrystalline cellulose, silicified microcrystalline cellulose kaolin, mannitol, sorbitol, xylitol, mannose, dextrose sodium chloride, dry starch, pregelatinized starch, compressible sugar, and combinations of any of the foregoing. The diluents, or fillers in the fixed dose pharmaceutical composition of the present disclosre may be present in an amount of about 1 % w/w to about 50% w/w of the composition. Preferably, may be present in an amount of about 10 % w/w to about 40% w/w of the composition. More preferably, may be present in an amount of about 20 % w/w to about 35 % w/w of the composition. In a preferred aspect, the diluent or filler is microcrystalline cellulose and lactose monohydrate .

In another aspect of the embodiment, the binding agents in the composition facilitates adhesion of the constituents. Examples of binding agents useful in composition is selected from the group consisting of but not limited to, starch, corn starch, pregelatinized starch, gum acacia, inulin, maltodextrin , sodium alginate, sorbitol, polyvinyl acetate phthalate, molasses, methylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose, microcrystalline cellulose (MCC), and polyvinyl pyrrolidone. Preferably, the binder is polyvinyl pyrrolidone. The binder may be present in an amount of about 1 % w/w to about 6 % w/w of the composition. Preferably, in an amount of about 1.5 % w/w to 5.5 % w/w of the composition. More preferably, in an amount of about 2.5% to 4.5% w/w of the composition.

In another aspect of the embodiment, lubricants may be added to the composition to reduce sticking effects during processing, film formation, and/or drying. Examples of lubricants useful in composition is selected from the group consisting of but not limited to, talc, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumerate, glycerol monostearate, glyceryl behenate, glyceryl monostearate, mineral oil, sodium lauryl sulfate, zinc stearate and combinations of any of the foregoing. Preferably, the lubricant is magnesium stearate. The lubricant may be present in an amount of about 1 % w/w to about 2% w/w of the composition. Preferably, in an amount of about 1.2% w/w to 1.5% w/w of the composition.

In another aspect of the embodiment, glidants may be added to the composition to improve powder flow. Examples of glidants useful in composition is selected from the group consisting of but not limited to, talc, colloidal silicon dioxide, precipitated silicon dioxide, fumed silicon dioxide, glyceryl monostearate and combinations of any of the foregoing. The glidant may be present in an amount of about less than about 1% w/w of the composition. Preferably, in an amount less than about 0.5% w/w of the composition. In a preferred aspect, the glidant is silicon dioxide.

In another aspect of the embodiment, disintegrants may be added to the composition to make it disintegrate. Examples of disintegrant useful in composition is selected from the group consisting of but not limited to, water swellable substances such as low substituted hydroxypropyl cellulose, cross-linked sodium carboxymethylcellulose (sodium croscarmellose), sodium starch glycolate, crosspovidone, sodium carboxymethylcellulose, sodium carboxymethyl starch, ion-exchange resins, microcrystalline cellulose, crosslinked polyvinyl pyrrolidone, starches and pregelatinized starch, formalin-casein, alginic acid, certain complex silicates, and combinations of any of the foregoing. The disintegrant may be present in an amount of about 0.5 % w/w to 5 % w/w of the composition. Preferably, the disintegrant may be present in an amount of about 1% w/w to 4 % w/w of the composition. More preferably, in an amount of about 1.5 % w/w to 3 % w/w of the composition. In a preferred aspect, the disintegrant is sodium starch glycolate, crosspovidone or mixtures thereof.

In another apect of the embodiment, the fixed-dose pharmaceutical composition may be film-coated. A typical film-coat comprises a film coating agent, a plasticizer, a glidant, and optionally one or more pigments and colors. For example, the film coat may comprise of polymers such as methyl hydroxyethyl cellulose, Hydroxyethycellulose, Sodium carboxymethyl cellulose, ethyl cellulose, hydroxypropylmethylcellulose (HPMC), Polyvenyl pyrollidone , Polyvinyl pyrrolidone-polyvinyl acetate copolymers, Polyvinyl alcohol (PVA), Polyvinyl alcohol-polyethylene glycol copolymers, Acrylic polymers, polyethylene glyco. The composition is coated using a coating suspension, preferably a tablet is coated with the coating suspension to a weight gain of about 2-4%, preferably about 3%, using standard film coater (such as e.g. a perforated pan coater). Alternatively, for preparing film-coated composition of the invention, the film coating suspension is prepared by using commercially available film coating pre-mixtures such as Opadry™. Preferably, the film coating pre-mixture is OpadryTM biege or OpadryTM yellow or OpadryTM II .

The fixed dose composition of the present invention may be in the form of tablet. The tablet composition may be prepared by wet granulation, dry granulation or direct compression. The present inventors found that the composition prepared by mixing the three drugs; sitagliptin, metformin and glimepiride in a single layer results in a tablet composition wherein, glimerpiride was released at a slow rate than an immediate-release glimepiride reference formulation.The dissolution testing was carried out in a USP II paddle apparatus at 75 rpm and in a 7.8 pH buffer medium. The dissolution profile of glimepiride in the mono layer tablet, on comparision with the dissolution profile of immediate release reference formulation of glimepiride results into slower release rate of glimepiride in a monolayer tablet as compared to the immediate release reference compositon of Glimeperide. Inorder to overcome this limitation bilayer tablet was formulated comprising a sepertae glimepiride layer and another layer comprising sitagliptin phosphate monohydrate and metformin hydrochloride. The dissolution profile of the bilayer tablet showed similar release rate, wherein at least 85% of glimepiride was release in 30 min, which when compared to the release rate in the dissolution profilel of immediate release glimepiride.
In one embodiment, the present disclosure provides a fixed dose tablet composition comprising,
a) one layer comprising glimepiride and one or more pharmaceutically acceptable excipients, and
b) another layer comprising sitagliptin and metformin or its pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
In another embodiment, the present disclosure provides a fixed dose bilayer tablet composition comprising,
a) one layer comprises of 1 mg og glimepiride and one or more pharmaceutically acceptable excipient.
b) another layer comprises of
i. sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50mg of sitagliptin base and
ii. 500mg or 100mg of metformin hydrochloride, and
iii. one or more pharmaceutically acceptable excipient
In another embodiment, the present disclosure provides a fixed dose tablet composition comprising,
a) one layer comprising glimepiride and one or more pharmaceutically acceptable excipients, and
b) another layer comprising sitagliptin and metformin or its pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

Wherein, the composition when tested for dissolution in a phosphate buffer at a pH of 7.8 exhibits at least 90% release of glimepiride in 180 min, for example 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100%.Preferably, wherein the composition when tested for dissolution in a phosphate buffer at a pH of 7.8 exhibits at least 85% release of glimepiride in 45 min, for example 85%, 86%, 87%, 885, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100%. More preferably,wherein, the composition when tested for dissolution in a phosphate buffer at a pH of 7.8 exhibits at least 85% release of glimepiride in 30 min, for example 85%, 86%, 87%, 885, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100%
In yet another embodiment, the present disclosure provides a fixed dose bilayer tablet composition, comprising:
a) one layer comrprising of glimepiride.
b) another layer comprising of metformin hydrochloride and sitagliptin phosphate monohydrate; and
c) Optionally, a film coating covering the first layer and the second layer.
In yet another embodiment, the present disclosure provides a fixed dose bilayer tablet composition, comprising:
a) one layer comrprising of glimepiride.
b) another layer comprising of metformin hydrochloride and sitagliptin phosphate; and
c) Optionally, a film coating covering the first layer and the second layer.
wherein, the composition when tested for dissolution in a phosphate buffer at a pH of 7.8 exhibits at least 90% release of glimepiride in 180 min, for example 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100%. Preferably, wherein the composition when tested for dissolution in a phosphate buffer at a pH of 7.8 exhibits at least 90% release of glimepiride in 45 min, for example 85%, 86%, 87%, 885, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100%. More preferably,wherein, the composition when tested for dissolution in a phosphate buffer at a pH of 7.8 exhibits at least 85% release of glimepiride in 30 min, for example 85%, 86%, 87%, 885, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100%.
In yet another embodiment, the present invention provides a fixed dose pharmaceutical bilayer tablet composition comprising:
a) one layer comprising 1 or 2 mg of glimepiride.
b) another comprising 500mg or 1000 mg of metformin hydrochloride and sitagliptin or its salt thereof, equivalent to 50mg sitagliptin base.
Preferably, the one layer comprises comprises 1mg of glimepiride and the another layer comprises 1000mg of metformin hydrochloride and sitagliptin phosphate monohydrate, equivalent to 50mg sitagliptin base.
In yet another aspect, the present invention provides a fixed dose pharmaceutical bilayer tablet composition comprising:
a) one layer comprising 1 or 2 mg of glimepiride.
b) another layer comprising 500mg or 1000 mg of Metformin hydrochloride and 50 mg of sitagliptin phosphate equivalent to sitagliptin base; and
c) Optionally, a film coating covering the first layer and the second layer.
wherein, the composition when tested for dissolution in a phosphate buffer at a pH of 7.8 exhibits at least 90% release of glimepiride in 180 min, for example 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100%.Preferably, wherein the composition when tested for dissolution in a phosphate buffer at a pH of 7.8 exhibits at least 85% release of glimepiride in 45 min, for example 85%, 86%, 87%, 885, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100%. More preferably,wherein, the composition when tested for dissolution in a phosphate buffer at a pH of 7.8 exhibits at least 85% release of glimepiride in 30 min, for example 85%, 86%, 87%, 885, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100%
In one embodiment, the fixed dose pharmaceutical composition of the present invention (Test product) was tested for its bioequivalence and safety against the Reference product (R) in healthy adult human subjects under fed condition. The pharmacokinetic parameters, Cmax, AUC0-t and AUC0-8 of the Test product (T) – fixed dose composition comprising sitagliptin phosphate, metformin hydrochloride and glimepiride tablets (50 mg/1000 mg/2mg) were compared to the Reference products (R) - (R1) Janumet® (Sitagliptin phosphate & Metformin Hydrochloride tablets) 50mg/1000 mg and (R2) Amaryl® (Glimepiride Tablets I.P.) 2 mg. Test/Reference (T/R)ratio was calculated using the LSM of log-transformed pharmacokinetic parameters (Cmax, AUC0-t and AUC0-8). Ratio of means will be expressed as a percentage of the LSM of the reference formulation. For a Test product to be bioequivalent to the Reference product, he ratio of Test (T) and Reference (R) product averages (least squares geometric means) for pharmacokinetic parameters (Cmax, AUC0-t and AUC0-8) should be between 80% and 125% for the log-transformed data. Example 4 discloses the bioequivalence study for the fixed dose pharmaceutical composition of the present invention (Test product) and it was found that T/R ratio for pharmacokinetic parameters (Cmax, AUC0-t and AUC0-8) were between 80% and 125% for the log-transformed data. Based on these results, the fixed dose pharmaceutical composition Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride 50 mg/ 1000 mg/ 2 mg tablets (Test Product) was found to be bioequivalent to the Reference products, Janumet® (Sitagliptin phosphate and Metformin Hydrochloride) tablets 50 mg/1000 mg [Reference Product (R1)] & Amaryl (Glimepiride) Tablets 2 mg [Reference Product (R2)]
In one embodiment, the present disclosure provides a fixed dose pharmaceutical composition comprising
a) sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50 mg of sitagliptin base;
b) 1000mg of metformin hydrochloride, and
c) glimepiride
wherein the composition is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin reference formulation and an equal dose of an immediate-release glimepiride reference formulation with the Cmax T/R ratio falling within 80% -125% range when administered to human subjects.
In another embodiment, the present disclosure provides a a fixed dose pharmaceutical composition comprising
a) sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50 mg of sitagliptin base;
b) 1000 mg of metformin hydrochloride, and
c) glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100ng/ml to about 300ng/ml, a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin reference formulations with the Cmax T/R ratio falling within 80% -125% range when administered to human subjects.
In one embodiment, the present disclosure provides a fixed dose pharmaceutical composition comprising
a) sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50 mg of sitagliptin base;
b) 1000 mg of metformin hydrochloride, and
c) 2mg of glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100ng/ml to about 200ng/ml, a a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml and a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin, and immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range.
In one embodiment, the present disclosure provides a fixed dose pharmaceutical composition comprising
a) sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50 mg of sitagliptin base;
b) 1000 mg of metformin hydrochloride, and
c) glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100ng/ml to about 200ng/ml, a a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin reference formulations with the Cmax T/R ratio falling within 80% -125% range when administered to human subjects.
In one embodiment, the present disclosure provides a fixed dose pharmaceutical composition comprising
a) sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50 mg of sitagliptin base;
b) 1000 mg of metformin hydrochloride, and
c) 2 mg of glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to human.
In yet another embodiment, the present disclosure provides a fixed dose pharmaceutical composition comprising
a) sitagliptin phosphate monohydrate,
b) metformin hydrochloride, and
c) glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100ng/ml to about 300ng/ml, a a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml and a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin, and immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range.
In another embodiment, the present disclosure provides a fixed dose pharmaceutical composition comprising
a) sitagliptin phosphate monohydrate,
b) metformin hydrochloride, and
c) glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100ng/ml to about 300ng/ml, a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to humans
In yet another embodiment, the present disclosure provides a fixed dose pharmaceutical composition comprising
a) sitagliptin phosphate monohydrate,
b) metformin hydrochloride, and
c) glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range when administered to humans subjects
In another embodiment, the present disclosure provides a fixed dose pharmaceutical composition comprising
a) sitagliptin phosphate monohydrate; equivalent to 50mg of sitagliptin base,
b) 1000mg of metformin hydrochloride, and
c) 2 mg of glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100ng/ml to about 300ng/ml, a a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml and a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin, and immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to human subjects
In yet another embodiment, the present disclosure provides a fixed dose pharmaceutical composition comprising
a) sitagliptin phosphate monohydrate; equivalent to 50mg of sitagliptin base,
b) 1000mg of metformin hydrochloride, and
c) glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100ng/ml to about 300ng/ml, a a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin reference formulations with the Cmax T/R ratio falling within 80% -125% range when administered to human subjects.
In yet another embodiment, the present disclosure provides a fixed dose pharmaceutical composition comprising
a) sitagliptin phosphate monohydrate; equivalent to 50mg of sitagliptin base,
b) 1000mg of metformin hydrochloride, and
c) 2 mg of glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to human.
In yet another embodiment, the present disclosure provides a fixed dose pharmaceutical bilayer tablet composition comprising:
a) one layer comprising 2mg of glimepiride.
b) another layer comprising 1000mg of metformin hydrochloride and sitagliptin or its salt thereof, equivalent to 50mg of sitagliptin base;
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100 ng/ml to about 300ng/ml, a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml and a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin, and immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to human.
In yet another embodiment, the present disclosure provides a fixed dose pharmaceutical bilayer tablet composition comprising:
a) one layer comprising glimepiride.
b) another layer comprising 1000mg of metformin hydrochloride and sitagliptin or its salt thereof, equivalent to 50mg of sitagliptin base;
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100 ng/ml to about 300ng/ml, a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to human
In yet another embodiment, the present disclosure provides a fixed dose pharmaceutical bilayer tablet composition comprising:
a) one layer comprising 2mg of glimepiride.
b) another layer comprising 1000mg of metformin hydrochloride and sitagliptin or its salt thereof, equivalent to 50mg of sitagliptin base;
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to humans.
In yet another embodiment, the present disclosure provides a fixed dose pharmaceutical bilayer tablet composition comprising:
a) one layer comprising glimepiride.
b) another layer comprising metformin hydrochloride and sitagliptin phosphate equivalent to sitagliptin base;
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100 ng/ml to about 300ng/ml, a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml and a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin, and immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to human.
In another emodiment the present disclosure provides a fixed dose pharmaceutical bilayer tablet composition comprising:
a) one layer comprising glimepiride.
b) another layer comprising metformin hydrochloride and sitagliptin phosphate monohydrate;
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100 ng/ml to about 300ng/ml, a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to human
In another emodiment the present disclosure provides a fixed dose pharmaceutical bilayer tablet composition comprising:
a) one layer comprising glimepiride.
b) another layer comprising metformin hydrochloride and sitagliptin phosphate monohydrate;
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to humans.
In yet another emodiment the present disclosure provides a fixed dose pharmaceutical bilayer tablet composition comprising:
a) a first layer comprising 2 mg of glimepiride.
b) a second layer comprising 1000 mg of Metformin hydrochloride and sitagliptin phosphate monohydrate equivalent to 50mg sitagliptin base; and
c) Optionally, a film coating covering the first layer and the second layer,
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of Sitagliptin, in the range of about 100 ng/ml to about 300ng/ml; a mean maximum plasma concentration(Cmax) of Metformin in the range of about 700ng/ml to 3200ng/ml; a mean maximum plasma concentration(Cmax) of Glimiperide in the range of about 85ng/ml to 280ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin, and immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range.
It is preferred that the fixed dose pharmaceutical composition, when administered once daily, exhibit a bioavailability, as expressed conventionally by Cmax, AUC0-24 or AUC0-8 of sitagliptin, metformin and glimepiride, that is substantially equivalent to the same daily dose of a reference formulation, for example Janumet® & Amaryl® tablet, administered once a day. In the present context, “substantially equivalent” means that the bioavailability of such a preferred composition is about 0.8 to about 1.25 times that of the reference formulation, i.e T/R ratio falling within 80% -125% range. The Pharmacokinetic study used to generate the parameters specified above for the composition of the invention is conducted according to a protocol that is generally accepted in the art.
In one embodiment, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of sitagliptin that is in the range of about 100 ng/ml to about 300ng/ml. Because of high variability in the subjects, the mean Cmax is calculated from Ln-transformed data as Least square geometric mean Cmax., herein referred to as mean Cmax. In one aspect of the embodiment, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of sitagliptin that is in the range of about about 110ng/ml to about 290 ng/ml. In yet another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of sitagliptin that is in the range of about 120ng/ml to about 280 ng/ml. In yet another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of sitagliptin that is in the range of about 130ng/ml to about 270ng/ml. In yet another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of sitagliptin that is in the range of about 140ng/ml to about 260 ng/ml. In yet another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of sitagliptin that is in the range of about 150ng/ml to about 250 ng/ml. In another aspect, following single dose administration of the present composition exhibit a mean maximum plasma concentration (Cmax) of sitagliptin that is in the range of about 160 ng/ml to about 240ng/ml. In a preferable aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of sitagliptin that is in the range of about 170ng/ml to about 230ng/ml,
In one embodiment, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin about 700 ng/ml to about 3200ng/ml. In one aspect of the embodiment, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 800ng/ml to about 3100 ng/ml. In another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 900 ng/ml to about 3000 ng/ml. In yet another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 1000 ng/ml to about 2900ng/ml. In yet another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 1100 ng/ml to about 2800 ng/ml. In yet another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 1200ng/ml to about 2700 ng/ml. In a another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 1300 ng/ml to about 2600ng/ml. In a preferable aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 1400 ng/ml to about 2500ng/ml. In a more preferable aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 1500 1ng/ml to about 2400 ng/ml,
In one embodiment, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of glimepiride that is in the range of about 90 ng/ml to about 300ng/ml. In one aspect of embodiment, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 100ng/ml to about 290 ng/ml. In yet another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 110 ng/ml to about 280 ng/ml. In yet another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 120ng/ml to about 270ng/ml. In yet another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 130 ng/ml to about 260 ng/ml. In yet another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 140 ng/ml to about 250 ng/ml. In a preferable aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 150 ng/ml to about 2400 ng/ml. In a more preferable aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 160 ng/ml to about 230 ng/ml.
In one embodiment, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a time to reach maximum plasma concentration (Tmax) of sitagliptin of about 4 hours.
In another embodiment, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a time to reach maximum plasma concentration (Tmax) of metformin of about 5 hours.
In another embodiment, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a time to reach maximum plasma concentration (Tmax) of glimepiride of about 4.3 hours
In one embodiment, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibits a concentration profile of sitagliptin further characterized by AUC values (AUC0-t, AUC0-8) between about 1800 ng.hr/ml to about 2200 ng.hr/ml. In one aspect of the embodiment, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibits a concentration profile of sitagliptin further characterized by AUC values (AUC0-t, AUC0-8) between about 1500 ng.hr/ml.mg to about 1600 ng.hr/ml. In another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibits a concentration profile of sitagliptin further characterized by AUC values (AUC0-t, AUC0-8) between about 1300 ng.hr/ml.mg to about 1500 ng.hr/ml.
In one embodiment the efficacy and safety of fixed dose pharmacetical composition of sitagliptin phosphate, metformin hydrochloride and glimepiride (50 mg/1000 mg/1 mg or 2mg) in patients with type 2 diabetes mellitus was determined by administering the composition twice daily (BID) for atleast 16 to 28 weeks, and compared to co-administration of metformin hydrochloride 1000mg tablet and glimepiride 2mg tablet. They were evaluated for mean change in HbA1c, mean change in Fasting Blood Sugar ( FBS) from baseline at the end of week 12, 16, & 28. In one aspect of the embodiment, the patients to whom the fixed dose combination is administered have an HbA1c = 8% - = 11%. In one aspect of the embodiment, the patients to whom the fixed dose combination is administered have a BMI of = 45 kg/m2. In yet another aspect, the patients are administered a fixed dose combination of metformin, sitagliptin and glimepiride for at least 16 weeks.
After 16 weeks of treatment period, the study will be continued in single-arm for 12 weeks (Week 28). Patients will continue to receive FDC of Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride tablets (50 mg/1000 mg/1 mg), if HbA1c at 16 weeks is < 8%. If HbA1c is = 8% then there will be uptitration and patients will receive FDC of Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride tablets (50 mg/1000 mg/2 mg) BID till Week 28.
The present inventors unexpectedly found that the fixed dose pharmaceutical composition comprising sitagliptin phosphate monohydrate equivalent to 50 mg of sitagliptin base, 1000 mg metformin, and 1mg glimepiride of present invention when administered to patients with diabetes, resulted in HbA1c = 7 % in patients and without any hypoglycaemic effect as shown in the table 9 even when the patient were administered the fixed dose combination twice daily for a period of at least 16 weeks. 3. Hypoglycemic events were recorded in the diary anytime a patient experience either of the following: 1) Signs and symptoms of hypoglycemia (regardless of blood glucose value by finger stick) OR 2) Blood glucose value by finger stick = 70 mg/dL (3.9 mmol/L) (regardless of symptoms). Number of patients requiring hypoglycemia management were evaluated during the study by count and percentages.
Hypoglycemia levels are defined as below: (as per American Diabetes Association 2021). 1) Level 1 hypoglycemia is defined as a measurable glucose concentration <70 mg/dL (3.9 mmol/L) and = 54 mg/dL (3.0 mmol/L). 2) Level 2 hypoglycemia (defined as a blood glucose concentration <54 mg/dL [3.0 mmol/L]). 3) Level 3 hypoglycemia is defined as a severe event characterized by altered mental and/or physical status requiring assistance for treatment of hypoglycemia.
In one aspect, the fixed dose pharmaceutical composition comprising sitagliptin phosphate monohydrate equivalent to 50 mg sitagliptin base, 1000 mg metformin, and 1mg glimepiride of present invention when administered to patients with Type II diabetes, results in an improvement in HbA1c levels, Postprandial Blood Glucose (PPBG), Fasting blood sugar (FBS), and hypoglycaemia management as presented in Example 5. It was observed that all hypoglycemic events were Level 1 and asymptomatic and none of the patient required hypoglycaemia management during the study period.
In one embodiment, the present disclosure, provides a fixed dose pharmaceutical composition comprising:
a) sitagliptin or a pharmaceutically acceptable salt thereof, equivalent to 50mg of sitagliptin base
b) 500mg or 1000mg of metformin or a pharmaceutically acceptable salt thereof,
c) 1mg of glimepiride, and
d) one or more pharmaceutically acceptable excipient,
which when administered twice daily for a period of at least 16 weeks to a diabetic patient having a HbA1c = 8% to = 11%, results in reducing HbA1c to = 7 % without the patients showing any hypoglycemic effect.
More preferably, the present disclosure, provides a fixed dose pharmaceutical composition comprising:
a) sitagliptin or a pharmaceutically acceptable salt thereof, equivalent to 50mg of sitagliptin base
b) 1000mg of metformin hydrochloride,
c) 1 mg of glimepiride, and
d) one or more pharmaceutically acceptable excipient,
which when administered twice daily for a period of at least 16 weeks to a diabetic patient having a HbA1c = 8% to = 11%, results in reducing HbA1c to = 7 % without the patients showing any hypoglycemic effect.
In yet another embodiment, the present disclosure provides a fixed dose pharmaceutical bilayer tablet composition comprising:
a) one layer comprising glimepiride.
b) another layer comprising metformin hydrochloride and sitagliptin phosphate monohydrate equivalent to sitagliptin base;
which when administered twice daily for a period of at least 16 weeks to a diabetic patient having a HbA1c = 8% to = 11%, results in reducing HbA1c to = 7 % without the patients showing any hypoglycemic effect.
In yet another embodiment, the present disclosure provides a fixed dose bilayer tablet composition comprising,
a) one layer comprises of 1 mg of glimepiride and one or more pharmaceutically acceptable excipient.
b) another layer comprises of
i. sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50mg of sitagliptin base and
ii. 500mg or 100mg of metformin hydrochloride, and
iii. one or more pharmaceutically acceptable excipient
which when administered twice daily for a period of at least 16 weeks to a diabetic patient having a HbA1c = 8% - = 11% and results into a reduced HbA1c = 7 % without showing any hypoglycemic effect.
In yet another emodiment the present disclosure provides a fixed dose pharmaceutical bilayer tablet composition comprising:
a) one layer comprising 1 mg of glimepiride.
b) other layer comprising 1000 mg of Metformin hydrochloride and of sitagliptin phosphate monohydrate equivalent to 50mg of sitagliptin base; and
c) optionally, a film coating covering the first layer and the second layer,
which when administered twice daily for a period of at least 16 weeks to a diabetic patient having a HbA1c = 8% to = 11%, results in reducing HbA1c to = 7 % without the patients showing any hypoglycemic effect.
It should be clearly understood that the following examples are illustrative only and are not intended to limit the scope of the present invention.
EXAMPLES:
Example 1: Monolayer Tablet composition of Sitagliptin, Metformin & Glimepiride.
The mono layer tablet comprising Sitagliptin, Metformin & Glimepiride 50/1000/1mg were prepared using wet granulation process, wherein the APIs and excipient were sifted, followed by introducing the binder solution and milling to obtain granules, which are further blended with extra granular excipients, and the blend is then compressed to obtain a tablet.
Table 1: Monolayer Tablet of Fixed Dose Composition of Sitagliptin, Metformin, & Glimepiride (50mg/1000mg/1mg)
INGREDIENTS % w/w
Glimepiride 0.12
Metformin HCl 60.55
Sitagliptin phosphate 3.76
Lactose Monohydrate 14.80
Microcrystalline cellulose pH 101 7.87
Polyvinylpyrrolidone 3.91
Ferric oxide Yellow 0.01
Microcrystalline cellulose pH 102 1.21
Sodium Starch Glycolate 0.61
Magnesium Stearate 0.47
Sodium lauryl sulphate 0.39
Cross povidone 3.03
Silicon dioxide 0.36
Opadry Yellow 2.91
Purified Water q.s.
Weight of Coated Tablet 100

Example 2: Bilayer Tablet Composition of Sitagliptin, Metformin & Glimepiride.
The Bilayer tablet of the Fixed dose combination of Sitagliptin, Metformin & Glimepiride were prepared using wet granulation process in two table strength 50/1000/2mg or 50/1000/1mg respectively.
Method of Manufacturing:
The bilayer tablet composition is prepared by a the process of wet granulation wherein the onelayer comprises of glimepiride and the other layer comprises of sitagliptin phosphate monohydrate and metformin hydrochloride. Both these layers were prepared by the process of wet granulation,
Glimepiride layer- the process comprises of sifting glimepirideand excipients in a sifter followed by process of granulation by introduction of water and preparing a wet mass which is followed by drying the wet mass and milled to obtain dry granules which are further blended with extra granular excipients.
Sitagliptin + metformin HCl layer - the process comprises of sifting sitagliptin phosphate monohydrate and metformin hydrochloride and excipients in a sifter followed by process of granulation by introduction of binder solution comprising SLS and preparing a wet mass which is followed by drying the wet mass and milled to obtain dry granules which are further blended with extra granular excipients. The lubricated blend of glimepiride layer with sitagliptin + metformin HCl layer were compressed into bilayer tablets. This core tablet was then coated with film coating dispersion.
Table 2: Composition Details of the Fixed Dose Composition of Sitagliptin, Metformin, & Glimepiride (50mg/500mg/1mg & 50mg/1000mg/1mg)
COMPOSITION 50/500/1mg 50/1000/1mg
1 2 3 4 5
INGREDIENTS %w/w %w/w %w/w %w/w %w/w
LAYER- 1
Glimepiride 0.35 0.35 0.35 0.353 0.353
Lactose Monohydrate 86.75 85.75 86.76 86.75 86.75
Microcrystalline Cellulose pH 101 3.53 4.09 3.54 3.53 3.53
Polyvinyl pyrollidone 1.60 1.58 1.6 1.59 1.59
Ferric oxide red 0.07 0.05 0.06 0.07 0.07
Microcrystalline Cellulose pH 102 3.53 3.83 3.47 3.54 3.54
Sodium Starch Glycolate 3.53 3.83 3.58 3.53 3.53
Magnesium Stearate 0.64 0.52 0.64 0.64 0.64
TOTAL 100.00 100.00 100.00 100.00 100.00
LAYER- 2
Metformin HCl 73.28 73.28 73.28 76.77 76.77
Sitagliptin Phosphate 9.09 9.09 9.09 4.76 4.76
Microcrystalline Cellulose pH 101 8.79 8.5 9.11 9.21 9.01
Polyvinyl pyrollidone 4.04 4.34 3.92 4.61 4.81
Sodium lauryl sulfate 0.48 0.5 0.5 0.5 0.5
Microcrystalline Cellulose pH 102 0.93 0.95 0.73 0.77 0.78
Crosspovidone 1.47 1.5 1.43 1.54 1.53
Colloidal Silicon dioxide 0.54 0.44 0.64 0.46 0.46
Magnesium Stearate 1.38 1.4 1.3 1.38 1.38
TOTAL 100.00 100 100 100 100
FILM COAT
Opadry Beige 2.91 2.01 2.61 2.91 2.91

Table 3: Composition Details of the Fixed Dose Composition of Sitagliptin, Metformin, & Glimepiride (50mg/500mg/2mg & 50mg/1000mg/2mg)
COMPOSITION 50/500/2mg 50/1000/2mg
6 7 8 9 10 11
INGREDIENTS %w/w %w/w %w/w %w/w %w/w %w/w
LAYER 1
Glimepiride 0.71 0.71 0.71 0.71 0.71 0.71
Lactose Monohydrate 86.4 85.9 86.98 86.4 84.56 86.4
Microcrystalline Cellulose pH101 3.53 3.73 3.36 3.53 3.67 3.53
Polyvinyl pyrollidone 1.59 1.62 1.54 1.59 1.6 1.59
Ferric oxide Yellow 0.07 0.1 0.1 0.07 0.08 0.07
Microcrystalline Cellulose pH102 3.53 3.95 3.53 3.53 4.5 3.53
Sodium Starch Glycolate 3.53 3.53 3.53 3.53 4.3 3.53
Magnesium Stearate 0.64 0.48 0.45 0.64 0.58 0.64
TOTAL 100 100.02 100.2 100 100 100
LAYER 2
Metformin HCl 73.28 73.28 73.28 76.77 76.77 76.77
Sitagliptin Phosphate 9.09 9.09 9.09 4.76 4.76 4.76
Microcrystalline Cellulose pH101 8.79 8.59 8.6 8.98 9.34 9.21
Polyvinyl pyrollidone 4.4 4.4 4.4 4.71 4.52 4.61
Sodium lauryl sulfate 0.48 0.48 0.4 0.5 0.53 0.5
Microcrystalline Cellulose pH101 0.73 0.73 0.99 0.74 0.74 0.77
Crosspovidone 1.47 1.67 1.42 1.54 1.67 1.54
Colloidal Silicon dioxide 0.44 0.44 0.48 0.56 0.39 0.46
Magnesium Stearate 1.32 1.32 1.34 1.44 1.28 1.38
TOTAL 100 100 100 100 100 100
FILM COATING
Opadry Yellow 2.91 2.94 2.89 2.93 2.9 2.96

Example 3: Dissolution Study Profile
The Comparative dissolution study of the bilayer tablet with a monolayer IR tablet of the Fixed dose combination of Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride 50 mg/ 1000 mg/ 1mg was carried out using USP II paddle apparatus at 75 rpm in a phosphate buffer with a 7.80 pH for the monolayer tablet of Example 1 in comparisiion with the bilayer tablet mentioned in Example 2 , composition 11. It was observed that Glimepiride was released at a slow rate in a mono layer tablet compared to the bilayer tablet.

TABLE 4: Comparative Dissolution Profile of Monolayer table vs. Bilayer tablet
Time (min) % Drug dissolved (Glimepiride)
Comparative Example 1 Example 2 – Composition 11
5 59 68
10 68 83
15 74 88
30 79 94
45 83 95
60 85 95
Infinity 86 96

Example 4: Dissolution Study Profile of the Fixed dose combination of Test vs. Reference
The comparative dissolution study was carried out using USP II paddle apparatus at 75 rpm in a phosphate buffer with a 7.80 pH. of test comprising the Fixed dose combination of Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride 50 mg/ 1000 mg/ 1mg or 2 mg tablets Tablet with the refernce product Janumet® (Sitagliptin phosphate and Metformin Hydrochloride) 50 mg/ 1000 mg tablets & Amaryl (Glimepiride) 1mg or 2mg Tablets.

TABLE 5: Dissolution Study Profile of the Fixed dose combination of Test vs. Reference
Product Janumet Tablets 50/1000 mg
(Reference product)
Amaryl Tablets
1 mg
(Reference product)
Sitagliptin Phosphate, Metformin HCl and Glimepiride Tablets 50/1000/1mg

% Drug Release
Time (mins) Sitagliptin Metformin HCl Glimepiride Sitagliptin Metformin HCl Glimepiride
10 70 73 85 67 67 77
15 89 92 90 101 100 85
30 98 100 95 103 102 93
45 98 101 95 103 102 94

TABLE 6: Dissolution Study Profile of the Fixed dose combination of Test vs. Reference )

Product Janumet Tablets 50/1000 mg
(Reference product)
Amaryl Tablets 2mg
(Reference product)
Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride Tablets 50/1000/2mg

% Drug Release
Time (mins) Sitagliptin Metformin HCl Glimepiride Sitagliptin Metformin HCl Glimepiride
10 70 73 95 95 93 78
15 89 92 98 100 99 85
30 98 100 99 100 99 91
45 98 101 98 100 99 94

The dissolution profile indicated that the test product has comparable drug release profile with Reference product

Example 4:Bioequivalence Study.
A Single dose two-way crossover bioequivalence study comprising 48 Forty Eight (48) healthy adult human subjects were performed to assess the bioequivalence between Test product (T) - Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride tablets 50 mg / 1000 mg / 2 mg, and; Reference product (R) - Reference Product (R1) immediately followed by Reference Product (R2) will be administered and will be coded as Reference product (R).
Reference (R1): Janumet® (Sitagliptin phosphate & Metformin Hydrochloride tablets) 50mg/1000 mg manufactured by MSD Pharmaceuticals Pvt. Ltd., India Reference (R2): Amaryl® (Glimepiride Tablets I.P.) 2 mg manufactured by Sanofi India Limitedand to monitor the safety of Test product (T) and Reference product (R) in healthy adult human subjects under fed condition.
The subjects were administered single oral dose of either Test (T) or Reference (R) products
Reference (R):A single oral dose of one tablet of Reference (R1), immediately followed by one tablet of Reference (R2) product was administered with 20% w/v glucose solution at an ambient temperature, 45 minutes after the start of high-fat high-calorie breakfast Test (T): A single oral dose of one tablet of Test (T) product was administered with 20% w/v glucose solution at an ambient temperature, 45 minutes after the start of high-fat highcalorie breakfast
A total of 56, 3ml samples were collected. Blood samples were collected at Pre-dose (duplicate) and at. 0.3- 72 hours post dose in each period of the study. Pharmacokinetic parameters AUC0-t, AUC0-inf , Cmax Tmax, t1/2, of Sitagliptin, Metformin and Glimepiride concentration data were calculated by quantifying the concentration in human plasma using LC-MS/MS method.

TABLE 7: Statistical Analysis- Sitagliptin (T vs R) [N=41]
Parameter (units) Geometric Least Square Mean % Ratio
(Ta/R) 90 %CI Intra Subject CV%
Test
(T) Reference (R)
Cmax (ng/mL) 173.6 157.95 109.87 102.79-117.44 18.04
AUC0-t (ng.hr/mL) 1973.32 2031.38 97.13 95.55-98.73 4.41
AUC0-8 (ng.hr/mL) 2030.10 2086.30 97.29 95.70-98.91 4.43
*T1/2 (h) 9.65 9.52
#Tmax (h) 4.0 4.0
*Arithmetic mean presented; #Median (Min-Max) presented
Figure 1A discloses the Linear plot of Mean Plasma of Sitagliptin Concentration v/s Time (hr)
TABLE 8: Statistical Analysis – Metformin (T vs R) [N=41]
Parameter (units) Geometric Least Square Mean % Ratio
(Tb/R) 90 %CI Intra Subject CV%
Test
(T) Reference (R)
Cmax (ng/mL) 1577.93 1500.84 105.02 97.80-112.76 19.29
AUC0-t (ng.hr/mL) 15001.45 15265.51 98.23 94.26-102.37 11.11
AUC0-8 (ng.hr/mL) 15313.89 15560.09 98.38 94.44-102.47 10.99
*T1/2 (h) 4.4 4.45
#Tmax (h) 5.000 5.000
*Arithmetic mean presented; #Median (Min-Max) presented
Figure 1b shows the Linear plot of Mean Plasma of Metformin Concentration v/s Time (hr)

TABLE 9: Statistical Analysis – Glimepiride (T vs R) [N=41]
Parameter (units) Geometric Least Square Mean % Ratio
(Tb/R) 90 %CI Intra Subject CV%
Test
(T) Reference (R)
Cmax (ng/mL) 169.59 149.97 113.12 103.15-124.06 25.17
AUC0-t (ng.hr/mL) 1340.26 1426.11 94.00 89.57-98.65 13.02
AUC0-8 (ng.hr/mL) 1369.8101 1452.04 94.36 89.95-98.98 12.89
*T1/2 (h) 9.19 8.14
#Tmax (h) 4.33 4.33
*Arithmetic mean presented; #Median (Min-Max) presented
Figure 1c shows the Linear plot of Mean Plasma of Glimepiride Concentration v/s Time (hr)

The ratio of test (T) and reference (R) product averages (least squares means) for pharmacokinetic parameters (Cmax, AUC0-t and AUC0-8) were between 80% and 125% for the log-transformed data. Based on these results, single oral dose of Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride 50 mg/ 1000 mg/ 2 mg tablets (Test Product) and Janumet® (Sitagliptin phosphate and Metformin Hydrochloride) tablets 50 mg/1000 mg [Reference Product (R1)] & Amaryl (Glimepiride) Tablets 2 mg [Reference Product (R2)] were bioequivalent in healthy adult human subjects under fed condition.

Example 5: Clinical Study -
The study assessed the efficacy of fixed dose composition of Sitagliptin phosphate monohydrate, Metformin hydrochloride and Glimepiride tablets (50 mg/1000 mg/1 mg) given twice daily (BID) in comparison to Co-administration of Metformin hydrochloride 500 mg (2 tablets given BID) and Glimepiride 2 mg tablets given BID in patients treated for type 2 diabetes mellitus. Figure 2 discloses the outline of the clinical studies. 127 human subjects were randomised initially with type 2 diabetes with HbA1c = 8 and = 11 % were selected to obtain an and efficacy data, with a total study duration of 16 weeks.

The study comprises of test arm and an comparator arm the test arm comprising
Test 1 comprises of FDC of Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride tablets 50 mg/1000 mg/1 mg.

The subjects to be up-titrated to test 2 if the HbA1c = 8% post 16 weeks.
Test 2 comprises of FDC of Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride tablets 50 mg/1000 mg/2 mg .

Comparator comprises of Metformin Hydrochloride tablets IP 500 mg and Glimepiride tablets IP 2 mg and the comparator arm comprises of Metformin Hydrochloride tablets IP 500 mg and Glimepiride tablets IP 2 mg
The subjects received glucometer with strips for self-monitoring of blood glucose levels, to check blood glucose levels whenever they experience any signs/symptoms of hypoglycaemia and the blood glucose monitored atleast once a week. Hypoglycemic events were recorded if a patient experienced either of the following: Signs and symptoms of hypoglycemia* (regardless of blood glucose value by finger stick) OR Blood glucose value by finger stick = 70 mg/dL (3.9 mmol/L) (regardless of symptoms). The subjects underwent laboratory investigation at week 1, 12, and 16

The 16 weeks results for efficacy of the Fixed Dose Combination of Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride Tablets in Comparison to Co-administration of Metformin Hydrochloride and Glimepiride Tablets in Patients were evaluated with Mean Change in HbA1c (%),PPBG (mg/dL), FBG and Proportion of Participants Achieving HbA1c < 7.0% at Week 12 and 16.

TABLE 10: Mean Change in HbA1c (%) from Baseline to the End of Week 16
Category TEST 1 (BID)
(N = 60) Comparator (BID)
(N=67) Test Vs Comparator
Visits Statistic Summary Actual Change from Baseline [3] Actual Change from Baseline [3] p-value [2] [4]
Visit 1 (Baseline) n 60 67 0.7671
Mean ± SD 9.18±0.86 9.13±0.90
Week 12 n 59 59 66 66 0.1632

Mean ± SD 7.72± 1.11 -1.48±1.06 7.92±1.10 -1.22±0.98
p value [1] <0.001 <0.001
Week 16 N 59 59 66 66 0.0080

Mean ± SD 7.28± 1.07 -1.92± 1.03 7.76± 1.24 -1.38± 1.20
p value [1] <0.001 <0.001
FDC: Fixed Dose [16 P-value for between group comparison is based on ANCOVA model with the treatment group as a fixed effect and baseline HbA1c value as a covariate.

TABLE 11: Mean Change in FBG from baseline at the end of Weeks 12, 16
Category TEST 1 (BID)
(N = 60) Comparator (BID)
(N=67) Test Vs Comparator
Visits Statistic Summary Actual Change from Baseline[3] Actual Change from Baseline[3] p-value
Visit 1 (Baseline) n 60 67 0.1767
Mean ± SD 183.0±38.48 192.5±40.16
Week 12 n 59 59 66 66 0.7596
Mean ± SD 143.8±42.03 -38.3±38.78 151.9±37.95 -40.4±37.83
p value <0.001 <0.001
Week 16 N 59 59 66 66 0.0971
Mean ± SD 137.2±33.51 -44.9±35.51 150.8±34.98 -41.5±35.14
p value <0.001 <0.001
FDC: Fixed Dose Combination; P-value for between group comparison is based on ANCOVA model with the treatment group as a fixed effect and baseline HbA1c value as a covariate.

Overall, Fixed Dose Combination of Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride tablets 50 mg/1000 mg/1 mg (BID) provided significantly better HbA1c reduction from baseline to Week 16 compared to Co-administration of Metformin Hydrochloride 500 mg (2 tablets BID) and Glimepiride tablets 2 mg (BID).

Example 6: Safety Evaluation of Fixed Dose Combination of Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride Tablets.
To assess the safety of FDC of Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride tablets (50 mg/1000 mg/1 mg) given twice daily (BID) in comparison to Co-administration of Metformin Hydrochloride 500 mg (2 tablets given BID) and Glimepiride 2 mg tablets given BID in patients treated for type 2 diabetes mellitus.

The total 127 subjects were evaluated for safety the test and comparator arm were as explained in example 5 for a study duration of 16 weeks. The 16 weeks results for safety of the Fixed Dose Combination of Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride Tablets in Comparison to Co-administration of Metformin Hydrochloride and Glimepiride Tablets in which comprises of safety assessment including Treatment Emergent Adverse Events (TEAEs) assessment during the study Week 12 and 16.

TABLE 12: Treatment Emergent Adverse Events by System Organ Class (SOC) and Preferred Term (PT) - Safety Population
System Organ Class Preferred Term TEST 1 (BID)
(N = 60) Comparator (BID)
(N=67) Overall
(N=127)
N (%) E N (%) E N (%) E
All TEAEs 12 (20.0%) 15 11 (16.4%) 14 23 (18.1%) 29
Gastrointestinal disorders 4 (6.7%) 5 8 (11.9%) 10 12 (9.4%) 15
Abdominal pain upper 1 (1.7%) 1 1 (1.5%) 1 2 (1.6%) 2
Diarrhoea 1 (1.7%) 1 2 (3.0%) 3 3 (2.4%) 4
Hyperchlorhydria 0 0 1 (1.5%) 1 1 (0.8%) 1
Nausea 0 0 3 (4.5%) 3 3 (2.4%) 3
Vomiting 2 (3.3%) 3 2 (3.0%) 2 4 (3.1%) 5
Metabolism and nutrition disorders 3 (5.0%) 5 1 (1.5%) 2 4 (3.1%) 7
Hypoglycaemia 3 (5.0%) 5 1 (1.5%) 2 4 (3.1%) 7
Musculoskeletal and connective tissue disorders 1 (1.7%) 1 0 0 1 (0.8%) 1
Arthralgia 1 (1.7%) 1 0 0 1 (0.8%) 1
Nervous system disorders 3 (5.0%) 3 2 (3.0%) 2 5 (3.9%) 5
Headache 3 (5.0%) 3 2 (3.0%) 2 5 (3.9%) 5
Respiratory, thoracic and mediastinal disorders 1 (1.7%) 1 0 0 1 (0.8%) 1
Rhinorrhoea 1 (1.7%) 1 0 0 1 (0.8%) 1
BID: Twice daily; E: Number of Events; FDC: Fixed dose combination; N: Number of subjects
[1] Body System totals are not necessarily the sum of the individual adverse events since a patient may have reported more than one adverse events in the same body system; [2] Adverse events are coded into system organ class and preferred term using MedDRA version 24.0; [3] Percentages are computed using N provided in the Column header; [4] If AE is with same Start date but different severity then worst case or latest (whichever applicable) will be consider.

15 TEAEs were reported in 12 (20.0%) subjects in test arm; and 14 TEAEs were reported in 11 (16.4%) subjects in comparator arm. All the events were mild in nature. No severe Adverse events, deaths, severe or life-threatening TEAEs reported during the study. All TEAEs were reported as recovered/resolved. All events were Level 1 and asymptomatic. No patient required hypoglycaemia management during the study period. Thus, study products were safe and well tolerated.

FIELD OF THE INVENTION
The present invention relates to a fixed dose pharmaceutical composition comprising a combination of sitagliptin, metformin and glimepiride or their pharmaceutically acceptable salt thereof. In particular, the invention relates to a fixed dose pharmaceutical composition comprising a combination of 50mg of sitagliptin or its pharmaceutically acceptable salt thereof, 500mg or 1000mg of metformin, and 1mg or 2mg of glimepiride, wherein the composition does not show any hypoglycemic effect when administered to a diabetic patient. The invention also includes process of preparing such compositions and use of such compositions for the treatment of diabetes.
BACKGROUND OF THE INVENTION
Diabetes mellitus (DM), commonly referred to as diabetes, is a group of metabolic disorders in which there are high blood sugar levels over a prolonged period. Type 2 diabetes is a chronic and progressive disease arising from a complex pathophysiology involving the dual endocrine defects of insulin resistance and impaired insulin secretion. The treatment of Type 2 diabetes typically begins with diet and exercise, followed by oral ant-idiabetic monotherapy. The haemoglobin A1c (HbA1c) goal for patients with type 2 diabetes mellitus (T2DM) – especially in those patients who have a longer duration of the disease – is often difficult to achieve. Exemplary drugs useful for managing type II diabetes and its precursor syndromes such as insulin resistance include classes of compounds, such as, biguanides, glitazones, sulfonylureas, thiazolidinediones a-glycosidase inhibitors, meglitinides and dipeptidyl peptidase IV inhibitors (DPP4 inhibitors).
Presently, dipeptidyl peptidase IV inhibitors, biguanides, glitazones and sulfonylureas are commercially available in the form of tablets of the individual drugs, either in immediate release (IR) formulations or in controlled release (CR) formulations.
For many patients, monotherapy do not sufficiently control glycaemia during long-term treatment, leading to a requirement for combination therapy within several years following diagnosis with complimentary mechanisms of action. However, this may result in treatment regimens that are complex and difficult for many patients to follow. Lack of adherence to the multidrug therapy, possibly due to greater number of pills, higher administration frequency and poor tolerability, may lead to deficiency in the clinical outcomes. One way of addressing these problems is through a use of fixed-dose combinations. Fixed-dose combinations (FDCs) offer an alternative to separately dispensed, individual medications the advantages that directly contribute to improved medication concordance are:
• the number of medications and the dosing/timing schedule may be simplified, which reduces the frequency of missed doses.
• The lower doses of two or more agents in fixed combinations may offer greater efficacy in combination than that achieved with a higher or maximal dose of a single agent.
• The glycaemic goals are obtained utilizing lower doses of agents in combination, the risk of adverse events that are more likely to occur with the higher doses of monotherapy can be avoided.
• A fixed combinations are typically less costly than free combination of the two or more agents and should offer a financial advantage for patients, since the cost of fixed combination often is no more than the cost of one of the included monotherapies.
Examples of marketed combination tablets include GlucovanceTM (metformin and glyburide), Janumet® (sitagliptin and metformin), Avandaryl® (rosiglitazone/glimepiride); Dapanorm Trio® (dapagliflozin, sitagliptin and metformin) AvandameTM (metformin and rosiglitazone), and MetaglipTM (metformin and glipizide).
Sitagliptin phosphate and metformin hydrochloride are two anti-hyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes mellitus: sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor which is believed to exert its actions by slowing the inactivation of incretin hormones, and metformin hydrochloride is a member of the biguanide class which decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Their combination is marketed as Janumet® (sitagliptin and metformin). Glimepiride primarily lowers blood glucose by stimulating the release of insulin from pancreatic ß cells. Combining glimepiride with Janumet® may further provide a rapid lowering of Hb1AC achieving HbA1C <7.0%. However, the dosage combination of dipeptidyl peptidase-4 (DPP-4) inhibitors and sulphonylureas have shown to increase the risk of hypoglycaemia. Salvo et al, BMJ. 2016 May 3; 353: i2231 discloses risk of hypoglycaemia associated with the concomitant use of dipeptidyl peptidase-4 (DPP-4) inhibitors and sulphonylureas and disclosed that a ddition of DPP-4 inhibitors to sulphonylurea to treat people with type 2 diabetes is associated with a 50% increased risk of hypoglycaemia. The present invention provides a fixed dose composition comprising Sitagliptin, Metformin and Glimepiride or their pharmaceutically acceptable salt thereof at a specific dose that does not show any hypoglycemic effect when administered to a diabetic patient.
However, formulating a novel fixed dose composition comprising two or more drugs is challenging. A balance must be struck between stability and release characteristics such that the composition is both stable and has acceptable dissolution and pharmacokinetic properties. Accordingly, there is a need to develop stable and effective pharmaceutical compositions that allow for a novel fixed dose composition of sitagliptin, metformin and glimepiride that have improved, desirable PK and release properties. The present disclosure overcomes difficulties associated with co-formulating these three drugs together.

SUMMARY OF THE INVENTION
The present invention provides oral fixed dose pharmaceutical composition comprising:
a) sitagliptin or its pharmaceutically acceptable salt thereof,
b) metformin or its pharmaceutically acceptable salt thereof,
c) glimepiride, and
d) one or more pharmaceutically acceptable excipient.
In one aspect, the present invention provides oral fixed dose pharmaceutical composition comprising:
a) sitagliptin or a pharmaceutically acceptable salt thereof, equivalent to 50mg of sitagliptin base
b) 1000mg of metformin or a pharmaceutically acceptable salt thereof,
c) 1mg of glimepiride, and
d) one or more pharmaceutically acceptable excipient,
which when administered twice daily for a period of at least 16 weeks to a diabetic patient having a HbA1c = 8% - = 11% and results into a reduced HbA1c = 7 % without showing any hypoglycemic effect
In another aspect of the invention the pharmaceutical fixed dose composition is a tablet, capsule, powder, pellets, suspension, solution.
In a another aspect of the invention the pharmaceutical fixed dose compositon is in the form of a tablet composition, wherein the tablet is an bilayer tablet.
In one of the aspect of the invention a fixed dose bilayer tablet composition comprising,
a) one layer comprises of glimepiride and one or more pharmaceutically acceptable excipient.
b) another layer comprises of sitagliptin and metformin or its pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipient
In another aspect of the invention provides a fixed dose bilayer tablet composition comprising,
a) one layer comprises of 1 mg og glimepiride and one or more pharmaceutically acceptable excipient.
b) another layer comprises of
i. sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50mg of sitagliptin base and
ii. 500mg or 100mg of metformin hydrochloride, and
iii. one or more pharmaceutically acceptable excipient
In another aspect of the invention provides a fixed dose bilayer tablet composition comprising,
a) one layer comprises of 1 mg og glimepiride and one or more pharmaceutically acceptable excipient.
b) another layer comprises of
i. sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50mg of sitagliptin base and
ii. 500mg or 100mg of metformin hydrochloride, and
iii. one or more pharmaceutically acceptable excipient
which when administered twice daily for a period of at least 16 weeks to a diabetic patient having a HbA1c = 8% - = 11% and results into a reduced HbA1c = 7 % without showing any hypoglycemic effect.
In a preferred aspect of the invention, the pharmaceutically acceptable salt of sitagliptin comprises of phosphate monohydrate, phosphate anhydrate or fumarate
In one of the aspect of the invention, the bilayer pharmaceutical composition is prepared by wet granulation
In one of the aspect of the invention a pharmaceutical bilayer composition comprises of
a) one layer comprises of, glimepiride and one or more pharmaceutically acceptable excipient,
b) another layer comprises of metformin hydrochloride and sitagliptin phosphate monohydrate; and one or more pharmaceutically acceptable excipient,
wherein, the compositon when tested for dissolution in a phosphate buffer at a pH 7.8 exhibits at least 90% release of glimepiride in 180 mins.
In yet another aspect of the invention, the pharmaceutical bilayer compositon when tested for dissolution in a phosphate buffer at a pH 7.8 exhibits at least 85% release of glimepiride in 45 mins
In another aspect of the inventon, the pharmaceutical bilayer compositon when tested for dissolution in a phosphate buffer at a pH 7.8 exhibits at least 85% release of glimepiride in 30 mins.
In another aspect of the an oral fixed dose pharmaceutical composition comprising
a) sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50 mg of sitagliptin base;
b) 1000mg of metformin hydrochloride, and
c) glimepiride
wherein the composition is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin reference formulation and an equal dose of an immediate-release glimepiride reference formulation with the Cmax T/R ratio falling within 80% -125% range when administered to human subjects.
In a preferred aspect of the invention an oral fixed dose pharmaceutical composition comprising
a) sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50 mg of sitagliptin base;
b) 1000mg of metformin hydrochloride, and
c) glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100ng/ml to about 300ng/ml, a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin reference formulations with the Cmax T/R ratio falling within 80% -125% range when administered to human subjects.
In a preferable aspect, the present invention provides an oral fixed dose pharmaceutical composition comprising
a) sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50 mg of sitagliptin base;
b) 1000 mg of metformin hydrochloride, and
c) 2mg of glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100ng/ml to about 200ng/ml, a a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml and a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin, and immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range.
In a more preferable aspect, the present invention provides a fixed dose pharmaceutical composition comprising
a) sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50 mg of sitagliptin base;
b) 1000 mg of metformin hydrochloride, and
c) glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100ng/ml to about 200ng/ml, a a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin reference formulations with the Cmax T/R ratio falling within 80% -125% range when administered to human subjects.
In a more preferable aspect, the present invention provides a fixed dose pharmaceutical composition comprising
a) sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50 mg of sitagliptin base;
b) 1000 mg of metformin hydrochloride, and
c) 2 mg of glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to human.
In yet another aspect, the present invention provides a fixed dose bilayer tablet composition comprising:
a) one layer comprising 2mg of glimepiride.
b) another layer comprising 1000 mg of metformin hydrochloride and sitagliptin or its salt thereof, equivalent to 50mg of sitagliptin base;
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100 ng/ml to about 300ng/ml, a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml and a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin, and immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to human.
In yet another aspect, the present invention provides a fixed dose bilayer tablet composition comprising:
a) one layer comprising glimepiride.
b) another layer comprising 1000mg of metformin hydrochloride and sitagliptin or its salt thereof, equivalent to 50mg of sitagliptin base;
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100 ng/ml to about 300ng/ml, a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to human
In yet another aspect, the present invention provides a fixed dose bilayer tablet composition comprising:
a) one layer comprising 2mg of glimepiride.
b) another layer comprising 1000mg of metformin hydrochloride and sitagliptin or its salt thereof, equivalent to 50mg of sitagliptin base;
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to humans.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 A illustrates the Linear plot of Mean Plasma of Sitagliptin Concentration v/s Time (hr)

Figure 1 B illustrates the Linear plot of Mean Plasma of Metformin Concentration v/s Time (hr)
Figure 1 C illustrates the Linear plot of Mean Plasma of Glimeperide Concentration v/s Time (hr)
Figure 2 illustrates the outline of the clinical studies of example 5

DETAILED DESCRITPTION OF THE INVENTION
It should be noted that, the singular forms “a,” “an,” and, “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an excipient” includes reference to one or more of such excipients, and reference to “the carrier” includes reference to one or more of such carriers.

As used herein, “drug,” “active agent,”, “pharmaceutically active agent,” “therapeutically active agent” and “pharmaceutical,” may be used interchangeably to refer to an agent or substance that has measurable specified or selected physiologic activity when administered to a subject in a significant or effective amount. These terms of art are well-known in the pharmaceutical and medicinal arts.

As used herein, the term “treatment” when used in conjunction with the administration of progesterone, refers to the administration of progesterone to subjects who are either asymptomatic or symptomatic. In other words, “treatment” can be to reduce, ameliorate, or eliminate symptoms associated with a condition or it can be prophylactic treatment, i.e. to prevent or reduce the occurrence or severity of the symptoms.

As used herein, the terms “formulation” and “composition” are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules. When any of the above terms is modified by the term “oral” such terms refer to compositions, formulations, or dosage forms formulated and intended for oral administration to subjects.

As used herein, “subject” refers to a mammal that may benefit from the administration of a drug composition or method of this invention. In one specific aspect, a subject is a human. In another aspect, the subject is a female. In one embodiment, the subject can be a non-pregnant female or woman.

The term “oral administration” represents any method of administration in which an active agent can be administered by swallowing, chewing, or sucking or drinking an oral dosage form.

A used herein connection with numerical values, the terms “approximately” and “about” mean ±10% of the indicated value, including the indicated value.
The present disclosure provides a fixed dose pharmaceutical composition comprising:
a) sitagliptin or its pharmaceutically acceptable salt thereof,
b) metformin or its pharmaceutically acceotable salt thereof,
c) glimepiride, and
d) one or more pharmaceutically acceptable excipient.
In one embodiment, the present disclosure provides a fixed dose pharmaceutical composition comprising:
a) sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50mg of sitagliptin base.
b) 500mg or 1000mg of metformin or its pharmaceutically acceptable salt thereof, and
c) 1mg or 2mg of glimepiride
d) one or more pharmaceutically acceptable excipient,
The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include ferric, ferrous, lithium, magnesium, aluminum, copper, ammonium, calcium, copper, manganous, zinc, sodium, potassium, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, substituted amines such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylene-diamine, N-ethyl-morpholine, N-ethylpiperidine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, glucamine, glucosamine, histidine, methylglucamine, morpholine, piperazine, piperidine, hydrabamine, isopropylamine, lysine, , polyamine resins, procaine, purines, tripropylamine, tromethamine, theobromine, triethylamine, trimethylamine, , and the like. When the compound is basic, salts may be prepared from pharmaceutically acceptable acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, lactic, maleic, malic, mandelic ethanesulfonic, fumaric, gluconic, glutamic, pamoic, pantothenic, phosphoric, succinic, sulfuric hydrobromic, hydrochloric, isethionic, , methanesulfonic, mucic, nitric, , tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are hydrochloric, and phosphoric acids.
Sitagliptin or its pharmaceutically acceptable salt may be present in the fixed-dose pharmaceutical composition of the present disclosure in an amount of 25mg, 50mg, 75mg, 100mg, 150mg, or 200mg, equivalent to sitagliptin base. Preferably, sitagliptin may be present in the form of its pharmaceutically acceptable salt, for example phosphateor fumarate. These salts may be in the form of anhydtate or monohydrate. More preferably, sitagliptin may be present in the form of sitagliptin phosphate monohydrate. An equivalent amount of Sitagliptin phosphate monohydrate to the Sitagliptin base may be present in the fixed-dose pharmaceutical composition of the invention in an amount of 32.13mg, 64.25mg, 96.38mg, 128.5mg, 192.75mg, and 257mg, respectively.

Metformin or its pharmaceutically acceptable salt may be present in the fixed-dose pharmaceutical composition of the present disclosure in an amount of 250mg, 500mg, 625mg, 750mg, 850mg, and 1000mg. Preferably, metformin is present in the form of metformin hydrochloride in an amount of 250mg, 500mg, 625mg, 750mg, 850mg, and 1000mg.

Glimepiride may be present in the fixed-dose pharmaceutical composition of the present disclosure in an amount of 1mg to 10mg. More preferably, in an amount of 1mg, 2mg, 3mg ot 4mg.

In yet another embodiment, the present disclosure provides a fixed dose pharmaceutical composition comprising
a) sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50mg of sitagliptin base,
b) 500mg or 1000mg of metformin hydrochloride,
c) 1mg or 2mg of glimepiride and
d) one or more pharmaceutically acceptable excipient
Preferably, sitaglitptin is in the form of sitagliptin phosphate monohydrate.
In one of embodiment of the invention the fixed dose composition is in the form of oral dosage form which is tablet, capsule, powder, pellets, suspension, solution, sachets.
As used herein, “pharmaceutically acceptable excipients” or “carrier” or “pharmaceutically acceptable carrier” refers to a substance with which a drug may be combined to achieve a specific dosage formulation or oral dosage form for delivery to a subject.

In one embodiment of the present disclosure, the fixed-dose pharmaceutical composition of the present disclosure may comprise one or more pharmaceutically acceptable excipients to improve performance, handling, or processing. Non-limiting examples include binders, surfactants, diluents, film forming agents, disintegrants, fillers, lubricants, glidants, and combinations thereof.

In one aspect of the embodiment, diluents, or fillers, may be added to increase the bulk to make the composition in a practical size for compression. Examples of diluents useful in composition is selected from the group consisting of but not limited to, lactose monohydrate, dibasic calcium phosphate anhydrous, dibasic calcium phosphate dihydrate, calcium sulfate, dicalcium phosphate, tricalcium phosphate, lactose, cellulose including microcrystalline cellulose, silicified microcrystalline cellulose kaolin, mannitol, sorbitol, xylitol, mannose, dextrose sodium chloride, dry starch, pregelatinized starch, compressible sugar, and combinations of any of the foregoing. The diluents, or fillers in the fixed dose pharmaceutical composition of the present disclosre may be present in an amount of about 1 % w/w to about 50% w/w of the composition. Preferably, may be present in an amount of about 10 % w/w to about 40% w/w of the composition. More preferably, may be present in an amount of about 20 % w/w to about 35 % w/w of the composition. In a preferred aspect, the diluent or filler is microcrystalline cellulose and lactose monohydrate .

In another aspect of the embodiment, the binding agents in the composition facilitates adhesion of the constituents. Examples of binding agents useful in composition is selected from the group consisting of but not limited to, starch, corn starch, pregelatinized starch, gum acacia, inulin, maltodextrin , sodium alginate, sorbitol, polyvinyl acetate phthalate, molasses, methylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose, microcrystalline cellulose (MCC), and polyvinyl pyrrolidone. Preferably, the binder is polyvinyl pyrrolidone. The binder may be present in an amount of about 1 % w/w to about 6 % w/w of the composition. Preferably, in an amount of about 1.5 % w/w to 5.5 % w/w of the composition. More preferably, in an amount of about 2.5% to 4.5% w/w of the composition.

In another aspect of the embodiment, lubricants may be added to the composition to reduce sticking effects during processing, film formation, and/or drying. Examples of lubricants useful in composition is selected from the group consisting of but not limited to, talc, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumerate, glycerol monostearate, glyceryl behenate, glyceryl monostearate, mineral oil, sodium lauryl sulfate, zinc stearate and combinations of any of the foregoing. Preferably, the lubricant is magnesium stearate. The lubricant may be present in an amount of about 1 % w/w to about 2% w/w of the composition. Preferably, in an amount of about 1.2% w/w to 1.5% w/w of the composition.

In another aspect of the embodiment, glidants may be added to the composition to improve powder flow. Examples of glidants useful in composition is selected from the group consisting of but not limited to, talc, colloidal silicon dioxide, precipitated silicon dioxide, fumed silicon dioxide, glyceryl monostearate and combinations of any of the foregoing. The glidant may be present in an amount of about less than about 1% w/w of the composition. Preferably, in an amount less than about 0.5% w/w of the composition. In a preferred aspect, the glidant is silicon dioxide.

In another aspect of the embodiment, disintegrants may be added to the composition to make it disintegrate. Examples of disintegrant useful in composition is selected from the group consisting of but not limited to, water swellable substances such as low substituted hydroxypropyl cellulose, cross-linked sodium carboxymethylcellulose (sodium croscarmellose), sodium starch glycolate, crosspovidone, sodium carboxymethylcellulose, sodium carboxymethyl starch, ion-exchange resins, microcrystalline cellulose, crosslinked polyvinyl pyrrolidone, starches and pregelatinized starch, formalin-casein, alginic acid, certain complex silicates, and combinations of any of the foregoing. The disintegrant may be present in an amount of about 0.5 % w/w to 5 % w/w of the composition. Preferably, the disintegrant may be present in an amount of about 1% w/w to 4 % w/w of the composition. More preferably, in an amount of about 1.5 % w/w to 3 % w/w of the composition. In a preferred aspect, the disintegrant is sodium starch glycolate, crosspovidone or mixtures thereof.

In another apect of the embodiment, the fixed-dose pharmaceutical composition may be film-coated. A typical film-coat comprises a film coating agent, a plasticizer, a glidant, and optionally one or more pigments and colors. For example, the film coat may comprise of polymers such as methyl hydroxyethyl cellulose, Hydroxyethycellulose, Sodium carboxymethyl cellulose, ethyl cellulose, hydroxypropylmethylcellulose (HPMC), Polyvenyl pyrollidone , Polyvinyl pyrrolidone-polyvinyl acetate copolymers, Polyvinyl alcohol (PVA), Polyvinyl alcohol-polyethylene glycol copolymers, Acrylic polymers, polyethylene glyco. The composition is coated using a coating suspension, preferably a tablet is coated with the coating suspension to a weight gain of about 2-4%, preferably about 3%, using standard film coater (such as e.g. a perforated pan coater). Alternatively, for preparing film-coated composition of the invention, the film coating suspension is prepared by using commercially available film coating pre-mixtures such as Opadry™. Preferably, the film coating pre-mixture is OpadryTM biege or OpadryTM yellow or OpadryTM II .

The fixed dose composition of the present invention may be in the form of tablet. The tablet composition may be prepared by wet granulation, dry granulation or direct compression. The present inventors found that the composition prepared by mixing the three drugs; sitagliptin, metformin and glimepiride in a single layer results in a tablet composition wherein, glimerpiride was released at a slow rate than an immediate-release glimepiride reference formulation.The dissolution testing was carried out in a USP II paddle apparatus at 75 rpm and in a 7.8 pH buffer medium. The dissolution profile of glimepiride in the mono layer tablet, on comparision with the dissolution profile of immediate release reference formulation of glimepiride results into slower release rate of glimepiride in a monolayer tablet as compared to the immediate release reference compositon of Glimeperide. Inorder to overcome this limitation bilayer tablet was formulated comprising a sepertae glimepiride layer and another layer comprising sitagliptin phosphate monohydrate and metformin hydrochloride. The dissolution profile of the bilayer tablet showed similar release rate, wherein at least 85% of glimepiride was release in 30 min, which when compared to the release rate in the dissolution profilel of immediate release glimepiride.
In one embodiment, the present disclosure provides a fixed dose tablet composition comprising,
a) one layer comprising glimepiride and one or more pharmaceutically acceptable excipients, and
b) another layer comprising sitagliptin and metformin or its pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
In another embodiment, the present disclosure provides a fixed dose bilayer tablet composition comprising,
a) one layer comprises of 1 mg og glimepiride and one or more pharmaceutically acceptable excipient.
b) another layer comprises of
i. sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50mg of sitagliptin base and
ii. 500mg or 100mg of metformin hydrochloride, and
iii. one or more pharmaceutically acceptable excipient
In another embodiment, the present disclosure provides a fixed dose tablet composition comprising,
a) one layer comprising glimepiride and one or more pharmaceutically acceptable excipients, and
b) another layer comprising sitagliptin and metformin or its pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

Wherein, the composition when tested for dissolution in a phosphate buffer at a pH of 7.8 exhibits at least 90% release of glimepiride in 180 min, for example 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100%.Preferably, wherein the composition when tested for dissolution in a phosphate buffer at a pH of 7.8 exhibits at least 85% release of glimepiride in 45 min, for example 85%, 86%, 87%, 885, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100%. More preferably,wherein, the composition when tested for dissolution in a phosphate buffer at a pH of 7.8 exhibits at least 85% release of glimepiride in 30 min, for example 85%, 86%, 87%, 885, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100%
In yet another embodiment, the present disclosure provides a fixed dose bilayer tablet composition, comprising:
a) one layer comrprising of glimepiride.
b) another layer comprising of metformin hydrochloride and sitagliptin phosphate monohydrate; and
c) Optionally, a film coating covering the first layer and the second layer.
In yet another embodiment, the present disclosure provides a fixed dose bilayer tablet composition, comprising:
a) one layer comrprising of glimepiride.
b) another layer comprising of metformin hydrochloride and sitagliptin phosphate; and
c) Optionally, a film coating covering the first layer and the second layer.
wherein, the composition when tested for dissolution in a phosphate buffer at a pH of 7.8 exhibits at least 90% release of glimepiride in 180 min, for example 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100%. Preferably, wherein the composition when tested for dissolution in a phosphate buffer at a pH of 7.8 exhibits at least 90% release of glimepiride in 45 min, for example 85%, 86%, 87%, 885, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100%. More preferably,wherein, the composition when tested for dissolution in a phosphate buffer at a pH of 7.8 exhibits at least 85% release of glimepiride in 30 min, for example 85%, 86%, 87%, 885, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100%.
In yet another embodiment, the present invention provides a fixed dose pharmaceutical bilayer tablet composition comprising:
a) one layer comprising 1 or 2 mg of glimepiride.
b) another comprising 500mg or 1000 mg of metformin hydrochloride and sitagliptin or its salt thereof, equivalent to 50mg sitagliptin base.
Preferably, the one layer comprises comprises 1mg of glimepiride and the another layer comprises 1000mg of metformin hydrochloride and sitagliptin phosphate monohydrate, equivalent to 50mg sitagliptin base.
In yet another aspect, the present invention provides a fixed dose pharmaceutical bilayer tablet composition comprising:
a) one layer comprising 1 or 2 mg of glimepiride.
b) another layer comprising 500mg or 1000 mg of Metformin hydrochloride and 50 mg of sitagliptin phosphate equivalent to sitagliptin base; and
c) Optionally, a film coating covering the first layer and the second layer.
wherein, the composition when tested for dissolution in a phosphate buffer at a pH of 7.8 exhibits at least 90% release of glimepiride in 180 min, for example 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100%.Preferably, wherein the composition when tested for dissolution in a phosphate buffer at a pH of 7.8 exhibits at least 85% release of glimepiride in 45 min, for example 85%, 86%, 87%, 885, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100%. More preferably,wherein, the composition when tested for dissolution in a phosphate buffer at a pH of 7.8 exhibits at least 85% release of glimepiride in 30 min, for example 85%, 86%, 87%, 885, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100%
In one embodiment, the fixed dose pharmaceutical composition of the present invention (Test product) was tested for its bioequivalence and safety against the Reference product (R) in healthy adult human subjects under fed condition. The pharmacokinetic parameters, Cmax, AUC0-t and AUC0-8 of the Test product (T) – fixed dose composition comprising sitagliptin phosphate, metformin hydrochloride and glimepiride tablets (50 mg/1000 mg/2mg) were compared to the Reference products (R) - (R1) Janumet® (Sitagliptin phosphate & Metformin Hydrochloride tablets) 50mg/1000 mg and (R2) Amaryl® (Glimepiride Tablets I.P.) 2 mg. Test/Reference (T/R)ratio was calculated using the LSM of log-transformed pharmacokinetic parameters (Cmax, AUC0-t and AUC0-8). Ratio of means will be expressed as a percentage of the LSM of the reference formulation. For a Test product to be bioequivalent to the Reference product, he ratio of Test (T) and Reference (R) product averages (least squares geometric means) for pharmacokinetic parameters (Cmax, AUC0-t and AUC0-8) should be between 80% and 125% for the log-transformed data. Example 4 discloses the bioequivalence study for the fixed dose pharmaceutical composition of the present invention (Test product) and it was found that T/R ratio for pharmacokinetic parameters (Cmax, AUC0-t and AUC0-8) were between 80% and 125% for the log-transformed data. Based on these results, the fixed dose pharmaceutical composition Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride 50 mg/ 1000 mg/ 2 mg tablets (Test Product) was found to be bioequivalent to the Reference products, Janumet® (Sitagliptin phosphate and Metformin Hydrochloride) tablets 50 mg/1000 mg [Reference Product (R1)] & Amaryl (Glimepiride) Tablets 2 mg [Reference Product (R2)]
In one embodiment, the present disclosure provides a fixed dose pharmaceutical composition comprising
a) sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50 mg of sitagliptin base;
b) 1000mg of metformin hydrochloride, and
c) glimepiride
wherein the composition is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin reference formulation and an equal dose of an immediate-release glimepiride reference formulation with the Cmax T/R ratio falling within 80% -125% range when administered to human subjects.
In another embodiment, the present disclosure provides a a fixed dose pharmaceutical composition comprising
a) sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50 mg of sitagliptin base;
b) 1000 mg of metformin hydrochloride, and
c) glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100ng/ml to about 300ng/ml, a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin reference formulations with the Cmax T/R ratio falling within 80% -125% range when administered to human subjects.
In one embodiment, the present disclosure provides a fixed dose pharmaceutical composition comprising
a) sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50 mg of sitagliptin base;
b) 1000 mg of metformin hydrochloride, and
c) 2mg of glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100ng/ml to about 200ng/ml, a a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml and a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin, and immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range.
In one embodiment, the present disclosure provides a fixed dose pharmaceutical composition comprising
a) sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50 mg of sitagliptin base;
b) 1000 mg of metformin hydrochloride, and
c) glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100ng/ml to about 200ng/ml, a a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin reference formulations with the Cmax T/R ratio falling within 80% -125% range when administered to human subjects.
In one embodiment, the present disclosure provides a fixed dose pharmaceutical composition comprising
a) sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50 mg of sitagliptin base;
b) 1000 mg of metformin hydrochloride, and
c) 2 mg of glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to human.
In yet another embodiment, the present disclosure provides a fixed dose pharmaceutical composition comprising
a) sitagliptin phosphate monohydrate,
b) metformin hydrochloride, and
c) glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100ng/ml to about 300ng/ml, a a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml and a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin, and immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range.
In another embodiment, the present disclosure provides a fixed dose pharmaceutical composition comprising
a) sitagliptin phosphate monohydrate,
b) metformin hydrochloride, and
c) glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100ng/ml to about 300ng/ml, a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to humans
In yet another embodiment, the present disclosure provides a fixed dose pharmaceutical composition comprising
a) sitagliptin phosphate monohydrate,
b) metformin hydrochloride, and
c) glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range when administered to humans subjects
In another embodiment, the present disclosure provides a fixed dose pharmaceutical composition comprising
a) sitagliptin phosphate monohydrate; equivalent to 50mg of sitagliptin base,
b) 1000mg of metformin hydrochloride, and
c) 2 mg of glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100ng/ml to about 300ng/ml, a a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml and a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin, and immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to human subjects
In yet another embodiment, the present disclosure provides a fixed dose pharmaceutical composition comprising
a) sitagliptin phosphate monohydrate; equivalent to 50mg of sitagliptin base,
b) 1000mg of metformin hydrochloride, and
c) glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100ng/ml to about 300ng/ml, a a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin reference formulations with the Cmax T/R ratio falling within 80% -125% range when administered to human subjects.
In yet another embodiment, the present disclosure provides a fixed dose pharmaceutical composition comprising
a) sitagliptin phosphate monohydrate; equivalent to 50mg of sitagliptin base,
b) 1000mg of metformin hydrochloride, and
c) 2 mg of glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to human.
In yet another embodiment, the present disclosure provides a fixed dose pharmaceutical bilayer tablet composition comprising:
a) one layer comprising 2mg of glimepiride.
b) another layer comprising 1000mg of metformin hydrochloride and sitagliptin or its salt thereof, equivalent to 50mg of sitagliptin base;
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100 ng/ml to about 300ng/ml, a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml and a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin, and immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to human.
In yet another embodiment, the present disclosure provides a fixed dose pharmaceutical bilayer tablet composition comprising:
a) one layer comprising glimepiride.
b) another layer comprising 1000mg of metformin hydrochloride and sitagliptin or its salt thereof, equivalent to 50mg of sitagliptin base;
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100 ng/ml to about 300ng/ml, a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to human
In yet another embodiment, the present disclosure provides a fixed dose pharmaceutical bilayer tablet composition comprising:
a) one layer comprising 2mg of glimepiride.
b) another layer comprising 1000mg of metformin hydrochloride and sitagliptin or its salt thereof, equivalent to 50mg of sitagliptin base;
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to humans.
In yet another embodiment, the present disclosure provides a fixed dose pharmaceutical bilayer tablet composition comprising:
a) one layer comprising glimepiride.
b) another layer comprising metformin hydrochloride and sitagliptin phosphate equivalent to sitagliptin base;
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100 ng/ml to about 300ng/ml, a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml and a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin, and immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to human.
In another emodiment the present disclosure provides a fixed dose pharmaceutical bilayer tablet composition comprising:
a) one layer comprising glimepiride.
b) another layer comprising metformin hydrochloride and sitagliptin phosphate monohydrate;
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100 ng/ml to about 300ng/ml, a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to human
In another emodiment the present disclosure provides a fixed dose pharmaceutical bilayer tablet composition comprising:
a) one layer comprising glimepiride.
b) another layer comprising metformin hydrochloride and sitagliptin phosphate monohydrate;
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml, and is bioequivalent to an equal dose of an immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range, when administered to humans.
In yet another emodiment the present disclosure provides a fixed dose pharmaceutical bilayer tablet composition comprising:
a) a first layer comprising 2 mg of glimepiride.
b) a second layer comprising 1000 mg of Metformin hydrochloride and sitagliptin phosphate monohydrate equivalent to 50mg sitagliptin base; and
c) Optionally, a film coating covering the first layer and the second layer,
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of Sitagliptin, in the range of about 100 ng/ml to about 300ng/ml; a mean maximum plasma concentration(Cmax) of Metformin in the range of about 700ng/ml to 3200ng/ml; a mean maximum plasma concentration(Cmax) of Glimiperide in the range of about 85ng/ml to 280ng/ml, and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin, and immediate-release glimepiride reference formulations with the Cmax T/R ratio falling within 80% -125% range.
It is preferred that the fixed dose pharmaceutical composition, when administered once daily, exhibit a bioavailability, as expressed conventionally by Cmax, AUC0-24 or AUC0-8 of sitagliptin, metformin and glimepiride, that is substantially equivalent to the same daily dose of a reference formulation, for example Janumet® & Amaryl® tablet, administered once a day. In the present context, “substantially equivalent” means that the bioavailability of such a preferred composition is about 0.8 to about 1.25 times that of the reference formulation, i.e T/R ratio falling within 80% -125% range. The Pharmacokinetic study used to generate the parameters specified above for the composition of the invention is conducted according to a protocol that is generally accepted in the art.
In one embodiment, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of sitagliptin that is in the range of about 100 ng/ml to about 300ng/ml. Because of high variability in the subjects, the mean Cmax is calculated from Ln-transformed data as Least square geometric mean Cmax., herein referred to as mean Cmax. In one aspect of the embodiment, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of sitagliptin that is in the range of about about 110ng/ml to about 290 ng/ml. In yet another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of sitagliptin that is in the range of about 120ng/ml to about 280 ng/ml. In yet another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of sitagliptin that is in the range of about 130ng/ml to about 270ng/ml. In yet another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of sitagliptin that is in the range of about 140ng/ml to about 260 ng/ml. In yet another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of sitagliptin that is in the range of about 150ng/ml to about 250 ng/ml. In another aspect, following single dose administration of the present composition exhibit a mean maximum plasma concentration (Cmax) of sitagliptin that is in the range of about 160 ng/ml to about 240ng/ml. In a preferable aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of sitagliptin that is in the range of about 170ng/ml to about 230ng/ml,
In one embodiment, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin about 700 ng/ml to about 3200ng/ml. In one aspect of the embodiment, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 800ng/ml to about 3100 ng/ml. In another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 900 ng/ml to about 3000 ng/ml. In yet another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 1000 ng/ml to about 2900ng/ml. In yet another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 1100 ng/ml to about 2800 ng/ml. In yet another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 1200ng/ml to about 2700 ng/ml. In a another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 1300 ng/ml to about 2600ng/ml. In a preferable aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 1400 ng/ml to about 2500ng/ml. In a more preferable aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 1500 1ng/ml to about 2400 ng/ml,
In one embodiment, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of glimepiride that is in the range of about 90 ng/ml to about 300ng/ml. In one aspect of embodiment, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 100ng/ml to about 290 ng/ml. In yet another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 110 ng/ml to about 280 ng/ml. In yet another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 120ng/ml to about 270ng/ml. In yet another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 130 ng/ml to about 260 ng/ml. In yet another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 140 ng/ml to about 250 ng/ml. In a preferable aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 150 ng/ml to about 2400 ng/ml. In a more preferable aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a mean maximum plasma concentration (Cmax) of metformin that is in the range of about 160 ng/ml to about 230 ng/ml.
In one embodiment, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a time to reach maximum plasma concentration (Tmax) of sitagliptin of about 4 hours.
In another embodiment, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a time to reach maximum plasma concentration (Tmax) of metformin of about 5 hours.
In another embodiment, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibit a time to reach maximum plasma concentration (Tmax) of glimepiride of about 4.3 hours
In one embodiment, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibits a concentration profile of sitagliptin further characterized by AUC values (AUC0-t, AUC0-8) between about 1800 ng.hr/ml to about 2200 ng.hr/ml. In one aspect of the embodiment, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibits a concentration profile of sitagliptin further characterized by AUC values (AUC0-t, AUC0-8) between about 1500 ng.hr/ml.mg to about 1600 ng.hr/ml. In another aspect, following single dose administration, the fixed dose pharmaceutical composition composition of the invention, exhibits a concentration profile of sitagliptin further characterized by AUC values (AUC0-t, AUC0-8) between about 1300 ng.hr/ml.mg to about 1500 ng.hr/ml.
In one embodiment the efficacy and safety of fixed dose pharmacetical composition of sitagliptin phosphate, metformin hydrochloride and glimepiride (50 mg/1000 mg/1 mg or 2mg) in patients with type 2 diabetes mellitus was determined by administering the composition twice daily (BID) for atleast 16 to 28 weeks, and compared to co-administration of metformin hydrochloride 1000mg tablet and glimepiride 2mg tablet. They were evaluated for mean change in HbA1c, mean change in Fasting Blood Sugar ( FBS) from baseline at the end of week 12, 16, & 28. In one aspect of the embodiment, the patients to whom the fixed dose combination is administered have an HbA1c = 8% - = 11%. In one aspect of the embodiment, the patients to whom the fixed dose combination is administered have a BMI of = 45 kg/m2. In yet another aspect, the patients are administered a fixed dose combination of metformin, sitagliptin and glimepiride for at least 16 weeks.
After 16 weeks of treatment period, the study will be continued in single-arm for 12 weeks (Week 28). Patients will continue to receive FDC of Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride tablets (50 mg/1000 mg/1 mg), if HbA1c at 16 weeks is < 8%. If HbA1c is = 8% then there will be uptitration and patients will receive FDC of Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride tablets (50 mg/1000 mg/2 mg) BID till Week 28.
The present inventors unexpectedly found that the fixed dose pharmaceutical composition comprising sitagliptin phosphate monohydrate equivalent to 50 mg of sitagliptin base, 1000 mg metformin, and 1mg glimepiride of present invention when administered to patients with diabetes, resulted in HbA1c = 7 % in patients and without any hypoglycaemic effect as shown in the table 9 even when the patient were administered the fixed dose combination twice daily for a period of at least 16 weeks. 3. Hypoglycemic events were recorded in the diary anytime a patient experience either of the following: 1) Signs and symptoms of hypoglycemia (regardless of blood glucose value by finger stick) OR 2) Blood glucose value by finger stick = 70 mg/dL (3.9 mmol/L) (regardless of symptoms). Number of patients requiring hypoglycemia management were evaluated during the study by count and percentages.
Hypoglycemia levels are defined as below: (as per American Diabetes Association 2021). 1) Level 1 hypoglycemia is defined as a measurable glucose concentration <70 mg/dL (3.9 mmol/L) and = 54 mg/dL (3.0 mmol/L). 2) Level 2 hypoglycemia (defined as a blood glucose concentration <54 mg/dL [3.0 mmol/L]). 3) Level 3 hypoglycemia is defined as a severe event characterized by altered mental and/or physical status requiring assistance for treatment of hypoglycemia.
In one aspect, the fixed dose pharmaceutical composition comprising sitagliptin phosphate monohydrate equivalent to 50 mg sitagliptin base, 1000 mg metformin, and 1mg glimepiride of present invention when administered to patients with Type II diabetes, results in an improvement in HbA1c levels, Postprandial Blood Glucose (PPBG), Fasting blood sugar (FBS), and hypoglycaemia management as presented in Example 5. It was observed that all hypoglycemic events were Level 1 and asymptomatic and none of the patient required hypoglycaemia management during the study period.
In one embodiment, the present disclosure, provides a fixed dose pharmaceutical composition comprising:
a) sitagliptin or a pharmaceutically acceptable salt thereof, equivalent to 50mg of sitagliptin base
b) 500mg or 1000mg of metformin or a pharmaceutically acceptable salt thereof,
c) 1mg of glimepiride, and
d) one or more pharmaceutically acceptable excipient,
which when administered twice daily for a period of at least 16 weeks to a diabetic patient having a HbA1c = 8% to = 11%, results in reducing HbA1c to = 7 % without the patients showing any hypoglycemic effect.
More preferably, the present disclosure, provides a fixed dose pharmaceutical composition comprising:
a) sitagliptin or a pharmaceutically acceptable salt thereof, equivalent to 50mg of sitagliptin base
b) 1000mg of metformin hydrochloride,
c) 1 mg of glimepiride, and
d) one or more pharmaceutically acceptable excipient,
which when administered twice daily for a period of at least 16 weeks to a diabetic patient having a HbA1c = 8% to = 11%, results in reducing HbA1c to = 7 % without the patients showing any hypoglycemic effect.
In yet another embodiment, the present disclosure provides a fixed dose pharmaceutical bilayer tablet composition comprising:
a) one layer comprising glimepiride.
b) another layer comprising metformin hydrochloride and sitagliptin phosphate monohydrate equivalent to sitagliptin base;
which when administered twice daily for a period of at least 16 weeks to a diabetic patient having a HbA1c = 8% to = 11%, results in reducing HbA1c to = 7 % without the patients showing any hypoglycemic effect.
In yet another embodiment, the present disclosure provides a fixed dose bilayer tablet composition comprising,
a) one layer comprises of 1 mg of glimepiride and one or more pharmaceutically acceptable excipient.
b) another layer comprises of
i. sitagliptin or its pharmaceutically acceptable salt thereof, equivalent to 50mg of sitagliptin base and
ii. 500mg or 100mg of metformin hydrochloride, and
iii. one or more pharmaceutically acceptable excipient
which when administered twice daily for a period of at least 16 weeks to a diabetic patient having a HbA1c = 8% - = 11% and results into a reduced HbA1c = 7 % without showing any hypoglycemic effect.
In yet another emodiment the present disclosure provides a fixed dose pharmaceutical bilayer tablet composition comprising:
a) one layer comprising 1 mg of glimepiride.
b) other layer comprising 1000 mg of Metformin hydrochloride and of sitagliptin phosphate monohydrate equivalent to 50mg of sitagliptin base; and
c) optionally, a film coating covering the first layer and the second layer,
which when administered twice daily for a period of at least 16 weeks to a diabetic patient having a HbA1c = 8% to = 11%, results in reducing HbA1c to = 7 % without the patients showing any hypoglycemic effect.
It should be clearly understood that the following examples are illustrative only and are not intended to limit the scope of the present invention.
EXAMPLES:
Example 1: Monolayer Tablet composition of Sitagliptin, Metformin & Glimepiride.
The mono layer tablet comprising Sitagliptin, Metformin & Glimepiride 50/1000/1mg were prepared using wet granulation process, wherein the APIs and excipient were sifted, followed by introducing the binder solution and milling to obtain granules, which are further blended with extra granular excipients, and the blend is then compressed to obtain a tablet.
Table 1: Monolayer Tablet of Fixed Dose Composition of Sitagliptin, Metformin, & Glimepiride (50mg/1000mg/1mg)
INGREDIENTS % w/w
Glimepiride 0.12
Metformin HCl 60.55
Sitagliptin phosphate 3.76
Lactose Monohydrate 14.80
Microcrystalline cellulose pH 101 7.87
Polyvinylpyrrolidone 3.91
Ferric oxide Yellow 0.01
Microcrystalline cellulose pH 102 1.21
Sodium Starch Glycolate 0.61
Magnesium Stearate 0.47
Sodium lauryl sulphate 0.39
Cross povidone 3.03
Silicon dioxide 0.36
Opadry Yellow 2.91
Purified Water q.s.
Weight of Coated Tablet 100

Example 2: Bilayer Tablet Composition of Sitagliptin, Metformin & Glimepiride.
The Bilayer tablet of the Fixed dose combination of Sitagliptin, Metformin & Glimepiride were prepared using wet granulation process in two table strength 50/1000/2mg or 50/1000/1mg respectively.
Method of Manufacturing:
The bilayer tablet composition is prepared by a the process of wet granulation wherein the onelayer comprises of glimepiride and the other layer comprises of sitagliptin phosphate monohydrate and metformin hydrochloride. Both these layers were prepared by the process of wet granulation,
Glimepiride layer- the process comprises of sifting glimepirideand excipients in a sifter followed by process of granulation by introduction of water and preparing a wet mass which is followed by drying the wet mass and milled to obtain dry granules which are further blended with extra granular excipients.
Sitagliptin + metformin HCl layer - the process comprises of sifting sitagliptin phosphate monohydrate and metformin hydrochloride and excipients in a sifter followed by process of granulation by introduction of binder solution comprising SLS and preparing a wet mass which is followed by drying the wet mass and milled to obtain dry granules which are further blended with extra granular excipients. The lubricated blend of glimepiride layer with sitagliptin + metformin HCl layer were compressed into bilayer tablets. This core tablet was then coated with film coating dispersion.
Table 2: Composition Details of the Fixed Dose Composition of Sitagliptin, Metformin, & Glimepiride (50mg/500mg/1mg & 50mg/1000mg/1mg)
COMPOSITION 50/500/1mg 50/1000/1mg
1 2 3 4 5
INGREDIENTS %w/w %w/w %w/w %w/w %w/w
LAYER- 1
Glimepiride 0.35 0.35 0.35 0.353 0.353
Lactose Monohydrate 86.75 85.75 86.76 86.75 86.75
Microcrystalline Cellulose pH 101 3.53 4.09 3.54 3.53 3.53
Polyvinyl pyrollidone 1.60 1.58 1.6 1.59 1.59
Ferric oxide red 0.07 0.05 0.06 0.07 0.07
Microcrystalline Cellulose pH 102 3.53 3.83 3.47 3.54 3.54
Sodium Starch Glycolate 3.53 3.83 3.58 3.53 3.53
Magnesium Stearate 0.64 0.52 0.64 0.64 0.64
TOTAL 100.00 100.00 100.00 100.00 100.00
LAYER- 2
Metformin HCl 73.28 73.28 73.28 76.77 76.77
Sitagliptin Phosphate 9.09 9.09 9.09 4.76 4.76
Microcrystalline Cellulose pH 101 8.79 8.5 9.11 9.21 9.01
Polyvinyl pyrollidone 4.04 4.34 3.92 4.61 4.81
Sodium lauryl sulfate 0.48 0.5 0.5 0.5 0.5
Microcrystalline Cellulose pH 102 0.93 0.95 0.73 0.77 0.78
Crosspovidone 1.47 1.5 1.43 1.54 1.53
Colloidal Silicon dioxide 0.54 0.44 0.64 0.46 0.46
Magnesium Stearate 1.38 1.4 1.3 1.38 1.38
TOTAL 100.00 100 100 100 100
FILM COAT
Opadry Beige 2.91 2.01 2.61 2.91 2.91

Table 3: Composition Details of the Fixed Dose Composition of Sitagliptin, Metformin, & Glimepiride (50mg/500mg/2mg & 50mg/1000mg/2mg)
COMPOSITION 50/500/2mg 50/1000/2mg
6 7 8 9 10 11
INGREDIENTS %w/w %w/w %w/w %w/w %w/w %w/w
LAYER 1
Glimepiride 0.71 0.71 0.71 0.71 0.71 0.71
Lactose Monohydrate 86.4 85.9 86.98 86.4 84.56 86.4
Microcrystalline Cellulose pH101 3.53 3.73 3.36 3.53 3.67 3.53
Polyvinyl pyrollidone 1.59 1.62 1.54 1.59 1.6 1.59
Ferric oxide Yellow 0.07 0.1 0.1 0.07 0.08 0.07
Microcrystalline Cellulose pH102 3.53 3.95 3.53 3.53 4.5 3.53
Sodium Starch Glycolate 3.53 3.53 3.53 3.53 4.3 3.53
Magnesium Stearate 0.64 0.48 0.45 0.64 0.58 0.64
TOTAL 100 100.02 100.2 100 100 100
LAYER 2
Metformin HCl 73.28 73.28 73.28 76.77 76.77 76.77
Sitagliptin Phosphate 9.09 9.09 9.09 4.76 4.76 4.76
Microcrystalline Cellulose pH101 8.79 8.59 8.6 8.98 9.34 9.21
Polyvinyl pyrollidone 4.4 4.4 4.4 4.71 4.52 4.61
Sodium lauryl sulfate 0.48 0.48 0.4 0.5 0.53 0.5
Microcrystalline Cellulose pH101 0.73 0.73 0.99 0.74 0.74 0.77
Crosspovidone 1.47 1.67 1.42 1.54 1.67 1.54
Colloidal Silicon dioxide 0.44 0.44 0.48 0.56 0.39 0.46
Magnesium Stearate 1.32 1.32 1.34 1.44 1.28 1.38
TOTAL 100 100 100 100 100 100
FILM COATING
Opadry Yellow 2.91 2.94 2.89 2.93 2.9 2.96

Example 3: Dissolution Study Profile
The Comparative dissolution study of the bilayer tablet with a monolayer IR tablet of the Fixed dose combination of Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride 50 mg/ 1000 mg/ 1mg was carried out using USP II paddle apparatus at 75 rpm in a phosphate buffer with a 7.80 pH for the monolayer tablet of Example 1 in comparisiion with the bilayer tablet mentioned in Example 2 , composition 11. It was observed that Glimepiride was released at a slow rate in a mono layer tablet compared to the bilayer tablet.

TABLE 4: Comparative Dissolution Profile of Monolayer table vs. Bilayer tablet
Time (min) % Drug dissolved (Glimepiride)
Comparative Example 1 Example 2 – Composition 11
5 59 68
10 68 83
15 74 88
30 79 94
45 83 95
60 85 95
Infinity 86 96

Example 4: Dissolution Study Profile of the Fixed dose combination of Test vs. Reference
The comparative dissolution study was carried out using USP II paddle apparatus at 75 rpm in a phosphate buffer with a 7.80 pH. of test comprising the Fixed dose combination of Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride 50 mg/ 1000 mg/ 1mg or 2 mg tablets Tablet with the refernce product Janumet® (Sitagliptin phosphate and Metformin Hydrochloride) 50 mg/ 1000 mg tablets & Amaryl (Glimepiride) 1mg or 2mg Tablets.

TABLE 5: Dissolution Study Profile of the Fixed dose combination of Test vs. Reference
Product Janumet Tablets 50/1000 mg
(Reference product)
Amaryl Tablets
1 mg
(Reference product)
Sitagliptin Phosphate, Metformin HCl and Glimepiride Tablets 50/1000/1mg

% Drug Release
Time (mins) Sitagliptin Metformin HCl Glimepiride Sitagliptin Metformin HCl Glimepiride
10 70 73 85 67 67 77
15 89 92 90 101 100 85
30 98 100 95 103 102 93
45 98 101 95 103 102 94

TABLE 6: Dissolution Study Profile of the Fixed dose combination of Test vs. Reference )

Product Janumet Tablets 50/1000 mg
(Reference product)
Amaryl Tablets 2mg
(Reference product)
Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride Tablets 50/1000/2mg

% Drug Release
Time (mins) Sitagliptin Metformin HCl Glimepiride Sitagliptin Metformin HCl Glimepiride
10 70 73 95 95 93 78
15 89 92 98 100 99 85
30 98 100 99 100 99 91
45 98 101 98 100 99 94

The dissolution profile indicated that the test product has comparable drug release profile with Reference product

Example 4:Bioequivalence Study.
A Single dose two-way crossover bioequivalence study comprising 48 Forty Eight (48) healthy adult human subjects were performed to assess the bioequivalence between Test product (T) - Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride tablets 50 mg / 1000 mg / 2 mg, and; Reference product (R) - Reference Product (R1) immediately followed by Reference Product (R2) will be administered and will be coded as Reference product (R).
Reference (R1): Janumet® (Sitagliptin phosphate & Metformin Hydrochloride tablets) 50mg/1000 mg manufactured by MSD Pharmaceuticals Pvt. Ltd., India Reference (R2): Amaryl® (Glimepiride Tablets I.P.) 2 mg manufactured by Sanofi India Limitedand to monitor the safety of Test product (T) and Reference product (R) in healthy adult human subjects under fed condition.
The subjects were administered single oral dose of either Test (T) or Reference (R) products
Reference (R):A single oral dose of one tablet of Reference (R1), immediately followed by one tablet of Reference (R2) product was administered with 20% w/v glucose solution at an ambient temperature, 45 minutes after the start of high-fat high-calorie breakfast Test (T): A single oral dose of one tablet of Test (T) product was administered with 20% w/v glucose solution at an ambient temperature, 45 minutes after the start of high-fat highcalorie breakfast
A total of 56, 3ml samples were collected. Blood samples were collected at Pre-dose (duplicate) and at. 0.3- 72 hours post dose in each period of the study. Pharmacokinetic parameters AUC0-t, AUC0-inf , Cmax Tmax, t1/2, of Sitagliptin, Metformin and Glimepiride concentration data were calculated by quantifying the concentration in human plasma using LC-MS/MS method.

TABLE 7: Statistical Analysis- Sitagliptin (T vs R) [N=41]
Parameter (units) Geometric Least Square Mean % Ratio
(Ta/R) 90 %CI Intra Subject CV%
Test
(T) Reference (R)
Cmax (ng/mL) 173.6 157.95 109.87 102.79-117.44 18.04
AUC0-t (ng.hr/mL) 1973.32 2031.38 97.13 95.55-98.73 4.41
AUC0-8 (ng.hr/mL) 2030.10 2086.30 97.29 95.70-98.91 4.43
*T1/2 (h) 9.65 9.52
#Tmax (h) 4.0 4.0
*Arithmetic mean presented; #Median (Min-Max) presented
Figure 1A discloses the Linear plot of Mean Plasma of Sitagliptin Concentration v/s Time (hr)
TABLE 8: Statistical Analysis – Metformin (T vs R) [N=41]
Parameter (units) Geometric Least Square Mean % Ratio
(Tb/R) 90 %CI Intra Subject CV%
Test
(T) Reference (R)
Cmax (ng/mL) 1577.93 1500.84 105.02 97.80-112.76 19.29
AUC0-t (ng.hr/mL) 15001.45 15265.51 98.23 94.26-102.37 11.11
AUC0-8 (ng.hr/mL) 15313.89 15560.09 98.38 94.44-102.47 10.99
*T1/2 (h) 4.4 4.45
#Tmax (h) 5.000 5.000
*Arithmetic mean presented; #Median (Min-Max) presented
Figure 1b shows the Linear plot of Mean Plasma of Metformin Concentration v/s Time (hr)

TABLE 9: Statistical Analysis – Glimepiride (T vs R) [N=41]
Parameter (units) Geometric Least Square Mean % Ratio
(Tb/R) 90 %CI Intra Subject CV%
Test
(T) Reference (R)
Cmax (ng/mL) 169.59 149.97 113.12 103.15-124.06 25.17
AUC0-t (ng.hr/mL) 1340.26 1426.11 94.00 89.57-98.65 13.02
AUC0-8 (ng.hr/mL) 1369.8101 1452.04 94.36 89.95-98.98 12.89
*T1/2 (h) 9.19 8.14
#Tmax (h) 4.33 4.33
*Arithmetic mean presented; #Median (Min-Max) presented
Figure 1c shows the Linear plot of Mean Plasma of Glimepiride Concentration v/s Time (hr)

The ratio of test (T) and reference (R) product averages (least squares means) for pharmacokinetic parameters (Cmax, AUC0-t and AUC0-8) were between 80% and 125% for the log-transformed data. Based on these results, single oral dose of Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride 50 mg/ 1000 mg/ 2 mg tablets (Test Product) and Janumet® (Sitagliptin phosphate and Metformin Hydrochloride) tablets 50 mg/1000 mg [Reference Product (R1)] & Amaryl (Glimepiride) Tablets 2 mg [Reference Product (R2)] were bioequivalent in healthy adult human subjects under fed condition.

Example 5: Clinical Study -
The study assessed the efficacy of fixed dose composition of Sitagliptin phosphate monohydrate, Metformin hydrochloride and Glimepiride tablets (50 mg/1000 mg/1 mg) given twice daily (BID) in comparison to Co-administration of Metformin hydrochloride 500 mg (2 tablets given BID) and Glimepiride 2 mg tablets given BID in patients treated for type 2 diabetes mellitus. Figure 2 discloses the outline of the clinical studies. 127 human subjects were randomised initially with type 2 diabetes with HbA1c = 8 and = 11 % were selected to obtain an and efficacy data, with a total study duration of 16 weeks.

The study comprises of test arm and an comparator arm the test arm comprising
Test 1 comprises of FDC of Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride tablets 50 mg/1000 mg/1 mg.

The subjects to be up-titrated to test 2 if the HbA1c = 8% post 16 weeks.
Test 2 comprises of FDC of Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride tablets 50 mg/1000 mg/2 mg .

Comparator comprises of Metformin Hydrochloride tablets IP 500 mg and Glimepiride tablets IP 2 mg and the comparator arm comprises of Metformin Hydrochloride tablets IP 500 mg and Glimepiride tablets IP 2 mg
The subjects received glucometer with strips for self-monitoring of blood glucose levels, to check blood glucose levels whenever they experience any signs/symptoms of hypoglycaemia and the blood glucose monitored atleast once a week. Hypoglycemic events were recorded if a patient experienced either of the following: Signs and symptoms of hypoglycemia* (regardless of blood glucose value by finger stick) OR Blood glucose value by finger stick = 70 mg/dL (3.9 mmol/L) (regardless of symptoms). The subjects underwent laboratory investigation at week 1, 12, and 16

The 16 weeks results for efficacy of the Fixed Dose Combination of Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride Tablets in Comparison to Co-administration of Metformin Hydrochloride and Glimepiride Tablets in Patients were evaluated with Mean Change in HbA1c (%),PPBG (mg/dL), FBG and Proportion of Participants Achieving HbA1c < 7.0% at Week 12 and 16.

TABLE 10: Mean Change in HbA1c (%) from Baseline to the End of Week 16
Category TEST 1 (BID)
(N = 60) Comparator (BID)
(N=67) Test Vs Comparator
Visits Statistic Summary Actual Change from Baseline [3] Actual Change from Baseline [3] p-value [2] [4]
Visit 1 (Baseline) n 60 67 0.7671
Mean ± SD 9.18±0.86 9.13±0.90
Week 12 n 59 59 66 66 0.1632

Mean ± SD 7.72± 1.11 -1.48±1.06 7.92±1.10 -1.22±0.98
p value [1] <0.001 <0.001
Week 16 N 59 59 66 66 0.0080

Mean ± SD 7.28± 1.07 -1.92± 1.03 7.76± 1.24 -1.38± 1.20
p value [1] <0.001 <0.001
FDC: Fixed Dose [16 P-value for between group comparison is based on ANCOVA model with the treatment group as a fixed effect and baseline HbA1c value as a covariate.

TABLE 11: Mean Change in FBG from baseline at the end of Weeks 12, 16
Category TEST 1 (BID)
(N = 60) Comparator (BID)
(N=67) Test Vs Comparator
Visits Statistic Summary Actual Change from Baseline[3] Actual Change from Baseline[3] p-value
Visit 1 (Baseline) n 60 67 0.1767
Mean ± SD 183.0±38.48 192.5±40.16
Week 12 n 59 59 66 66 0.7596
Mean ± SD 143.8±42.03 -38.3±38.78 151.9±37.95 -40.4±37.83
p value <0.001 <0.001
Week 16 N 59 59 66 66 0.0971
Mean ± SD 137.2±33.51 -44.9±35.51 150.8±34.98 -41.5±35.14
p value <0.001 <0.001
FDC: Fixed Dose Combination; P-value for between group comparison is based on ANCOVA model with the treatment group as a fixed effect and baseline HbA1c value as a covariate.

Overall, Fixed Dose Combination of Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride tablets 50 mg/1000 mg/1 mg (BID) provided significantly better HbA1c reduction from baseline to Week 16 compared to Co-administration of Metformin Hydrochloride 500 mg (2 tablets BID) and Glimepiride tablets 2 mg (BID).

Example 6: Safety Evaluation of Fixed Dose Combination of Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride Tablets.
To assess the safety of FDC of Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride tablets (50 mg/1000 mg/1 mg) given twice daily (BID) in comparison to Co-administration of Metformin Hydrochloride 500 mg (2 tablets given BID) and Glimepiride 2 mg tablets given BID in patients treated for type 2 diabetes mellitus.

The total 127 subjects were evaluated for safety the test and comparator arm were as explained in example 5 for a study duration of 16 weeks. The 16 weeks results for safety of the Fixed Dose Combination of Sitagliptin Phosphate, Metformin Hydrochloride and Glimepiride Tablets in Comparison to Co-administration of Metformin Hydrochloride and Glimepiride Tablets in which comprises of safety assessment including Treatment Emergent Adverse Events (TEAEs) assessment during the study Week 12 and 16.

TABLE 12: Treatment Emergent Adverse Events by System Organ Class (SOC) and Preferred Term (PT) - Safety Population
System Organ Class Preferred Term TEST 1 (BID)
(N = 60) Comparator (BID)
(N=67) Overall
(N=127)
N (%) E N (%) E N (%) E
All TEAEs 12 (20.0%) 15 11 (16.4%) 14 23 (18.1%) 29
Gastrointestinal disorders 4 (6.7%) 5 8 (11.9%) 10 12 (9.4%) 15
Abdominal pain upper 1 (1.7%) 1 1 (1.5%) 1 2 (1.6%) 2
Diarrhoea 1 (1.7%) 1 2 (3.0%) 3 3 (2.4%) 4
Hyperchlorhydria 0 0 1 (1.5%) 1 1 (0.8%) 1
Nausea 0 0 3 (4.5%) 3 3 (2.4%) 3
Vomiting 2 (3.3%) 3 2 (3.0%) 2 4 (3.1%) 5
Metabolism and nutrition disorders 3 (5.0%) 5 1 (1.5%) 2 4 (3.1%) 7
Hypoglycaemia 3 (5.0%) 5 1 (1.5%) 2 4 (3.1%) 7
Musculoskeletal and connective tissue disorders 1 (1.7%) 1 0 0 1 (0.8%) 1
Arthralgia 1 (1.7%) 1 0 0 1 (0.8%) 1
Nervous system disorders 3 (5.0%) 3 2 (3.0%) 2 5 (3.9%) 5
Headache 3 (5.0%) 3 2 (3.0%) 2 5 (3.9%) 5
Respiratory, thoracic and mediastinal disorders 1 (1.7%) 1 0 0 1 (0.8%) 1
Rhinorrhoea 1 (1.7%) 1 0 0 1 (0.8%) 1
BID: Twice daily; E: Number of Events; FDC: Fixed dose combination; N: Number of subjects
[1] Body System totals are not necessarily the sum of the individual adverse events since a patient may have reported more than one adverse events in the same body system; [2] Adverse events are coded into system organ class and preferred term using MedDRA version 24.0; [3] Percentages are computed using N provided in the Column header; [4] If AE is with same Start date but different severity then worst case or latest (whichever applicable) will be consider.

15 TEAEs were reported in 12 (20.0%) subjects in test arm; and 14 TEAEs were reported in 11 (16.4%) subjects in comparator arm. All the events were mild in nature. No severe Adverse events, deaths, severe or life-threatening TEAEs reported during the study. All TEAEs were reported as recovered/resolved. All events were Level 1 and asymptomatic. No patient required hypoglycaemia management during the study period. Thus, study products were safe and well tolerated.

, Claims:1) An oral fixed dose pharmaceutical composition comprising
a) Sitagliptin or a pharmaceutically acceptable salt thereof, equivalent to 50mg of sitagliptin base
b) 1000mg of Metformin or a pharmaceutically acceptable salt thereof,
c) 1mg of Glimepiride pharmaceutically acceptable salt thereof, and
d) One or more pharmaceutically acceptable excipient,
which when administered twice daily for a period of at least 16 weeks to a diabetic patient having a HbA1c = 8% - = 11% results into a reduced HbA1c = 7 % without showing any hypoglycemic effect.
2) The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable salt of sitagliptin is selected from phosphate monohydrate, phosphate anhydrate or fumarate
3) The pharmaceutical composition as claimed in claim 1, wherein the sitagliptin is in the form of sitagliptin phosphate monohydrate.
4) The pharmaceutical composition as claimed in claim 1, where metformin is in the form of metformin hydrochloride
5) The composition as claimed in claim 1, wherein the composition is a tablet, capsule, powder, pellets, suspension or solution.
6) The composition as claimed in claim 5, wherein the composition is a tablet composition.
7) A fixed dose bilayer tablet composition comprising,
a) one layer comprises of glimepiride or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipient.
b) Another layer comprises of Sitagliptin and Metformin or its pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient.
which when administered twice daily for a period of at least 16 weeks to a diabetic patient having a HbA1c = 8% - = 11% and results into a reduced HbA1c = 7 % without showing any hypoglycemic effect.

8) The pharmaceutical composition as claimed in claim 7, wherein the pharmaceutically acceptable salt of sitagliptin is selected from phosphate monohydrate, phosphate anhydrate or fumarate
9) The pharmaceutical composition as claimed in claim 7, wherein the sitagliptin is in the form of sitagliptin phosphate monohydrate.
10) The pharmaceutical composition as claimed in claim 7, where metformin is metformin hydrochloride.
11) The pharmaceutical composition as claimed in claim 9, wherein the metformin is present in an amount of 500mg or 1000mg.
12) The pharmaceutical composition as claimed in claim 10, wherein sitagliptin phosphate monohydrate is present in an amount equivalent to 50 mg of sitagliptin base.
13) The pharmaceutical composition as claimed in claim 1, wherein glimepiride is present in the amount of 1mg.
14) The pharmaceutical composition as claimed in claim 7, wherein the first and second layer are prepared by the process of wet granulation
15) The pharmaceutical composition as claimed in claim 7, wherein the pharmaceutical acceptable excipient comprises of diluent, binder, disintegrant.
16) The pharmaceutical composition as claimed in claim 15, wherein disintegrant is selected from croscarmellose sodium, crospovidone, and sodium starch glycolate.
17) The pharmaceutical composition as claimed in claim 15, wherein binder is selected from hydroxypropylcellulose (HPC),hydroxypropylmethyl cellulose (HMPC), hydroxyethyl cellulose, starch 1500, polyvinylpyrrolidone (povidone), and crospovidone.
18) The pharmaceutical composition as claimed in claim 15, wherein diluent is selected from mannitol, Sorbitol, dibasic calcium phosphate dihydrate, microcrystalline cellulose, and powdered cellulose.
19) The pharmaceutical composition as claimed in claim 15, wherein diluent is present in an amount of about of 10% to 40 %, binder is present in an amount of about 1.5 % w/w to 5.5 % & disntegrant is present in an amount of about 1% to 4%
20) A fixed dose bilayer tablet comprising:
a) one layer comprises of, glimepiride and pharmaceutically acceptable excipient
b) another layer comprises of metformin hydrochloride and sitagliptin phosphate monohydrate; and one or more pharmaceutically acceptable excipient
wherein, the composition when tested for dissolution in a phosphate buffer at a pH 7.8 exhibits at least 90% release of glimepiride in 180 mins.
21) The composition as claimed in claim 20, wherein, the composition when tested for dissolution in a phosphate buffer at a pH 7.8 exhibits at least 85% release of glimepiride in 45 mins
22) The composition as claimed in claim 20, wherein, the composition when tested for dissolution in a phosphate buffer at a pH 7.8 exhibits at least 90% release of glimepiride in 30 mins.
23) A fixed dose pharmaceutical composition comprising
a) sitagliptin or its pharmaceutically acceptable salt thereof;
b) metformin or its pharmaceutically acceptable salt thereof; and
c) glimepiride
wherein the composition is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin reference formulations and immediate release glimepiride reference formulation with the Cmax T/R ratio falling within 80% -125% range when administered to human subjects.
24) The fixed dose pharmaceutical composition as claimed in claim 23, wherein the sitagliptin is in the form of sitagliptin phosphate monohydrate.
25) The fixed dose pharmaceutical composition as claimed in claim 23, wherein the metformin is in the form of metformin hydrochloride.
26) A fixed dose pharmaceutical composition comprising
a) sitagliptin phosphate monohydrate; equivalent to 50mg of sitagliptin base,
b) 1000mg of metformin hydrochloride, and
c) 2mg of glimepiride
wherein the composition exhibits a mean maximum plasma concentration (Cmax) of sitagliptin in the range of about 100ng/ml to about 300ng/ml, a mean maximum plasma concentration (Cmax) of metformin in the range of about 700ng/ml to about 3200ng/ml, mean maximum plasma concentration (Cmax) of glimepiride in the range of about 85ng/ml to about 280ng/ml and is bioequivalent to an equal dose of an immediate-release sitagliptin and metformin reference formulations, and immediate-release glimepiride reference formulation with the Cmax T/R ratio falling within 80% -125% range when administered to human subjects.