DESC:FIELD OF THE INVENTION
The present invention relates to a stable pharmaceutical composition comprising dipeptidylpeptidase-4 (DPP-4) inhibitor, sodium-glucose linked transporter 2 (SGLT-2) inhibitor, and biguanide or a pharmaceutically acceptable salt thereof. The present invention, more particularly, relates to bi-layer tablet formulation comprising Sitagliptin, Dapagliflozin, and Metformin or a pharmaceutically acceptable salt thereof, methods of preparation thereof, and their use in medical therapy.

BACKGROUND OF THE INVENTION
Diabetes is a chronic (long-lasting) health condition that affects how your body turns food into energy. Your body breaks down most of the food you eat into sugar (glucose) and releases it into your bloodstream. When your blood sugar goes up, it signals your pancreas to release insulin. Insulin acts like a key to letting the blood sugar into your body’s cells for use as energy.
The most common types of diabetes are type 1, type 2, and gestational diabetes. Type 1 diabetes is an autoimmune disease. The immune system attacks and destroys cells in the pancreas, where insulin is made. It’s unclear what causes this attack. Type 2 diabetes occurs when your body becomes resistant to insulin, and sugar builds up in your blood. Gestational diabetes is high blood sugar during pregnancy. Insulin-blocking hormones produced by the placenta cause this type of diabetes.
Type 2 diabetes patients are generally accompanied by overweight, abdominal obesity, and high blood pressure, and for this reason, diabetes is known as a disease that causes secondary chronic diseases or metabolic syndromes such as hypertension, hyperlipidemia, myocardial infarction, and stroke. According to the medical guidelines of the Society, drug combination therapy is actively recommended to improve symptoms.
Sitagliptin is a dipeptidylpeptidase-4 (DPP-4) inhibitor class drug, and the chemical name is (R)-3-amino-1-(3-(trifluoromethyl) -5,6-diphadro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane -1-one.

Compound A: Sitagliptin
Sitagliptin controls blood sugar by inhibiting the breakdown of the gastrointestinal hormone called incretin so that incretin, which regulates insulin and glucagon, works well in the body. It is known that the incretin level is significantly reduced, and the secretion of fasting blood glucose and postprandial blood glucose is reduced. Merck, the original developer, is marketing a tablet form (JANUVIA – strength 25 mg, 50 mg, and 100 mg) containing sitagliptin phosphate as an active ingredient. JANUVIA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Dapagliflozin is a sodium-glucose linked transporter 2 (SGLT-2) inhibitor class drug, and the chemical name is (2S,3R,4R,5S,6R) -2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

Compound B: Dapagliflozin
Dapagliflozin selectively inhibits SGLT-2 in the kidney, enhances the excretion of glucose in the urine, and may thereby normalize plasma glucose levels by improving insulin sensitivity and delaying the onset of diabetic complications. AstraZeneca AB, the original developer, is marketing a tablet form (FARXIGA – strength 5mg and 10 mg) containing dapagliflozin propanediol hydrate as an active ingredient. FARXIGA is indicator as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus, reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus, and either established cardiovascular disease or multiple cardiovascular risk factors, to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure with reduced ejection fraction (NYHA class II-IV), to reduce the risk of sustained eGFR decline, end-stage kidney disease cardiovascular death and hospitalization for heart failure in adults with chronic kidney disease at risk of progression.
Metformin is the antihyperglycemic agent, which is a biguanide, and the chemical name is N, N-dimethylimidodicarbonimidic diamide.

Compound C: Metformin
Metformin is an oral antihyperglycemic drug mainly used for the treatment of type 2 diabetes patients as a biguanide-based diabetes treatment agent. It is known that metformin's glycemic control mechanism works independently of insulin secretion, eg, activates glucose transporters in the liver. Metformin induces weight loss in diabetic patients and has the effect of reducing blood triglycerides and low-density lipoproteins and increasing high-density lipoproteins. Therefore, it can be used as a first-line drug for non-insulin-dependent diabetes mellitus patients who show insulin resistance. EMD Serono, the original developer, marketed the film film-coated and extended-release form (GLUCOPHAGE XR - strength 500 mg and 750 mg / GLUCOPHAGE – strength 500 mg, 625 mg, 750 mg, 850 mg, and 1000 mg). GLUCOPHAGE is indicated as an adjunct to diet and exercise to improve glycemic control in adults and paediatric patients 10 years of age and older with type 2 diabetes mellitus, and GLUCOPHAGE XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
List of US-FDA Approved Drug Products
Table 1:
Active Ingredient Brand Dosage Strength Applicant
Sitagliptin Phosphate JANUVIA Tablet eq 25mg base, eq 50mg base and eq 100mg base Merck
Dapagliflozin FARXIGA Tablet 5mg and 10mg AstraZeneca
Metformin Hcl GLUCOPHAGE Tablet 500mg, 625mg, 750mg, 850mg and 1gm EMD Serono
Metformin Hcl GLUCOPHAGE XR ER Tablet 500mg and 750mg EMD Serono
Metformin Hcl GLUMETZA ER Tablet 500mg and 1gm Santarus
Metformin Hcl FORTAMET ER Tablet 500mg and 1gm Andrx Labs
Dapagliflozin; metformin Hcl; saxagliptin Hcl QTERNMET XR ER Tablet 2.5mg; 1gm; eq 2.5mg base, 5mg; 1gm; eq 5mg base, 5mg; 1gm; eq 2.5mg base and 10mg; 1gm; eq 5mg base AstraZeneca
Empagliflozin; Linagliptin; Metformin Hcl TRIJARDY XR ER Tablet 5mg; 2.5mg; 1gm, 10mg; 5mg; 1gm, 12.5mg; 2.5mg; 1gm and 25mg; 5mg; 1gm Boehringer
Metformin Hcl; Sitagliptin Phosphate JANUMET XR ER Tablet 500mg; eq 50mg base, 1gm; eq 50mg base and 1gm; eq 100mg base Merck
Metformin Hcl; Sitagliptin Phosphate JANUMET Tablet 500mg; eq 50mg base and 1gm; eq 50mg base Merck
Dapagliflozin; metformin Hcl XIGDUO XR Tablet 2.5mg; 1gm, 5mg; 500mg, 5mg; 1gm, 10mg; 500mg and 10mg; 1gm. AstraZeneca
Dapagliflozin; saxagliptin Hcl QTERN Tablet 5mg; eq 5mg base and 10mg; eq 5mg AstraZeneca
Ertugliflozin; Sitagliptin Phosphate STEGLUJAN Tablet 5mg; eq 100mg and 15mg; eq 100mg base Merck
Simvastatin; Sitagliptin Phosphate JUVISYNC Tablet 10mg; eq 50mg base, 10mg; eq 100mg base, 20mg; eq 50mg base, 20mg; eq 100mg base, 40mg; eq 50mg base and 40mg; eq 100mg base Merck
Empagliflozin; Metformin Hcl SEGLUROMET Tablet 2.5mg; 500mg, 2.5mg; 1gm, 7.5mg; 500mg and 7.5mg; 1gm Merck
Empagliflozin; Metformin Hcl SYNJARDY XR ER Tablet 5mg; 1gm, 10mg; 1gm, 12.5mg; 1gm and 25mg; 1gm Boehringer
Linagliptin; Metformin Hcl JENTADUETO XR ER Tablet 2.5mg; 1gm and 5mg; 1gm Boehringer
Empagliflozin; Metformin Hcl SYNJARDY Tablet 5mg; 500mg, 5mg; 1gm, 12.5mg; 500mg and 12.5mg; 1gm Boehringer
Canagliflozin; Metformin Hcl INVOKAMET XR ER Tablet 50mg; 500mg, 50mg; 1gm, 150mg; 500mg and 150mg; 1gm Janssen
Canagliflozin; Metformin Hcl INVOKAMET Tablet 50mg; 500mg, 50mg; 1gm, 150mg; 500mg and 150mg; 1gm Janssen
Alogliptin benzoate; Metformin Hcl KAZANO Tablet eq 12.5mg base; 500mg and eq 12.5mg base; 1gm Takeda
Linagliptin; Metformin Hcl JENTADUETO Tablet 2.5mg; 500mg, 2.5mg; 850mg and 2.5mg; 1gm Boehringer
Metformin Hcl; Saxagliptin Hcl KOMBIGLYZE XR ER Tablet 500mg; eq 5mg base, 1gm; eq 2.5mg base and 1gm; eq 5mg base AstraZeneca
Metformin Hcl; Repaglinide PRANDIMET Tablet 500mg; 1mg and 500mg; 2mg Novo Nordisk
Metformin Hcl; Pioglitazone Hcl ACTOPLUS MET XR ER Tablet 1gm; eq 15mg base and 1gm; eq 30mg base Takeda
Metformin Hcl; Pioglitazone Hcl ACTOPLUS MET Tablet 850mg; eq 15mg base and 500mg; eq 15mg base Takeda
Glipizide; Metformin Hcl METAGLIP Tablet 2.5mg; 250mg, 2.5mg; 500mg and 5mg; 500mg BMS
Metformin Hcl;
Rosiglitazone Maleate AVANDAMET Tablet 500mg; eq 1mg base, 500mg; eq 2mg base, 500mg; eq 4mg base, 1gm; eq 2mg base and 1gm; eq 4mg base SB Pharmco

Diabetes is a chronic disease, and its condition is complicated, so the symptoms of the disease often progress with various complications. Therefore, it is necessary to select the most appropriate drug for the individual patient, and when the individual drugs are used alone, sufficient effects may not be obtained depending on the symptoms. Due to various problems such as the appearance of side effects, the choice is often difficult in the clinical field. Therefore, in connection with the preparation for the treatment of diabetes mellitus, diabetes-related diseases, and diabetic complications, a method of concurrently administering two or more drugs with different mechanisms has been proposed, rather than one drug alone. However, when manufacturing a combination formulation of two or more drugs, it is necessary to consider various factors such as the interaction of two or more drugs, the dissolution rate of individual drugs, and the content uniformity, which is why the preparation of the combination formulation is not easy.
In addition, in the case of diabetic patients, as diabetes progresses, it is difficult to control blood sugar, resulting in complications. In particular, elderly diabetic patients are more likely to suffer from hypertension, obesity, and hyperlipidemia. Due to the characteristics of these diabetic patients, medication adherence is a very important factor, and a decrease in medication compliance may not only lower the quality of life of the patient, but also reduce the patient's treatment rate, increase personal medical expenses, and worsen insurance finances. Therefore, there is a need to develop a combination formulation which is beneficial to the patient.
Oral antidiabetic drugs conventionally used in therapy (such as e.g. first- or second-line, and/or mono- or (initial or add-on) combination therapy) include, without being restricted thereto, metformin, sulphonylureas, thiazolidinediones, glinides, and a-glucosidase inhibitors. After a long duration of disease, most patients with type 2 diabetes will eventually stop oral therapy and become insulin dependent with the necessity for daily injections and multiple daily glucose measurements.
The side effects associated with the use of metformin include loss of appetite, bloating, nausea, and diarrhea that occurs in 20 to 30% of patients taking metformin, and most often disappear after 2 to 3 weeks after taking it as transients. If diarrhea or severe abdominal bloating does not go away, it is better to stop taking it. Rarely, skin rashes and hives may occur. These side effects can be partially avoided by reducing the minimum and/or sustained dose or by using sustained release formulations that can reduce the number of dosing.
However, the development of the combination tablet is difficult due to several problems such as productivity and stability of the tablet due to the difference in the physical properties of each active ingredient (API). For example, metformin requires wet granulation to overcome the problems such as followability during manufacturing, while sitagliptin and dapagliflozin are unstable in the moisture and undergo degradation. In addition, to this, the density of dapagliflozin is low, and the volume of the main component is large despite a small amount, so the productivity is poor, which finally leads to the high possibility of layer separation with other main components and excipients.
IN209816 discloses sitagliptin composition-of-matter. IN5948/DELNP/2005 discloses Sitagliptin dihydrogen phosphate salt. IN1130/DELNP/2006 discloses crystalline anhydrate form I and III, crystalline solvate anhydrate form II, and crystalline solvates, preferably ethanolate of sitagliptin dihydrogen phosphate. IN2710/CHENP/2008 discloses combination formulation Sitagliptin and metformin.
US2448448A discloses the metformin compound. GB935980 discloses biguanide treatment for diabetes mellitus.
IN205147 and IN235625 disclose dapagliflozin composition-of-matter. IN10757/DELNP/2008 discloses polymorphic forms of dapagliflozin. US8685934 discloses combination of dapagliflozin and metformin. IN4976/CHENP/2010 disclose combination of dipeptidylpeptidase-4 (DPP-4) inhibitor and sodium-glucose linked transporter 2 (SGLT-2) inhibitor.
WO2021201461A1 discloses an oral tablet containing sitagliptin, dapagliflozin, and metformin as active ingredients, and more particularly, a tablet comprising, a first layer comprising dry granules of sitagliptin and dapagliflozin; and a complex tablet comprising wet granules containing metformin second layer containing colloidal silicon dioxide. By including colloidal silicon dioxide, the tableting pressure can be lowered, and thus a two-layer tablet having an appropriate hardness can be manufactured without tableting disorders.
WO2021133023A1 discloses the combination formulation containing sitagliptin and dapagliflozin and the method for manufacturing the same. Further discloses manufacturing method of granulating step performed by a dry granulation method. The dry granulation method forming compressed flakes using a roller compactor. Further comprising the step of tableting the mixture mixed with an additional lubricant.
WO2022010078A1 discloses the combination formulation containing sitagliptin and dapagliflozin and manufacturing method thereof. Further discloses manufacturing method granulating step performed by a dry granulation method. The dry granulation method includes forming compressed flakes using a roller compactor. Further discloses result of the experiment, it was confirmed that magnesium stearate, which is generally most commonly used as a lubricant, increases the productivity and tableting properties of the composite formulation of the present application, but is very disadvantageous because it increases the related substances of the main component over time (Test Example) 1 and 3). On the other hand, sodium stearyl fumarate can form a combination formulation stable enough to satisfy the standards of related substances as well as increase productivity and tableting properties (Test Example 3).
WO2020194052A1 discloses low-dose triple combination formulation. Specifically, the compositions comprise a) a dipeptidyl peptidase IV (DPPIV) inhibitor such as sitagliptin, b) a subtype 2 sodium-glucose transport (SGLT2) inhibitor such as either dapagliflozin or empagliflozin, and c) a biguanide such as metformin. wherein (a), (b), and (c) are each at about 20% to about 75% of the lowest diabetes therapeutic dose (LDTD). Further discloses the use of low dose amounts of each of the components results in beneficial effects, including but not limited to, avoiding or ameliorating negative side effects while retaining or improving benefits.
WO2018124497A1 discloses pharmaceutical composite preparation containing dapagliflozin L-proline and at least one antidiabetic agent. Further discloses a combination formulation of dapagliflozin L-proline and an anti-diabetic agent, and to improve the effects through the administration of a combination formulation with various mechanisms and reduce side effects.
WO2010092125A1 discloses pharmaceutical composition comprising an SGLT2 inhibitor, a DPPIV inhibitor, and a third antidiabetic agent which is suitable in the treatment or prevention of one or more conditions selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance, and hyperglycaemia. Further discloses methods for preventing or treating metabolic disorders and related conditions.
Jabbour SA, et al “Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24-week, multicenter, randomized, double-blind, placebo-controlled study” discloses the efficacy and safety of dapagliflozin in patients whose HbA1c levels were not adequately controlled with a dipeptidyl peptidase-4 (DPP-4) inhibitor, sitagliptin. Dapagliflozin was evaluated as a dual combination therapy with sitagliptin and as a triple combination therapy with sitagliptin plus metformin.
Despite the above-mentioned prior art disclosing various pharmaceutical compositions of sitagliptin, dapagliflozin, and metformin or a pharmaceutically acceptable salt and a combination thereof, there still exists a need for a stable pharmaceutical composition of sitagliptin, dapagliflozin, in an immediate release dosage form and metformin in an extended release dosage form, which ensures the desired therapeutic effect, when administered orally, thereby increasing medication compliance.
Within the scope of the present invention it has now surprisingly been found that a stable bi-layer pharmaceutical composition comprising a DPP IV inhibitor, a SGLT2 inhibitor and biguanide can advantageously be prepared and used for preventing, slowing the progression of, delaying or treating a metabolic disorder, in particular for improving glycemic control in patients. This opens up new therapeutic possibilities in the treatment and prevention of type 2 diabetes mellitus, overweight, obesity, and complications of diabetes mellitus.
Additionally, the present inventor surprisingly found that a bi-layer tablet of sitagliptin, dapagliflozin (both are in immediate-release form), and metformin (extended-release form) or a pharmaceutically acceptable salt and the combination thereof has excellent stability, productivity, dissolution, and compounding compatibility, and at the same time, it is possible to miniaturize the size of the dosage form, thereby increasing medication compliance also providing a synergistic efficacy in diabetic patients. Although sitagliptin and dapagliflozin are moisture sensitive, and metformin has a low flowability still this invention developed a stable bi-layer tablet formulation by using the wet granulation method.

OBJECT OF THE INVENTION
It is an object of the present invention to provide a stable pharmaceutical composition and method for improving glycemic control in a patient with insufficient glycemic control despite monotherapy with an antidiabetic drug, for example, dapagliflozin, or despite combination therapy with two antidiabetic drugs.
It is another object of the present invention to provide a stable pharmaceutical composition with a high efficacy for the treatment of metabolic disorders, in particular diabetes mellitus, impaired glucose tolerance (IGT), and impaired fasting blood glucose (IFG) which has good pharmacological and/or pharmacokinetic and/or physicochemical properties.
It is another object of the present invention to provide a stable pharmaceutical composition and method for reducing the weight or preventing an increase of the weight in a patient in need thereof.
It is another object of the present invention to provide a formulation that minimizes side effects while increasing medication compliance and increasing the effect of the patient by providing a complex formulation of therapeutic agents for diabetes with a variety of mechanisms of action. In addition, it increases bioavailability by improving the dissolution properties and content uniformity of the individual active ingredients in the complex formulation.
It is another object of the present invention to provide a stable pharmaceutical composition, comprising a first component, and a second component, and one or more excipients.
It is another object of the present invention to provide a stable pharmaceutical composition, comprising a first component, part or composition comprising biguanide in an extended-release form and one or more excipients, and a second component, part or composition comprising DPP-4 inhibitor and SGLT-2 inhibitor, particularly in the immediate release form, and one or more excipients.
It is another object of the present invention to provide a stable pharmaceutical composition, comprising a first component, part or composition comprising metformin or a pharmaceutically acceptable salt in an extended-release form and one or more excipients, and a second component, part or composition comprising sitagliptin and dapagliflozin or a pharmaceutically acceptable salt, particularly in the immediate release form, and one or more excipients.
It is another object of the present invention to provide a stable pharmaceutical composition in a bi-layer tablet form.
It is another object of the present invention to provide a stable pharmaceutical composition in a bi-layer tablet dosage form which provides a synergistic efficacy in diabetic patients.

SUMMARY OF THE INVENTION
The present invention provides the following aspects, subject-matters and preferred embodiments, which respectively taken alone or in combination, further contribute to solving the object of the present invention. More particularly, the present invention relates to
A) A stable pharmaceutical composition, comprising a first component, a second component, and one or more excipients.
B) The stable pharmaceutical composition according to A), wherein a first component, part or composition comprising biguanide and a second component, and part or composition comprising dipeptidylpeptidase-4 (DPP-4) inhibitor and sodium-glucose linked transporter 2 (SGLT-2) inhibitor.
C) The stable pharmaceutical composition according to A), wherein a first component, part or composition comprising metformin or a pharmaceutically acceptable salt and a second component, and part or composition comprising sitagliptin and dapagliflozin or a pharmaceutically acceptable salt.
D) The stable pharmaceutical composition according to A), wherein a first component, part or composition comprising metformin or a pharmaceutically acceptable salt in an extended-release form and one or more excipients, and a second component, part or composition comprising sitagliptin and dapagliflozin or a pharmaceutically acceptable salt, particularly in the immediate release form, and one or more excipients.
E) The stable pharmaceutical composition according to A), wherein composition in the form of a tablet.
F) The stable pharmaceutical composition according to A), wherein composition in the form of a bi-layer tablet.
G) The bi-layer tablet according to F), wherein a first layer comprising metformin hydrochloride in extended-release form and one or more excipients, and a second layer comprising sitagliptin phosphate and dapagliflozin propanediol in the immediate release form, and one or more excipients and the final composition is coated with coating solution.

DESCRIPTION OF THE INVENTION
Before the present process and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas, or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is to describe particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.
Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "the step" includes a reference to one or more steps and equivalents thereof known to those skilled in the art, and so forth.
The publications discussed herein are provided solely for their availability to the applicant before the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by the prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
In one of embodiment, the present invention provides a stable pharmaceutical composition and method for improving glycemic control in a patient with insufficient glycemic control despite monotherapy with an antidiabetic drug, for example, dapagliflozin, or despite combination therapy with two antidiabetic drugs.
In another embodiment, the present invention provides a stable pharmaceutical composition with a high efficacy for the treatment of metabolic disorders, in particular of diabetes mellitus, impaired glucose tolerance (IGT), and impaired fasting blood glucose (IFG) which has good to very good pharmacological and/or pharmacokinetic and/or physicochemical properties.
In yet another embodiment, the present invention provides a stable pharmaceutical composition and method for reducing the weight or preventing an increase of the weight in a patient in need thereof.
In further embodiment, the present invention provides a formulation that minimizes side effects while increasing medication compliance and increasing the effect on the patient by providing a complex formulation of therapeutic agents for diabetes with a variety of mechanisms of action. In addition, it increases bioavailability by improving the dissolution properties and content uniformity of the individual active ingredients in the complex formulation.
In another embodiment, the present invention provides a stable pharmaceutical composition, comprising a first component, a second component, and one or more excipients.
In yet another embodiment, the present invention provides a stable pharmaceutical composition, comprising a first component, part or composition comprising biguanide in an extended-release form and one or more excipients, and a second component, part or composition comprising DPP-4 inhibitor and SGLT-2 inhibitor, particularly in the immediate release form, and one or more excipients.
In a further embodiment, the present invention provides a stable pharmaceutical composition, comprising a first component, part or composition comprising metformin or a pharmaceutically acceptable salt in an extended-release form and one or more excipients, and a second component, part or composition comprising sitagliptin and dapagliflozin or a pharmaceutically acceptable salt, particularly in the immediate release form, and one or more excipients.
In one embodiment, the present invention provides a stable pharmaceutical composition in bi-layer tablet form.
In another embodiment, the present invention provides a stable pharmaceutical composition in bi-layer tablet form, wherein a first layer comprising metformin hydrochloride in extended-release form and one or more excipients, and a second layer comprising sitagliptin phosphate and dapagliflozin propanediol in the immediate release form, and one or more excipients and the final composition is coated with coating solution.
In yet another embodiment, the present invention provides a stable pharmaceutical composition comprising: a) an extended release layer comprising metformin or a pharmaceutically acceptable salt thereof; b) immediate release layer comprising sitagliptin or pharmaceutically acceptable salt thereof, dapagliflozin or pharmaceutically acceptable salt thereof; and c) pharmaceutically acceptable excipients.
In one embodiment, the present invention provides a stable pharmaceutical composition in bi-layer tablet wherein the first layer comprises about 70-75% metformin hydrochloride, about 1-5% microcrystalline cellulose, about 3-8% Hypromellose, about 1-5% carboxymethylcellulose sodium, about 1-5% polyvinylpyrrolidone, about 0.1-2% colloidal silicon dioxide, about 0.1-2% talc and 0.1-2% magnesium stearate. Second layer comprises about 1-5% dapagliflozin propanediol, about 10-15% sitagliptin phosphate, about 2-8% microcrystalline cellulose, about 2-8% dibasic calcium phosphate, about 0.1-2% croscarmellose sodium, about 0.01-0.1% colour sunset yellow, about 0.1-2% polyvinylpyrrolidone, about 1-5% croscarmellose sodium, about 0.1-2% sodium stearyl fumarate, and about 0.1-2% magnesium stearate. The optional film coating can be Novomix pink 600062 (mixture of Hydroxypropyl methyl cellulose, Polyethylene glycol, Talc, Titanium Dioxide, Red Iron Oxide and yellow iron oxide or Novomix light orange 50058 (mixture of Hydroxypropyl methyl cellulose, Polyethylene glycol, Talc, Titanium Dioxide and lake sunset yellow).
In another embodiment, the present invention provides a stable pharmaceutical composition in bi-layer tablet wherein first layer comprises about 45-65% w/w of metformin hydrochloride, about 1-7% w/w of microcrystalline cellulose, about 7-15% w/w of Hypromellose, about 1-7% w/w of carboxymethylcellulose sodium, about 0.1-5% w/w of polyvinylpyrrolidone, about 0.1-5% w/w of colloidal silicon dioxide, about 0.1-2% w/w of talc and 0.1-2% w/w of magnesium stearate based on the total weight of the composition; Second layer comprises about 0.4-5% w/w of dapagliflozin propanediol, about 5-15% w/w of sitagliptin phosphate, about 1-8% w/w of microcrystalline cellulose, about 1-8% w/w of dibasic calcium phosphate, about 0.1-2% w/w of croscarmellose sodium, about 0.01-0.5% w/w of colour sunset yellow, about 0.1-2% w/w of polyvinylpyrrolidone, about 1-5% w/w of croscarmellose sodium, about 0.1-2% w/w of sodium stearyl fumarate, and about 0.1-2% w/w of magnesium stearate and optionally third layer in the form of film coating comprising Novomix 600062 and/or Novomix 50058.
In yet another embodiment, the stable pharmaceutical composition is optionally coated with about 1.5-5% w/w of Novomix 600062 and Novomix 50058 based on the total weight of the composition.
In one embodiment the present invention provides a stable pharmaceutical composition comprising: a) an extended release layer comprising about 61% w/w of metformin hydrochloride, about 1.1 % w/w of microcrystalline cellulose, about 12% w/w of hydroxypropyl methyl cellulose, about 4.2% w/w of sodium carboxymethylcellulose, about 1.2% w/w of polyvinylpyrrolidone, about 0.6% w/w of colloidal silicon dioxide, about 0.6% w/w of talc, about 0.61% w/w of magnesium stearate based on the total weight of the composition. b) an immediate release layer comprising about 0.75% w/w of dapagliflozin propanediol monohydrate, about 8% w/w of sitagliptin phosphate, about 3%w/w of microcrystalline cellulose, about 2% w/w of dibasic calcium phosphate, about 0.3% w/w of croscarmellose sodium, about 0.02% w/w of colour sunset yellow, about 0.3% w/w of polyvinylpyrrolidone, about 1.2% w/w of croscarmellose sodium, about 0.3% w/w of sodium stearyl fumarate, and about 0.3% w/w of magnesium stearate based on the total weight of the composition.
In yet another embodiment, the stable pharmaceutical composition is optionally coated with about 2.7% w/w of Novomix 600062 and about 3.1% w/w of Novomix 50058.
The term "composition" or "formulation" or "dosage form" or “pharmaceutical composition” as used herein synonymously include solid dosage forms such as granules, multiunit particulate systems (MUPS), pellets, spheres, tablets, capsules, mini-tablets, layered tablets (e.g. bilayer or trilayer), beads, particles, granules and the like; and liquid dosage forms such as solutions, suspensions, emulsions, colloids and the like, meant for oral administration.
The compositions in accordance with the present invention can be prepared either by direct compression, dry granulation, or wet granulation method.
As term “active ingredient” as used herein means an ingredient or compound having an intended biological effect. “Active ingredient” may be broadly construed to include an active compound and vice versa. Such active ingredients or active compounds are thus considered to be “biologically active”.
The term "pharmaceutically acceptable salt" is suitable for use in contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., within the scope of a reasonable medical evaluation, and has a reasonable benefit. In yet another embodiment the sitagliptin, dapagliflozin and metformin salts of the present invention are in the form of hydrates of solvates, for example, hemi-, mono-, di-, tri-, tetra-, penta-, or hexa-solvates or – hydrates.
The term "excipient" as used herein means a pharmacologically inactive component such as, but not limited to, a diluent or filler, binder, disintegrant, lubricant, glidant, surfactant, colorant, or the like. The excipients that are useful in preparing a stable pharmaceutical composition are generally safe, non-toxic, and acceptable for human use.
The term "first component" and “second component” is used herein means a part / layer of the composition.
The term "stable", as used herein, refers to chemical stability, in which not more than the limits of ICH standard for the total related substances is formed in storage under accelerated conditions of stability at 30°C/75%RH relative humidity for the period necessary for using the composition.
The term "HbA1c" refers to the product of non-enzymatic glycation of the hemoglobin B chain. Its determination is well known to one skilled in the art. In monitoring the treatment of diabetes mellitus, the HbA1c value is of exceptional importance. As its production depends essentially on the blood sugar level and the life of the erythrocytes, the HbA1c in the sense of a "blood sugar memory" reflects the average blood sugar levels of the preceding 4-6 weeks. Diabetic patients whose HbA1c value is consistently well adjusted by intensive diabetes treatment (i.e. < 6.5 % of the total hemoglobin in the sample), are significantly better protected against diabetic microangiopathy.
The term "insufficient glycemic control" or "inadequate glycemic control" in the scope of the present invention means a condition wherein patients show HbA1c values above 6.5 %, in particular above 7.0 %, even more preferably above 7.5 %, especially above 8 %.
The term "impaired fasting blood glucose" or "IFG" or "impaired fasting plasma glucose" is defined as the condition in which a subject has a fasting blood glucose concentration or fasting serum glucose concentration in a range from 100 to 125 mg/dl (i.e. from 5.6 to 6.9 mmol/l), in particular, greater than 110 mg/dL and less than 126 mg/dl (7.00 mmol/L). A subject with "normal fasting glucose" has a fasting glucose concentration smaller than 100 mg/dl, i.e. smaller than 5.6 mmol/l.
The term "impaired glucose tolerance" or "IGT" is defined as a condition in which the blood glucose or serum glucose concentration at 2 hours post-prandial of a subject is greater than 140 mg/dL (7.8 mmol/L) and less than 200 mg/dL (11.11 mmol/L). . Abnormal glucose tolerance, that is, the blood glucose or serum glucose concentration at 2 hours after a meal can be measured as the blood glucose level of a glucose (mg) per 1 dl of plasma 2 hours after ingestion of 75 g of sugar after fasting. Subjects with "normal glucose tolerance" had a blood glucose or serum glucose concentration of less than 140 mg/dL (7.8 mmol/L) at 2 hours post-prandial.
The term "Immediate release" (IR) as used herein means a release of an active agent into an environment for a period of seconds to no more than about 30 minutes once the release has begun and the release begins within a second to no more than approximately 15 minutes after exposure to an aqueous environment. An immediate release composition, which does not possess a substantial delay in drug release, should be considered as a subset of a rapid release composition. An immediate release composition releases drugs into the oral cavity, esophagus and/or stomach.
The term "Extended release" (ER) as used herein means a controlled release of an active agent from a dosage form into an environment for (over or during) an extended period of time, for example greater than or equal to one hour. As used herein, the term "extended-release" profile assumes the definition widely recognized in the art of pharmaceutical sciences. An extended release dosage form will release the drug at a substantially constant rate over an extended period of time or a substantially constant amount of the drug will be incrementally released over an extended period of time. The term "extended release," in relation to drug release, includes the terms "controlled release," "prolonged release," "sustained release," or "slow release," as these terms are used in pharmaceutical sciences.
In one embodiment, the extended-release polymer used in the composition of the present invention is selected from ethylcellulose, polymethacrylate(s), cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate butyrate, cellulose acetate trimellitate, cellulose acetate, hydroxy propylcellulose, povidone, polyvinyl alcohol, polyvinyl acetate, polyethylene glycol, hydroxypropylmethylcellulose, starch, hydroxy ethylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, methylcellulose, or mixtures thereof.
In a further embodiment, the lubricants used in the composition of the present invention are selected from metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, and the like and mixtures thereof.
In a further embodiment, the fillers or diluents used in the composition of the present invention are selected from sugars such as lactose, dextrose, glucose, sucrose, cellulose, starches, and carbohydrate derivatives, polysaccharides (including dextrose and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, calcium carbonates, magnesium carbonates, microcrystalline cellulose, dibasic calcium phosphate combinations thereof, and the like. In certain preferred embodiments, the filler or diluent is lactose, microcrystalline cellulose, or a combination thereof. Several types of lactose are suitable for use in the formulations described herein, for example, lactose is selected from the group consisting of anhydrous lactose, lactose monohydrate, lactose fast flow, directly compressible anhydrous lactose, and modified lactose monohydrate. In one embodiment of the invention, the filler or diluent is a combination of microcrystalline cellulose and lactose.
In a further embodiment, the binders used in the composition of the present invention are selected from cellulose derivatives (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, ethylcellulose and sodium carboxymethyl cellulose), sugar (including sucrose, glucose, dextrose, molasses, lactose, dextrin, xylitol, sorbitol), glycol, corn syrup, polysaccharides (including acacia, tragacanth, guar, alginates, and starch), corn starch, pregelatinized starch, modified corn starch, gelatin, polyvinylpyrrolidone, polyethylene, polyethylene glycol, combinations thereof and the like. Preferably, the binding agent, if present, is hydroxypropyl cellulose.
In a further embodiment, the disintegrants used in the composition of the present invention are selected from starches, clays, celluloses, alginates, and gums, and crosslinked starches, celluloses, and polymers, combinations thereof, and the like. Representative disintegrants include microcrystalline cellulose, croscarmellose sodium, alginic acid, sodium alginate, crospovidone, cellulose, agar, and related gums, sodium starch glycolate, corn starch, potato starch, sodium starch glycolate, Veegum HV, methylcellulose, agar, bentonite, carboxymethylcellulose, alginic acid, guar gum combinations thereof, and the like. Preferably, the disintegrant, if present, is cross-linked cellulose, more preferably cross-linked sodium carboxymethylcellulose or croscarmellose sodium.
In a further embodiment, the glidants and/or anti-adherents used in the composition of the present invention are from selected silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel, or mixtures thereof. Glidant may be used in the range of 0.01 - 4 % w/w of the total weight of the stable pharmaceutical composition.
“Colorants” may be selected from, but are not limited to, iron oxide yellow, iron oxide red, titanium dioxide, sunset yellow color, or mixtures thereof. Colorants may be used in the range of 0.01 - 1.5 % w/w of the total weight of the stable pharmaceutical composition.
The stable pharmaceutical compositions of the present invention may be further coated with a functional or non-functional coating. The coating composition may be comprised of pharmaceutically acceptable excipients such as coating agents, binders, plasticizers, coloring agents, and opacifiers. The total weight gain after coating may be about 1% w/w to 10% w/w of the uncoated stable pharmaceutical composition.
“Coating agents” which are useful in the coating process, may be selected from, but not limited to, water-soluble polymers such as, but not limited to, polyvinylpyrrolidone or water-soluble cellulose such as, but not limited to, hydroxypropyl methylcellulose or hydroxypropyl cellulose. It may be selected from, but not limited to, soluble agents such as polysorbate 80, polysaccharides such as maltodextrin, acacia, com, sucrose, gelatin, shellac, cellulose acetate phthalate, lipids, synthetic resins, acrylic polymers, opadry, polyvinyl alcohol, copolymers of vinylpyrrolidone, vinyl acetate or combinations thereof. These may be applied from aqueous or non-aqueous systems or combinations of the aqueous and non-aqueous systems as appropriate.
Examples of binders for coating include cellulose or cellulose derivatives such as, but not limited to, methylcellulose, hydroxypropylmethylcellulose, hydroxypropyl cellulose, and carboxymethyl cellulose sodium, and microcrystalline cellulose, alginic acid, sodium alginate and gelatin, polyvinyl pyrrolidone, crospovidone, starch, pregelatinized starch, or mixtures thereof. Examples of plasticizers for coating include, but are not limited to, propylene glycol, triethyl citrate, tributyl citrate, dibutyl sebacate, triacetin, polyethylene glycol, diethyl phthalate, acetylated monoglycerides, or mixtures thereof. Examples of opacifiers for coating include, but are not limited to, titanium dioxide, talc, calcium carbonate, behenic acid, cetyl alcohol, or mixtures thereof. Antitacking agents such as, but are not limited to, talc, stearic acid, magnesium stearate, colloidal silicon dioxide, or the like. Examples of coloring agents for coating include, but are not limited to, FDA-approved colorants such as iron oxide, the lake of tartrazine, allura red, the lake of quinoline yellow, the lake of erythrosine, titanium dioxide, or mixtures thereof. Suitable solvents for the coating include but are not limited to, ethanol, methanol, isopropyl alcohol, methylene chloride, acetone, or mixtures thereof.
In further embodiments the disclosed stable pharmaceutical compositions are prepared using a “wet granulation”. The “wet granulation” refers to method of mixing or blending the ingredients using granulating fluid, carried out using methods known to the skilled artisan. With little or no experimentation, the skilled artisan can determine the conditions necessary to obtain the wet granulate.
Stability studies carried out for the bi-layer tablet provided satisfactory data for all the physical and chemical parameters, wherein initial, 1M, 2M,3M, 6M, 9M, 12M and 18M stability studies were performed at 30°C/75%RH
It should be appreciated that the invention can be embodied / aspects in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will convey the scope of the invention to those skilled in the art. Other features and embodiments of the invention will become apparent from the following examples, which are given for illustration of the invention rather than for limiting its intended scope.
The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto.
Example 1:
Table 2:
Sr. No. Ingredient Amount (mg / Tablet)
Extended Release
1. Metformin HCl 1006.00
2. Microcrystalline cellulose 20.00
3. Hypromellose 220.00
4. Carboxymethylcellulose Sodium 60.00
5. Polyvinylpyrrolidone 15.00
6. Purified water qs
7. Colloidal Silicon Dioxide 8.00
8. Talc 8.00
9. Magnesium Stearate 8.00
Immediate Release
10. Dapagliflozin Propanediol 15.00
11. Sitagliptin Phosphate 132.00
12. Microcrystalline cellulose 45.00
13. Dibasic Calcium Phosphate 25.00
14. Crosscarmellose sodium 5.00
15. Colour sunset yellow 0.50
16. Polyvinylpyrrolidone 5.50
17. Purified water qs
18. Crosscarmellose sodium 10.00
19. Sodium Stearyl Fumarate 9.00
20. Magnesium Stearate 8.00
Total 1600
Coating
21. Novomix 600062 (Light Pink) 50.00
22. Purified water qs
Total 1650
*qs: quantity sufficient
A. Manufacturing Process:
• First component: Extended Release form
Metformin hydrochloride, microcrystalline cellulose, Hypromellose, and Carboxymethylcellulose sodium were passed through 40 mesh. The passed materials were dried and mixed in a rapid mixer granulator (RMG) at slow speed for 15 min. Wet granulation was done with water and polyvinylpyrrolidone in RMG granulation at slow speed. The prepared granules were dried in FBD at 55-60 degrees Celsius for 30 min. The dried granules were blended in blender at slow speed for 10 min.
• Second component: Immediate Release form
Dapagliflozin propanediol, sitagliptin phosphate, microcrystalline cellulose, dibasic calcium phosphate, crosscarmellose sodium were passed through 30 mesh and colour sunset yellow was passed through 80 mesh. The passed materials were dried and mixed in RMG at slow speed for 15 min. The wet granulation was done with water and polyvinylpyrrolidone in RMG granulation at slow speed. The prepared granules were dried in FBD at 55-60 degrees Celsius for 30 min. The dried granules were blended in blender by croscarmellose sodium at slow speed for 10 min and sodium stearyl fumarate and magnesium stearate at slow speed for 5 min.
• Compression and Coating:
First component: The granules of Metformin HCl Extended-Release were added in Hopper I tablet compression machine and for Second component: The granules of Sitagliptin and Dapagliflozin Immediate Release were added in Hopper II and compressed in the tablet compression machine. The compressed bi-layered tablets were coated with a coating solution.
Example 2:
Table 3:
Sr. No. Ingredient Amount (mg / Tablet)
Extended Release
1. Metformin HCl 501.00
2. Microcrystalline cellulose 15.00
3. Hypromellose 70.00
4. Carboxymethylcellulose Sodium 30.00
5. Polyvinylpyrrolidone 15.00
6. Purified water qs
7. Colloidal Silicon Dioxide 4.00
8. Talc 4.00
9. Magnesium Stearate 4.00
Immediate Release
10. Dapagliflozin Propanediol 13.00
11. Sitagliptin Phosphate 132.00
12. Microcrystalline cellulose 55.00
13. Dibasic Calcium Phosphate 30.00
14. Crosscarmellose sodium 5.00
15. Colour sunset yellow 0.50
16. Polyvinylpyrrolidone 5.50
17. Purified water qs
18. Crosscarmellose sodium 10.00
19. Sodium Stearyl Fumarate 9.00
20. Magnesium Stearate 8.00
Total 911.00
Coating
21. Novomix 600062 (Light Pink) 34.00
22. Purified water qs
Total 945
*qs: quantity sufficient
Manufacturing Process: Same as per example 1.
Example 3:
Table 4:
Sr. No. Ingredient 4A
Amount (% w/w) 4B
Amount (% w/w)
Extended Release
1. Metformin HCl 70-75 45-65
2. Microcrystalline cellulose 1-5 1-7
3. Hypromellose 3-8 7-15
4. Carboxymethylcellulose Sodium 1-5 1-7
5. Polyvinylpyrrolidone 1-5 0.1-5
6. Purified water Qs Qs
7. Colloidal Silicon Dioxide 0.1-2 0.1-5
8. Talc 0.1-2 0.1-2
9. Magnesium Stearate 0.1-2 0.1-2
Immediate Release
10. Dapagliflozin Propanediol 1-5 0.4-5
11. Sitagliptin Phosphate 10-15 5-15
12. Microcrystalline cellulose 2-8 1-8
13. Dibasic Calcium Phosphate 2-8 1-8
14. Crosscarmellose sodium 0.1-2 0.1-2
15. Colour sunset yellow 0.01-0.1 0.01-0.5
16. Polyvinylpyrrolidone 0.1-2 0.1-2
17. Purified water Qs Qs
18. Crosscarmellose sodium 1-5 1-5
19. Sodium Stearyl Fumarate 0.1-2 0.1-2
20. Magnesium Stearate 0.1-2 0.1-2
Coating
21. Novomix 600062 (Light Pink) 1-5 1.5-5
22. Purified water qs
*qs: quantity sufficient
Manufacturing Process: Same as per example 1.
B. Stability Study results: 30°C/75%RH
Table 5 – Dissolution and Assay Study
TESTS SPECIFICATION INITIAL 6 MONTH 12 MONTH

Uniformity of Content For Dapagliflozin Between 85% to 115% of average content 106.5% NA NA
For Sitagliptin 97.5% NA NA
Dissolution Metformin HCL 1st Hour 20 % to 50% 28% 29% 29%
3rd Hour 40% to 80% 52% 58% 58%
10th Hour Not less than 80% 89% 93% 96%
Dapagliflozin Propanediol Monohydrate equivalent to Dapagliflozin Not less than 70% (D) in 45 min 104%
107%
100%

Sitagliptin Phosphate equivalent to Sitagliptin Not less than 70% (D) in 45 min 103%
98%
94%

Assay Metformin HCl 90% to 110% 100.2% 98.9% 99.3%
Dapagliflozin Propanediol Monohydrate equivalent to Dapagliflozin 90% to 110% 105.4% 101.8% 103.8%
Sitagliptin Phosphate equivalent to Sitagliptin 90% to 110% 99.8% 98.4% 99.2%

C. Stability Study Results: 30°C/75%RH
Table 6 – Related Substance Study
TESTS SPECIFICATION INITIAL 6 MONTH 12 MONTH
Related Substance For Dapagliflozin &Sitagliptin:
Hydroxy impurity
Single highest unknown impurity
Total unknown impurities
Not more than 1.0%
Not more than 0.5%
Not more than 3.0%
0.197%
0.134%
0.480%
0.346%
0.159%
0.806%
0.188%
0.120%
0.536%
For Metformin HCl:
Dicyandiamide
Single highest unknown impurity
Total unknown impurities
Not more than 0.02%
Not more than 0.5%
Not more than 2.0%
0.011%
0.013%
0.019%
0.017%
0.015%
0.048%
0.010%
0.013%
0.021%

Conclusion:
The stability study conducted for the composition present in examples 2 & 3 shows that the all the physical, and chemical parameters including the impurity levels were found to be satisfactory and the initial, 1 Month, 2 Month, and 3 Month stability data at 400C /75 %RH, for dissolution, Assay and the Impurity levels were found to be satisfactory and within acceptable limits.
Example 4: The Clinical Study:
A. Scientific Title of Study: A Phase 3, multicenter, randomized, double-blind, double-dummy, parallel-group, active-controlled study to compare the efficacy and safety of a fixed dose combination (FDC) of Metformin hydrochloride 1000 mg ER, Sitagliptin phosphate 100 mg and Dapagliflozin Propanediol 10 mg tablets as described in the Examples 1 and 3 versus Janumet XR CP (Combipack of Metformin hydrochloride 1000 mg SR and Sitagliptin phosphate 100 mg) in patients with Type 2 Diabetes Mellitus (T2DM)
B. Reference product (Reference-Arm)- Janumet XR (Combipack of Metformin Hydrochloride 1000 mg SR and Sitagliptin phosphate 100 mg)
C. Test Product (Test-Arm): Fixed-Dose Combination (FDC) of Metformin Hydrochloride 1000 mg ER, Sitagliptin phosphate 100 mg and Dapagliflozin Propanediol 10 mg tablets
D. Efficacy Analysis
a. Primary Efficacy Endpoint
The mean HbA1C was 8.94 + 0.55 in test arm while 8.97 + 0.58 in reference arm at baseline. The baseline values of HbA1C were comparable. After completion of 16 weeks in the study, the mean HbA1c was 7.44 + 0.9 (with mean reduction of 1.5 + 0.99) in the test arm and it was 7.94 + 1.1 (with mean reduction of 1.02 + 1.07) in the reference arm. The reduction of HbA1c was statistically significant in both the arms (p value of 0.0001 in both arms). However, there was more reduction of HbA1C in test are compared to reference arm which was statistically significant (p value 0.0024). The least square mean change in HbA1C from baseline was 1.5 in test arm compared to 1 in the reference arm. The difference in the LSM change was statistically significant with 95% confidence interval of (-0.8025, -0.1767) indicating test is superior when compared to reference.
b. Secondary Efficacy Endpoints
The mean Fasting Plasma Glucose (FPG) at baseline was 154.88 + 38.20 in the test arm and 161.82 + 42.5 in reference arm. There was significant reduction in FPG (19.24) from baseline in test arm (p value <0.0001) and non-significant reduction in FPG (3.67) from baseline in the reference arm (p value 0.3939). The difference between reduction of FPG was statistically significant in both arms (p value 0.0074). At baseline, the postprandial glucose (PPG) was 234.33 + 67.45 in test arm and 239.20 + 76.8 in reference arm. The baseline values were comparable. After 16 weeks in study, compared to baseline there was mean reduction of 48.96 + 45.21 in test arm which was statistically significant (p value < 0.0001) and mean reduction of 13.1 + 58.1 in reference arm which was statistically non-significant (p value 0.2387). The difference between mean change of PPG values at 16 weeks compared to baseline was statistically significant in test vs reference arm (p value 0.0081). There was significant reduction in mean body weight at 16 weeks as compared to baseline (Mean reduction of 1.31 + 1.95 kg in test arm and 1.2 + 1.83 kg in reference arm).
c. Safety Analysis
There were total 28 AEs in total of 22 subjects (8 %) reported during the study, out of that 14 AEs in 11 subjects (8%) were in the test arm and 14 AEs in 11 subjects (8 %) were in the reference arm. All AEs were mild (grade I) in severity. There were 0 SAEs reported during the study period. In terms of causality, there were 7 events in 5 patients in test arm, while there were 6 events in 6 patients in reference arm which were considered to be related to the Investigational product. In the test arm, the TEAEs which were reported as related were as follows: gastritis 3 events, vomiting 1 event, dizziness 2 events and fatigue 1 event In reference arm, the TEAEs which were reported as related were as follows: Headache 2 events, vomiting 2 events, pain in extremity 1 event and Nasopharyngitis 1 event. The vital parameters and important laboratory parameters (CBC, LFT and RFT) of all subjects were within normal clinical limits and were comparable between the groups throughout the study period.
E. Conclusions:
a. Efficacy Conclusion:
There was significant reduction in HbA1c (1.5 vs 1.02) after 16 weeks of treatment with FDC of Dapagliflozin, Sitagliptin and Metformin as compared to the treatment of sitagliptin and metformin. Based on the primary efficacy analysis with respect to least square mean change in HbA1C values from baselines to 16 weeks, it was observed that the lower and upper limits of the 95 % CI for treatment difference was below 0 indicating superiority.
b. Safety Conclusion:
The FDC of Test product (Dapagliflozin, sitagliptin and metformin) was found to be safe and well tolerated.
In conclusion, this study established superiority and synergistic effect of FDC of Test product (Dapagliflozin, Sitagliptin and Metformin) compared to the combination of Sitagliptin and metformin in Type 2 Diabetes patients uncontrolled on metformin monotherapy.
Example 5: The Bioequivalence Study:
Bioequivalence study of Dapagliflozin, Sitagliptin and Metformin Hydrochloride (Extended Release) Tablets (10 mg + 100 mg + 1000 mg)
Table 7:
Treatment Test (T) Reference (R1) Reference (R2)
Drug Dapagliflozin, Sitagliptin
and Metformin
Hydrochloride Extended
Release Tablets (10 mg +100 mg + 1000 mg)
[Example 1 & 2] Xigduo® XR (Dapagliflozin and Metformin Hydrochloride Extended
Release Tablets (10 mg +
1000 mg) Januvia®100mg
(Sitagliptin
Phosphate Tablets IP
100 mg)
Dose One Tablet (1 X
Dapagliflozin, Sitagliptin
and Metformin
Hydrochloride Extended
Release Tablets (10 mg
+100 mg + 1000 mg) One Tablet (1 X
Dapagliflozin and
Metformin Hydrochloride Extended-Release Tablets
(10 mg + 1000 mg) One Tablet (1 X
Sitagliptin
Phosphate Tablets IP
100 mg)
Mode of administration Oral Oral Oral
Manufactured by Alkem Laboratories Ltd.,
India AstraZeneca Pharmaceuticals
LP, USA MSD
Pharmaceuticals Pvt.
Ltd.

CONCLUSION:
Based on the statistical analysis of Dapagliflozin, Sitagliptin and Metformin, it is concluded that the Test Product (T) [Example 1 & 3]: Dapagliflozin, Sitagliptin and Metformin Hydrochloride (Extended Release) Tablets (10 mg + 100 mg + 1000 mg) manufactured by Alkem Laboratories Ltd., India is bioequivalent to the Reference Product (R1): Xigduo XR 10 mg / 1000 mg (Dapagliflozin & Metformin HCl Extended-Release Tablets 10 mg + 1000 mg) manufactured by AstraZeneca Pharmaceuticals LP, USA, marketed by AstraZeneca Pharma India Ltd., INDIA and Reference Product (R2): Januvia 100 mg (Sitagliptin Phosphate Tablets IP 100 mg) manufactured by MSD Pharmaceuticals Pvt. Ltd., in terms of rate and extent of absorption under fasting conditions
While this provisional application contains the principal inventive concepts, the complete patent application pursuant hereto, willfully and particularly describes the preferred embodiments of the present invention. ,CLAIMS:We Claim:
1. A stable pharmaceutical composition comprising: a) an extended release layer comprising metformin or a pharmaceutically acceptable salt thereof b) immediate release layer comprising sitagliptin or pharmaceutically acceptable salt thereof, dapagliflozin or pharmaceutically acceptable salt thereof; and c) pharmaceutically acceptable excipients.
2. The stable composition as claimed in claim 1, wherein the composition comprises about 45-65 %w/w of metformin hydrochloride, about 5-15% w/w of sitagliptin phosphate and about 0.4-5%w/w of dapagliflozin propanediol based on the total weight of the composition.
3. The stable composition as claimed in claim 1, wherein the extended release layer comprises one or more rate-controlling polymers selected from the group consisting of ethylcellulose, polymethacrylate(s), cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate butyrate, cellulose acetate trimellitate, cellulose acetate, hydroxy propylcellulose, povidone, polyvinyl alcohol, polyvinyl acetate, polyethylene glycol, hydroxypropylmethylcellulose, starch, hydroxy ethylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, methylcellulose, or mixtures thereof.
4. The stable composition as claimed in claim 3, wherein the rate controlling polymer is about 7-15% w/w of the total composition.
5. The stable composition as claimed in claim 1, wherein the composition is manufactured using dry granulation or wet granulation method.
6. A stable pharmaceutical composition comprising: a) an extended release layer comprising about 61% w/w of metformin hydrochloride, about 1.1 % w/w of microcrystalline cellulose, about 12% w/w of hydroxypropyl methyl cellulose, about 4.2% w/w of sodium carboxymethylcellulose, about 1.2% w/w of polyvinylpyrrolidone, about 0.6% w/w of colloidal silicon dioxide, about 0.6% w/w of talc, about 0.61% w/w of magnesium stearate based on the total weight of the composition; b) an immediate release layer comprising about 0.75% w/w of dapagliflozin propanediol monohydrate, about 8% w/w of sitagliptin phosphate, about 3%w/w of microcrystalline cellulose, about 2% w/w of dibasic calcium phosphate, about 0.3% w/w of croscarmellose sodium, about 0.02% w/w of colour sunset yellow, about 0.3% w/w of polyvinylpyrrolidone, about 1.2% w/w of croscarmellose sodium, about 0.3% w/w of sodium stearyl fumarate, and about 0.3% w/w of magnesium stearate based on the total weight of the composition.
7. The stable composition as claimed in claim 6, wherein croscarmellose is present intragranular as well as extra granular in immediate release layer.
8. The stable composition as claimed in claim 7, wherein croscarmellose is present in a weight ratio of about 5:1 to about 1:5.
9. The stable composition as claimed in preceding claims, wherein the composition is indicated for the treatment of diabetes.
10. A stable pharmaceutical composition in the form of bi-layer tablet wherein a) first layer comprises about 45-65% w/w of metformin hydrochloride, about 1-7% w/w of microcrystalline cellulose, about 7-15% w/w of Hypromellose, about 1-7% w/w of carboxymethylcellulose sodium, about 0.1-5% w/w of polyvinylpyrrolidone, about 0.1-5% w/w of colloidal silicon dioxide, about 0.1-2% w/w of talc and 0.1-2% w/w of magnesium stearate based on the total weight of the composition; b) second layer comprises about 0.4-5% w/w of dapagliflozin propanediol, about 5-15% w/w of sitagliptin phosphate, about 1-8% w/w of microcrystalline cellulose, about 1-8% w/w of dibasic calcium phosphate, about 0.1-2% w/w of croscarmellose sodium, about 0.01-0.5% w/w of colour sunset yellow, about 0.1-2% w/w of polyvinylpyrrolidone, about 1-5% w/w of croscarmellose sodium, about 0.1-2% w/w of sodium stearyl fumarate, and about 0.1-2% w/w of magnesium stearate and c) optionally third layer in the form of film coating comprising Novomix 600062 and/or Novomix 50058.