RU2824129C2 - Two-layer tablet composition - Google Patents

Abstract

FIELD: chemistry; medicine.

SUBSTANCE: invention relates to compositions of a two-layer tablet containing a sustained release (XR) composition of metformin or a reduced weight metformin composition as a first layer, an SGLT2 inhibitor composition as a second layer and optionally a film coating.

EFFECT: present invention provides methods of producing a two-layer tablet composition and methods of treating diseases and disorders associated with SGLT2 activity using the two-layer tablet compositions.

6 cl, 2 tbl, 15 ex

Description

Field of technology to which the invention relates

The invention relates to a bilayer tablet composition comprising a metformin composition with a delayed release (XR) or a metformin composition of reduced weight XR as a first layer, a composition of a sodium-dependent glucose transporter (SGLT2) inhibitor as a second layer and, optionally, a film coating. The present invention provides methods for producing bilayer tablet compositions and methods for treating diseases and disorders associated with SGLT2 activity using bilayer tablet compositions.

State of the art

Type 2 diabetes is the most common form of diabetes, accounting for 90% of diabetes cases. More than 100 million people worldwide have type 2 diabetes (about 17 million in the United States), and the prevalence of the disease is increasing dramatically in both developed and developing countries. Type 2 diabetes is a lifelong disease that usually begins in middle age or later, but can begin at any age. People with type 2 diabetes do not respond properly to insulin, the hormone that normally allows the body to convert glucose in the blood into energy and store it in cells for later use. The problem with type 2 diabetes is a condition called insulin resistance, in which the body produces insulin in normal or even excessive amounts, but some mechanism interferes with the insulin's ability to move glucose into cells. Because the body does not use insulin properly, glucose levels in the blood rise to dangerous levels, a condition known as hyperglycemia.

Over time, persistent hyperglycemia leads to glucotoxicity, which worsens insulin resistance and contributes to pancreatic beta-cell dysfunction. The degree of persistent hyperglycemia is directly related to the microvascular complications of diabetes and may also contribute to the development of macrovascular complications. Hyperglycemia thus perpetuates a cycle of deleterious effects that complicate the management of type 2 diabetes and exacerbate complications.

It is now widely recognized that glycemic control is of great importance in patients with type 2 diabetes mellitus. The goal of diabetes therapy today is to achieve and maintain glucose levels as close to normal as possible to prevent long-term microvascular and macrovascular complications associated with elevated blood glucose levels. Oral medications used to treat type 2 diabetes mellitus include compounds such as sulfonylureas, biguanides (metformin), thiazolidinediones, and alpha-glucosidase inhibitors. The active agents of each class are usually administered to patients separately. However, when monotherapy is insufficient, combination therapy becomes an attractive and rational approach to the treatment of hyperglycemia, despite the known side effect of weight gain associated with sulfonylurea and thiazolidinone therapy.

Recently, a new class of antidiabetic agents known as sodium-glucose co-transporter 2 (SGLT2) inhibitors has been discovered. SGLT2 inhibitors prevent the kidneys from reabsorbing glucose into the blood. The kidneys continually filter glucose through the glomerulus into the capsule, but almost all of this glucose is reabsorbed. SGLT2 is the protein responsible for most of the glucose reabsorption, helping the body retain glucose for its energy needs. For patients with diabetes, storing excess glucose in this way contributes to persistent hyperglycemia. Inhibiting SGLT2 activity inhibits the kidneys from reabsorbing glucose into the body, resulting in the excretion of glucose in the urine.

Accordingly, the present invention provides bilayer tablet compositions that consist of metformin and an SGLT2 inhibitor for oral administration for treating a disease or disorder associated with SGLT2 activity without the weight gain associated with other treatments. The first layer of the bilayer tablet is a metformin composition with a delayed release (XR) or a reduced-weight metformin composition XR. The second layer is an SGLT2 inhibitor composition. The metformin/SGLT2 bilayer tablets of the present invention provide antidiabetic therapy for patients that is convenient and effective in controlling blood glucose levels.

Disclosure of invention

The present invention provides bilayer tablets comprising (1) a metformin XR composition or a reduced weight metformin XR composition as a first layer, (2) an SGLT2 inhibitor composition as a second layer and (3), optionally, a film coating that covers both layers. Metformin may be in the form of a pharmaceutically acceptable salt, where metformin hydrochloride (HCl) is preferred. A preferred SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt thereof, dapagliflozin (S) propylene glycol hydrate (1:1:1) or dapagliflozin (R) propylene glycol hydrate (1:1:1). The most preferred SGLT2 inhibitor is dapagliflozin or dapagliflozin (S) propylene glycol hydrate (1:1:1). The SGLT2 inhibitor composition is an immediate release composition or a sustained release composition, wherein the immediate release composition is preferred.

The metformin XR layer (1000 mg) comprises metformin, a binder, a release modifier, a lubricant, and optionally a glidant. The preferred binder is sodium carboxymethylcellulose. Hydroxypropyl methylcellulose 2208 is the preferred release modifier. Magnesium stearate is the preferred lubricant, and silicon dioxide or colloidal silicon dioxide are the preferred glidants. The SGLT2 inhibitor layer comprises an SGLT2 inhibitor, two or three fillers, a disintegrant, a glidant, and a lubricant. The preferred filler is lactose anhydrous, microcrystalline cellulose 302, pregelatinized starch, and mannitol. The preferred disintegrant is crospovidone. Silicon dioxide is the preferred glidant and magnesium stearate is the preferred lubricant. Hydroxypropyl cellulose EXF is the preferred binder.

The metformin XR layer (500 mg) comprises metformin, a binder, at least one release modifier, a filler, a lubricant, and optionally a glidant. A preferred binder is sodium carboxymethylcellulose. Hydroxypropyl methylcellulose 2208 in combination with hydroxypropyl methylcellulose 2910 is a preferred release modifier. Magnesium stearate is a preferred lubricant, and silicon dioxide or colloidal silicon dioxide are preferred glidants. The SGLT2 inhibitor layer comprises an SGLT2 inhibitor, two or three fillers, a disintegrant, a glidant, and a lubricant. Preferred fillers are anhydrous lactose, microcrystalline cellulose 302, pregelatinized starch, and mannitol. The preferred disintegrant is crospovidone. Silicon dioxide is the preferred glidant and magnesium stearate is the preferred lubricant. Hydroxypropyl cellulose EXF is the preferred binder.

In another aspect, the present invention provides methods for treating diseases or disorders associated with SGLT2 activity, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a bilayer tablet comprising metformin XR or metformin reduced weight XR, an SGLT2 inhibitor and, optionally, a film coating. The bilayer tablet composition of the present invention can be administered to a mammal, preferably a human, for the treatment of a variety of conditions and disorders associated with SGLT2 activity, including but not limited to the treatment or slowing of the progression or onset of diabetes mellitus (including type I diabetes and type II diabetes), impaired glucose tolerance, insulin resistance and diabetic complications such as nephropathy, retinopathy, neuropathy and cataract, hyperglycemia, hyperinsulinemia, hypercholesterolemia, dyslipidemia, elevated levels of free fatty acids and glycerol in the blood, hyperlipidemia, hypertriglyceridemia, obesity, delayed wound healing, tissue ischemia, atherosclerosis and hypertension. The compositions of the present invention can also be used to increase the content of high-density lipoproteins (HDL) in the blood. In addition, conditions, diseases and disorders collectively referred to as "syndrome X" or metabolic syndrome, as described by Johannsson, J. Clin. Endocrinol. Metab., 82, 727-34 (1997), can be treated using the compositions of the present invention.

In another aspect, the present invention provides methods for producing a bilayer tablet comprising metformin XR or metformin reduced weight XR, an SGLT2 inhibitor, and, optionally, a film coating.

Disclosure of invention

Manufacturing a bilayer tablet with significantly different weights of the two layers can result in cracks in the interface area of the layers, separation of the layers, or even cross-contamination of the two layers. The large difference in weight between the metformin and SGLT2 inhibitor layers in Examples 4-15 creates challenges in maintaining the active ingredient content and content uniformity of the lower weight layer, the SGLT2 inhibitor layer. In addition, cracks were found to form in the SGLT2 layer on the surface of the tablets in the region adjacent to the interface area of the layers, but not in the interface area itself, parallel to the interface area of the layers in a variety of test formulations. Formulations with an SGLT2 layer containing increased levels of microcrystalline cellulose, for example, showed reduced or no cracks, separation, or cross-contamination of the two layers, while maintaining the active ingredient content and uniformity of the second layer. In addition, pregelatinized starch, hydroxypropylcellulose EXF or mannitol can be used to replace part of the microcrystalline cellulose. Finally, adjusting the total weight of the second layer to about 300 mg - 400 mg contributed to reducing or eliminating cracks, separation and cross-contamination of the two layers. The preferred weight of the second layer is 300 mg. Accordingly, the present invention provides bilayer tablet compositions in which cracks, separation and cross-contamination of the metformin and SGLT2 layers are reduced or eliminated and the active substance content and homogeneity of the SGLT2 layer are maintained or improved.

The present invention relates to a bilayer tablet comprising metformin XR compositions (1000 mg), SGLT2 inhibitor compositions (2.5, 5.0 or 10.0 mg), and optionally a film coating. The metformin XR composition comprises metformin hydrochloride (HCl), sodium carboxymethylcellulose, hydroxypropyl methylcellulose, magnesium stearate. The SGLT2 composition comprises SGLT2 inhibitor, anhydrous lactose, microcrystalline cellulose, crospovidone, silicon dioxide, magnesium stearate. For the second layer, pregelatinized starch, hydroxypropyl cellulose EXF or mannitol (pearlitol SD 200) can be used to replace part of the microcrystalline cellulose. In addition, the total weight of the second layer is from about 300 mg to about 400 mg. The preferred weight of the second layer is 300 mg. The additional film coating may be an Opadry® II coating. In a preferred embodiment, the SGLT2 inhibitor is dapagliflozin, dapagliflozin (S) PGS or dapagliflozin (R) PGS.

In another aspect, the present invention provides bilayer tablets in which the metformin (1000 mg) XR composition comprises about 50-87% metformin hydrochloride (HCl), about 1-10% sodium carboxymethylcellulose, about 10-40% hydroxypropyl methylcellulose, 0.1-75% magnesium stearate, and about 0-2% silicon dioxide or about 0-1.5% colloidal silicon dioxide. The SGLT2 inhibitor composition comprises about 0.1-10% SGLT2 inhibitor, about 5-30% anhydrous lactose, about 40-90% microcrystalline cellulose, about 0-25% pregelatinized starch, about 0-20% hydroxypropyl cellulose, about 0-25% mannitol, about 1-10% crospovidone, about 0.1-5% silicon dioxide and about 0.1-5% magnesium stearate. The additional film coating may be Opadry® II coating. In a preferred embodiment, the SGLT2 inhibitor is dapagliflozin or dapagliflozin (S) PGS.

In another aspect, the present invention provides bilayer tablets in which the metformin (1000 mg) XR composition comprises about 64-82% metformin hydrochloride (HCl), about 3-5% sodium carboxymethylcellulose, about 15-30% hydroxypropyl methylcellulose, 0.1-75% magnesium stearate, and about 0-2% silicon dioxide or about 0-1.5% colloidal silicon dioxide. The SGLT2 inhibitor composition comprises about 0.5-4% SGLT2 inhibitor, about 14-18% anhydrous lactose, about 50-80% microcrystalline cellulose, about 0-20% pregelatinized starch, about 0-15% hydroxypropyl cellulose, about 0-20% mannitol, about 2-6% crospovidone, about 0.5-2.5% silicon dioxide, and about 0.49-2% magnesium stearate. The additional film coating may be Opadry® II coating. In a preferred embodiment, the SGLT2 inhibitor is dapagliflozin or dapagliflozin (S) PGS.

In another aspect, the present invention provides bilayer tablets wherein the metformin (1000 mg) XR formulation comprises about 67-71% metformin hydrochloride (HCl), about 3-5% sodium carboxymethylcellulose, about 25-29% hydroxypropyl methylcellulose 2208, and about 0.1-75% magnesium stearate. The SGLT2 inhibitor formulation comprises about 0.5-4% dapagliflozin or dapagliflozin (S) PGS, about 14-18% lactose anhydrous, about 72-80% microcrystalline cellulose 302, about 2-6% crospovidone, about 0.5-2.5% silicon dioxide, and about 0.5-1.5% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be an Opadry® II coating.

In another aspect, the present invention provides bilayer tablets wherein the metformin (1000 mg) XR formulation comprises about 67-71% metformin hydrochloride (HCl), about 3-5% sodium carboxymethylcellulose, about 25-29% hydroxypropyl methylcellulose 2208, and about 0.1-75% magnesium stearate. The SGLT2 inhibitor formulation comprises about 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 14-18% anhydrous lactose, about 50-70% microcrystalline cellulose 302, about 10-22% pregelatinized starch, about 2-6% crospovidone, about 0.5-2.5% silicon dioxide, and about 0.1-1.5% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg.

In another aspect, the present invention provides bilayer tablets wherein the metformin (1000 mg) XR formulation comprises about 67-71% metformin hydrochloride (HCl), about 3-5% sodium carboxymethylcellulose, about 25-29% hydroxypropyl methylcellulose 2208, and about 0.1-75% magnesium stearate. The SGLT2 inhibitor formulation comprises about 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 14-18% lactose anhydrous, about 60-70% microcrystalline cellulose 302, about 5-15% hydroxypropyl cellulose EXF, about 2-6% crospovidone, about 0.5-2.5% silicon dioxide, and about 0.1-1.5% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg.

In another aspect, the present invention provides bilayer tablets wherein the metformin (1000 mg) XR formulation comprises about 67-71% metformin hydrochloride (HCl), about 3-5% sodium carboxymethylcellulose, about 25-29% hydroxypropyl methylcellulose 2208, and about 0.1-75% magnesium stearate. The SGLT2 inhibitor formulation comprises about 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 14-18% lactose anhydrous, about 55-65% microcrystalline cellulose 302, about 10-20% mannitol, about 2-6% crospovidone, about 0.5-2.5% silicon dioxide, and about 0.1-1.5% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg.

In another aspect, the present invention provides bilayer tablets wherein the metformin (1000 mg) XR formulation comprises about 69% metformin hydrochloride (HCl), about 3.5% sodium carboxymethylcellulose, about 27% hydroxypropyl methylcellulose 2208, and about 0.49% magnesium stearate. The SGLT2 inhibitor formulation comprises about 0.5-4% dapagliflozin (S) PGS, about 16% anhydrous lactose, about 57-77% microcrystalline cellulose 302, about 0-19% pregelatinized starch, about 0-10% hydroxypropyl cellulose EXF, about 0-15% mannitol, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be an Opadry® II coating.

In another aspect, the present invention provides bilayer tablets wherein the metformin (1000 mg) XR formulation comprises about 69% metformin hydrochloride (HCl), about 3.5% sodium carboxymethylcellulose, about 27% hydroxypropyl methylcellulose 2208, and about 0.49% magnesium stearate. The SGLT2 inhibitor formulation comprises about 0.8% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% lactose anhydrous, about 77% microcrystalline cellulose 302, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be an Opadry® II coating.

In another aspect, the present invention provides bilayer tablets wherein the metformin (1000 mg) XR formulation comprises about 69% metformin hydrochloride (HCl), about 3.5% sodium carboxymethylcellulose, about 27% hydroxypropyl methylcellulose 2208, and about 0.49% magnesium stearate. The SGLT2 inhibitor formulation comprises about 1.7% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% lactose anhydrous, about 76% microcrystalline cellulose 302, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be an Opadry® II coating.

In another aspect, the present invention provides bilayer tablets wherein the metformin (1000 mg) XR formulation comprises about 69% metformin hydrochloride (HCl), about 3.5% sodium carboxymethylcellulose, about 27% hydroxypropyl methylcellulose 2208, and about 0.49% magnesium stearate. The SGLT2 inhibitor formulation comprises about 3.4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% lactose anhydrous, about 74% microcrystalline cellulose 302, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be an Opadry® II coating.

In another aspect, the present invention provides bilayer tablets wherein the metformin (1000 mg) XR formulation comprises about 69% metformin hydrochloride (HCl), about 3.5% sodium carboxymethylcellulose, about 27% hydroxypropyl methylcellulose 2208, and about 0.49% magnesium stearate. The SGLT2 inhibitor formulation comprises about 1.7% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% lactose anhydrous, about 64% microcrystalline cellulose 302, about 13% pregelatinized starch, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be an Opadry® II coating.

In another aspect, the present invention provides bilayer tablets wherein the metformin (1000 mg) XR formulation comprises about 69% metformin hydrochloride (HCl), about 3.5% sodium carboxymethylcellulose, about 27% hydroxypropyl methylcellulose 2208, and about 0.49% magnesium stearate. The SGLT2 inhibitor formulation comprises about 1.7% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% lactose anhydrous, about 57% microcrystalline cellulose 302, about 19% pregelatinized starch, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be an Opadry® II coating.

In another aspect, the present invention provides bilayer tablets wherein the metformin (1000 mg) XR formulation comprises about 69% metformin hydrochloride (HCl), about 3.5% sodium carboxymethylcellulose, about 27% hydroxypropyl methylcellulose 2208, and about 0.49% magnesium stearate. The SGLT2 inhibitor formulation comprises about 1.7% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% lactose anhydrous, about 66% microcrystalline cellulose 302, about 10% hydroxypropyl cellulose EXF, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be an Opadry® II coating.

In another aspect, the present invention provides bilayer tablets wherein the metformin (1000 mg) XR formulation comprises about 69% metformin hydrochloride (HCl), about 3.5% sodium carboxymethylcellulose, about 27% hydroxypropyl methylcellulose 2208, and about 0.49% magnesium stearate. The SGLT2 inhibitor formulation comprises about 1.7% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% lactose anhydrous, about 61% microcrystalline cellulose 302, about 15% mannitol, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be an Opadry® II coating.

In another aspect, the present invention provides bilayer tablets wherein the metformin (1000 mg) XR formulation comprises about 67-73% metformin hydrochloride (HCl), about 3-5% sodium carboxymethylcellulose, about 25-30% hydroxypropyl methylcellulose 2208, and about 0.08-0.2% magnesium stearate. The SGLT2 inhibitor formulation comprises about 0.5-4% dapagliflozin (S) PGS, about 14-18% anhydrous lactose, about 55-70% microcrystalline cellulose 302, about 10-25% pregelatinized starch, about 3-5% crospovidone, about 0.5-2.5% silicon dioxide, and about 0.5-2% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be an Opadry® II coating.

In another aspect, the present invention provides bilayer tablets wherein the metformin (1000 mg) XR formulation comprises about 69% metformin hydrochloride (HCl), about 3.5% sodium carboxymethylcellulose, about 27% hydroxypropyl methylcellulose 2208, and about 0.49% magnesium stearate. The SGLT2 inhibitor formulation comprises about 1.7% dapagliflozin (S) PGS, about 16% anhydrous lactose, about 56-64% microcrystalline cellulose 302, about 13-19% pregelatinized starch, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be an Opadry® II coating.

In another aspect, the present invention provides bilayer tablets wherein the metformin (1000 mg) XR formulation comprises about 67-73% metformin hydrochloride (HCl), about 3-5% sodium carboxymethylcellulose, about 25-30% hydroxypropyl methylcellulose 2208, and about 0.08-0.2% magnesium stearate. The SGLT2 inhibitor formulation comprises about 0.5-4% dapagliflozin (S) PGS, about 14-18% lactose anhydrous, about 55-70% microcrystalline cellulose 302, about 5-20 hydroxypropyl cellulose EXF, about 3-5% crospovidone, about 0.5-2.5% silicon dioxide, and about 0.5-2% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be an Opadry® II coating.

In another aspect, the present invention provides bilayer tablets wherein the metformin (1000 mg) XR formulation comprises about 69% metformin hydrochloride (HCl), about 3.5% sodium carboxymethylcellulose, about 27% hydroxypropyl methylcellulose 2208, and about 0.49% magnesium stearate. The SGLT2 inhibitor formulation comprises about 1.7% dapagliflozin (S) PGS, about 16% lactose anhydrous, about 66% microcrystalline cellulose 302, about 10% hydroxypropyl cellulose EXF, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be an Opadry® II coating.

In another aspect, the present invention provides bilayer tablets wherein the metformin (1000 mg) XR formulation comprises about 67-73% metformin hydrochloride (HCl), about 3-5% sodium carboxymethylcellulose, about 25-30% hydroxypropyl methylcellulose 2208, and about 0.08-0.2% magnesium stearate. The SGLT2 inhibitor formulation comprises about 0.5-4% dapagliflozin (S) PGS, about 14-18% lactose anhydrous, about 55-70% microcrystalline cellulose 302, about 5-25 mannitol, about 3-5% crospovidone, about 0.5-2.5% silicon dioxide, and about 0.5-2% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be an Opadry® II coating.

In another aspect, the present invention provides bilayer tablets wherein the metformin (1000 mg) XR formulation comprises about 69% metformin hydrochloride (HCl), about 3.5% sodium carboxymethylcellulose, about 27% hydroxypropyl methylcellulose 2208, and about 0.49% magnesium stearate. The SGLT2 inhibitor formulation comprises about 1.7% dapagliflozin (S) PGS, about 16% lactose anhydrous, about 61% microcrystalline cellulose 302, about 15% mannitol, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be an Opadry® II coating.

The present invention also relates to bilayer tablets containing metformin XR compositions (500 mg), SGLT2 inhibitor compositions (2.5, 5.0, or 10.0 mg), and, optionally, a film coating. The metformin XR composition comprises metformin hydrochloride (HCl), sodium carboxymethylcellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium stearate. The SGLT2 inhibitor composition comprises SGLT2 inhibitor, anhydrous lactose, microcrystalline cellulose, crospovidone, silicon dioxide, magnesium stearate. For the second layer, pregelatinized starch, hydroxypropyl cellulose EXF or mannitol (pearlitol SD 200) can be used to replace part of the microcrystalline cellulose. In addition, the total weight of the second layer is from about 300 mg to about 400 mg. The preferred weight of the second layer is 300 mg. The additional film coating may be an Opadry® II coating. In a preferred embodiment, the SGLT2 inhibitor is dapagliflozin, dapagliflozin (S) PGS or dapagliflozin (R) PGS.

In another aspect, the present invention provides bilayer tablets in which the metformin (500 mg) XR composition comprises about 40-60% metformin hydrochloride (HCl), about 1-10% sodium carboxymethylcellulose, about 20-45% hydroxypropyl methylcellulose, 5-15% microcrystalline cellulose, about 0.1-0.75% magnesium stearate and about 0-2% silicon dioxide or about 0-1.5% colloidal silicon dioxide. The SGLT2 inhibitor composition comprises about 0.1-10% SGLT2 inhibitor, about 5-30% anhydrous lactose, about 40-90% microcrystalline cellulose, about 0-25% pregelatinized starch, about 0-20% hydroxypropyl cellulose, about 0-25% mannitol, about 1-10% crospovidone, about 0.1-5% silicon dioxide and about 0.1-5% magnesium stearate. The additional film coating may be Opadry® II coating. In a preferred embodiment, the SGLT2 inhibitor is dapagliflozin or dapagliflozin (S) PGS.

In another aspect, the present invention provides bilayer tablets in which the metformin (500 mg) XR composition comprises about 42-55% metformin hydrochloride (HCl), about 4-6% sodium carboxymethylcellulose, about 30-40% hydroxypropyl methylcellulose, 5-15% microcrystalline cellulose, about 0.1-0.75% magnesium stearate and about 0-2% silicon dioxide or about 0-1.5% colloidal silicon dioxide. The SGLT2 inhibitor composition comprises about 0.5-4% SGLT2 inhibitor, about 14-18% anhydrous lactose, about 65-80% microcrystalline cellulose, about 0-20% pregelatinized starch, about 0-15% hydroxypropyl cellulose, about 0-20% mannitol, about 2-6% crospovidone, about 0.5-2.5% silicon dioxide and about 0.49-2% magnesium stearate. The additional film coating may be Opadry® II coating. In a preferred embodiment, the SGLT2 inhibitor is dapagliflozin or dapagliflozin (S) PGS.

In another aspect, the present invention provides bilayer tablets in which the metformin (500 mg) XR composition comprises about 46-50% metformin hydrochloride (HCl), about 4-6% sodium carboxymethylcellulose, about 30-40% hydroxypropyl methylcellulose 2208, about 0.1-1.5% hydroxypropyl methylcellulose 2910, about 5-15% microcrystalline cellulose, about 0.1-0.75% magnesium stearate, and about 0-2% silicon dioxide or about 0-1.5% colloidal silicon dioxide. The SGLT2 inhibitor composition comprises about 0.5-4% dapagliflozin or dapagliflozin (S) PGS, about 14-18% anhydrous lactose, about 72-80% microcrystalline cellulose 302, about 2-6% crospovidone, about 0.5-2.5% silicon dioxide, and about 0.5-1.5% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be Opadry® II coating.

In another aspect, the present invention provides bilayer tablets wherein the metformin (500 mg) XR formulation comprises about 46-50% metformin hydrochloride (HCl), about 4-6% sodium carboxymethylcellulose, about 30-40% hydroxypropyl methylcellulose 2208, about 0.1-1.5% hydroxypropyl methylcellulose 2910, about 5-15% microcrystalline cellulose, and about 0.1-0.75% magnesium stearate. The SGLT2 inhibitor formulation comprises about 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 14-18% lactose anhydrous, about 50-70% microcrystalline cellulose 302, about 2-6% crospovidone, about 0.5-2.5% silicon dioxide, and about 0.5-1.5% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, where the preferred weight is about 300 mg.

In another aspect, the present invention provides bilayer tablets wherein the metformin (500 mg) XR formulation comprises about 46-50% metformin hydrochloride (HCl), about 4-6% sodium carboxymethylcellulose, about 30-40% hydroxypropyl methylcellulose 2208, about 0.1-1.5% hydroxypropyl methylcellulose 2910, about 5-15% microcrystalline cellulose, and about 0.1-0.75% magnesium stearate. The SGLT2 inhibitor formulation comprises about 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 14-18% lactose anhydrous, about 60-70% microcrystalline cellulose 302, about 5-15% hydroxypropyl cellulose EXF, about 2-6% crospovidone, about 0.5-2.5% silicon dioxide and about 0.5-1.5% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, where the preferred weight is about 300 mg.

In another aspect, the present invention provides bilayer tablets in which the metformin (500 mg) XR composition comprises about 46-50% metformin hydrochloride (HCl), about 4-6% sodium carboxymethylcellulose, about 30-40% hydroxypropyl methylcellulose 2208, about 0.1-1.5% hydroxypropyl methylcellulose 2910, about 5-15% microcrystalline cellulose and about 0.1-0.75% magnesium stearate. The SGLT2 inhibitor composition comprises about 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 14-18% anhydrous lactose, about 55-65% microcrystalline cellulose 302, about 10-20% mannitol, about 2-6% crospovidone, about 0.5-2.5% silicon dioxide and about 0.5-1.5% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg.

In another aspect, the present invention provides bilayer tablets in which the metformin (500 mg) XR composition comprises about 48-49% metformin hydrochloride (HCl), about 4.5-5% sodium carboxymethylcellulose, about 34.5-35% hydroxypropyl methylcellulose 2208, about 0.8-1.2% hydroxypropyl methylcellulose 2910, about 9.75-10.25% microcrystalline cellulose and about 0.34% magnesium stearate. The SGLT2 inhibitor composition comprises about 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% anhydrous lactose, about 72-77% microcrystalline cellulose 302, about 0-19% pregelatinized starch, about 0-10% hydroxypropyl cellulose EXF, about 0-15% mannitol, about 4% crospovidone, about 0.5-1.5% silicon dioxide and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be Opadry® II coating.

In another aspect, the present invention provides bilayer tablets in which the metformin (500 mg) XR composition comprises about 48-49% metformin hydrochloride (HCl), about 4.5-5% sodium carboxymethylcellulose, about 34.5-35% hydroxypropyl methylcellulose 2208, about 0.8-1.2% hydroxypropyl methylcellulose 2910, about 9.75-10.25% microcrystalline cellulose and about 0.34% magnesium stearate. The SGLT2 inhibitor composition comprises about 0.5-4% dapagliflozin or dapagliflozin (S) PGS, about 16% anhydrous lactose, about 72-77% microcrystalline cellulose 302, about 4% crospovidone, about 0.5-1.5% silicon dioxide and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be Opadry® II coating.

Compositions with a reduced metformin XR layer weight compared to known or currently available metformin XR compositions without reducing the amount of active ingredient are preferred because these compositions provide a smaller weight difference between the two layers, thereby reducing or eliminating problems associated with the production of a bilayer tablet (cracks, separation of layers, cross-contamination). In addition, the bilayer tablets are smaller in size and more suitable for oral use by patients. The invention provides a reduction in the weight of metformin XR compositions that include silicon dioxide or colloidal silicon dioxide and a reduced amount of hydroxypropyl methylcellulose. The content of hydroxypropyl methylcellulose is reduced from about 27% to about 18%. These compositions are characterized by improved compactness and a reduced layer weight ratio from about 4.8:1 to about 4.4:1 while maintaining a similar release rate of metformin.

Accordingly, the present invention provides bilayer tablets comprising reduced weight metformin XR compositions (1000 mg), SGLT2 inhibitor compositions (2.5, 5.0, 10.0 mg) and, optionally, a film coating. Reduced weight metformin XR compositions comprise metformin HCl, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, silicon dioxide or colloidal silicon dioxide, magnesium stearate. SGLT2 inhibitor compositions comprise SGLT2 inhibitor, anhydrous lactose, microcrystalline cellulose, crospovidone, silicon dioxide, magnesium stearate. For the second layer, pregelatinized starch, hydroxypropyl cellulose or mannitol can be used to replace part of the microcrystalline cellulose. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The additional film coating may be an Opadry® II coating. In a preferred embodiment, the SGLT2 inhibitor is dapagliflozin, dapagliflozin (S) PGS or dapagliflozin (R) PGS.

In another aspect, the present invention provides bilayer tablets in which the metformin (1000 mg) XR composition comprises about 70-85% metformin hydrochloride (HCl), about 2-6% sodium carboxymethylcellulose, about 15-27% hydroxypropyl methylcellulose 2208, about 0.75-1.25% silicon dioxide, about 0.25%-0.75% colloidal silicon dioxide, and about 0.05-5% magnesium stearate. The SGLT2 inhibitor composition comprises about 0.1-10% SGLT2 inhibitor, about 5-30% anhydrous lactose, about 40-90% microcrystalline cellulose 302, about 0-25% pregelatinized starch, about 0-20% hydroxypropyl cellulose EXF, about 0-25% mannitol (pearlitol SD 200), about 4% crospovidone, about 0.1-5% silicon dioxide and about 0.1-5% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The additional film coating may be Opadry® II coating. In a preferred embodiment, the SGLT2 inhibitor is dapagliflozin or dapagliflozin (S) PGS.

In another aspect, the present invention provides bilayer tablets in which the metformin (1000 mg) XR composition comprises about 72-82% metformin hydrochloride (HCl), about 3-5% sodium carboxymethylcellulose, about 15-22% hydroxypropyl methylcellulose 2208, about 0.75-1.25% silicon dioxide, about 0.25%-0.75% colloidal silicon dioxide, and about 0.1-0.6% magnesium stearate. The SGLT2 inhibitor composition comprises about 0.1-10% SGLT2 inhibitor, about 5-30% anhydrous lactose, about 40-90% microcrystalline cellulose 302, about 0-25% pregelatinized starch, about 0-20% hydroxypropyl cellulose EXF, about 0-25% mannitol (pearlitol SD 200), about 1-10% crospovidone, about 0.1-5% silicon dioxide and about 0.1-5% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The additional film coating may be Opadry® II coating. In a preferred embodiment, the SGLT2 inhibitor is dapagliflozin or dapagliflozin (S) PGS.

In another aspect, the present invention provides bilayer tablets in which the metformin (1000 mg) XR composition comprises about 72-82% metformin hydrochloride (HCl), about 3-5% sodium carboxymethylcellulose, about 15-22% hydroxypropyl methylcellulose 2208, about 0.75-1.25% silicon dioxide, about 0.25%-0.75% colloidal silicon dioxide, and about 0.1-0.6% magnesium stearate. The SGLT2 inhibitor composition comprises about 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 14-18% anhydrous lactose, about 72-80% microcrystalline cellulose 302, about 2-6% crospovidone, about 0.5-2.5% silicon dioxide and about 0.5-1.5% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be Opadry® II coating.

In another aspect, the present invention provides bilayer tablets in which the metformin (1000 mg) XR composition comprises about 72-82% metformin hydrochloride (HCl), about 3-5% sodium carboxymethylcellulose, about 15-22% hydroxypropyl methylcellulose 2208, about 0.75-1.25% silicon dioxide, about 0.25%-0.75% colloidal silicon dioxide, and about 0.1-0.6% magnesium stearate. The SGLT2 inhibitor composition comprises about 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 14-18% anhydrous lactose, about 50-70% microcrystalline cellulose 302, about 10-22% pregelatinized starch, about 2-6% crospovidone, about 0.5-2.5% silicon dioxide, and about 0.5-1.5% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be Opadry® II coating.

In another aspect, the present invention provides bilayer tablets in which the metformin (1000 mg) XR composition comprises about 72-82% metformin hydrochloride (HCl), about 3-5% sodium carboxymethylcellulose, about 15-22% hydroxypropyl methylcellulose 2208, about 0.75-1.25% silicon dioxide, about 0.25%-0.75% colloidal silicon dioxide, and about 0.1-0.6% magnesium stearate. The SGLT2 inhibitor composition comprises about 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 14-18% lactose anhydrous, about 60-70% microcrystalline cellulose 302, about 5-15% hydroxypropyl cellulose EXF, about 2-6% crospovidone, about 0.5-2.5% silicon dioxide and about 0.5-1.5% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be Opadry® II coating.

In another aspect, the present invention provides bilayer tablets in which the metformin (1000 mg) XR composition comprises about 72-82% metformin hydrochloride (HCl), about 3-5% sodium carboxymethylcellulose, about 15-22% hydroxypropyl methylcellulose 2208, about 0.75-1.25% silicon dioxide, about 0.25%-0.75% colloidal silicon dioxide, and about 0.1-0.6% magnesium stearate. The SGLT2 inhibitor composition comprises about 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 14-18% anhydrous lactose, about 55-65% microcrystalline cellulose 302, about 10-20% mannitol, about 2-6% crospovidone, about 0.5-2.5% silicon dioxide and about 0.5-1.5% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be Opadry® II coating.

In another aspect, the present invention provides bilayer tablets in which the metformin (1000 mg) XR composition comprises about 72-82% metformin hydrochloride (HCl), about 3-5% sodium carboxymethylcellulose, about 15-22% hydroxypropyl methylcellulose 2208, about 0.75-1.25% silicon dioxide, about 0.25%-0.75% colloidal silicon dioxide, and about 0.1-0.6% magnesium stearate. The SGLT2 inhibitor composition comprises about 1.7% dapagliflozin (S) propylene glycol hydrate, about 16% anhydrous lactose, about 56-64% microcrystalline cellulose 302, about 13-19% pregelatinized starch, about 4% crospovidone, about 1.5% silicon dioxide and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be Opadry® II coating.

In another aspect, the present invention provides bilayer tablets in which the metformin (1000 mg) XR composition comprises about 72-82% metformin hydrochloride (HCl), about 3-5% sodium carboxymethylcellulose, about 15-22% hydroxypropyl methylcellulose 2208, about 0.75-1.25% silicon dioxide, about 0.25%-0.75% colloidal silicon dioxide, and about 0.1-0.6% magnesium stearate. The SGLT2 inhibitor composition comprises about 1.7% dapagliflozin (S) propylene glycol hydrate, about 16% anhydrous lactose, about 66% microcrystalline cellulose 302, about 10% hydroxypropyl cellulose, about 4% crospovidone, about 1.5% silicon dioxide and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be Opadry® II coating.

In another aspect, the present invention provides bilayer tablets in which the metformin (1000 mg) XR composition comprises about 72-82% metformin hydrochloride (HCl), about 3-5% sodium carboxymethylcellulose, about 15-22% hydroxypropyl methylcellulose 2208, about 0.75-1.25% silicon dioxide, about 0.25%-0.75% colloidal silicon dioxide, and about 0.1-0.6% magnesium stearate. The SGLT2 inhibitor composition comprises about 1.7% dapagliflozin (S) propylene glycol hydrate, about 16% anhydrous lactose, about 61% microcrystalline cellulose 302, about 15% mannitol, about 4% crospovidone, about 1.5% silicon dioxide and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be Opadry® II coating.

In another aspect, the present invention provides bilayer tablets wherein the metformin (1000 mg) XR formulation comprises about 76.6% metformin hydrochloride (HCl), about 3.84% sodium carboxymethylcellulose, about 18% hydroxypropyl methylcellulose 2208, about 0.75-1.25% silicon dioxide, about 0.25%-0.75% colloidal silicon dioxide, and about 0.53% magnesium stearate. The SGLT2 inhibitor formulation comprises about 0.8% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% lactose anhydrous, about 77% microcrystalline cellulose 302, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be an Opadry® II coating.

In another aspect, the present invention provides bilayer tablets wherein the metformin (1000 mg) XR formulation comprises about 76.6% metformin hydrochloride (HCl), about 3.84% sodium carboxymethylcellulose, about 18% hydroxypropyl methylcellulose 2208, about 0.75-1.25% silicon dioxide, about 0.25%-0.75% colloidal silicon dioxide, and about 0.53% magnesium stearate. The SGLT2 inhibitor formulation comprises about 1.7% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% lactose anhydrous, about 76% microcrystalline cellulose 302, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be an Opadry® II coating.

In another aspect, the present invention provides bilayer tablets wherein the metformin (1000 mg) XR formulation comprises about 76.6% metformin hydrochloride (HCl), about 3.84% sodium carboxymethylcellulose, about 18% hydroxypropyl methylcellulose 2208, about 0.75-1.25% silicon dioxide, about 0.25%-0.75% colloidal silicon dioxide, and about 0.53% magnesium stearate. The SGLT2 inhibitor formulation comprises about 3.4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% lactose anhydrous, about 74% microcrystalline cellulose 302, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be an Opadry® II coating.

In another aspect, the present invention provides bilayer tablets in which the metformin (1000 mg) XR composition comprises about 76.6% metformin hydrochloride (HCl), about 3.84% sodium carboxymethylcellulose, about 18% hydroxypropyl methylcellulose 2208, about 0.75-1.25% silicon dioxide, about 0.25%-0.75% colloidal silicon dioxide, and about 0.53% magnesium stearate. The SGLT2 inhibitor composition comprises about 1.7% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% anhydrous lactose, about 64% microcrystalline cellulose 302, about 13% pregelatinized starch, about 4% crospovidone, about 1.5% silicon dioxide and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be Opadry® II coating.

In another aspect, the present invention provides bilayer tablets in which the metformin (1000 mg) XR composition comprises about 76.6% metformin hydrochloride (HCl), about 3.84% sodium carboxymethylcellulose, about 18% hydroxypropyl methylcellulose 2208, about 0.75-1.25% silicon dioxide, about 0.25%-0.75% colloidal silicon dioxide, and about 0.53% magnesium stearate. The SGLT2 inhibitor composition comprises about 1.7% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% anhydrous lactose, about 57% microcrystalline cellulose 302, about 19% pregelatinized starch, about 4% crospovidone, about 1.5% silicon dioxide and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be Opadry® II coating.

In another aspect, the present invention provides bilayer tablets in which the metformin (1000 mg) XR composition comprises about 76.6% metformin hydrochloride (HCl), about 3.84% sodium carboxymethylcellulose, about 18% hydroxypropyl methylcellulose 2208, about 0.75-1.25% silicon dioxide, about 0.25%-0.75% colloidal silicon dioxide, and about 0.53% magnesium stearate. The SGLT2 inhibitor composition comprises about 1.7% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% lactose anhydrous, about 66% microcrystalline cellulose 302, about 10% hydroxypropyl cellulose EXF, about 4% crospovidone, about 1.5% silicon dioxide and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be Opadry® II coating.

In another aspect, the present invention provides bilayer tablets in which the metformin (1000 mg) XR composition comprises about 76.6% metformin hydrochloride (HCl), about 3.84% sodium carboxymethylcellulose, about 18% hydroxypropyl methylcellulose 2208, about 0.75-1.25% silicon dioxide, about 0.25%-0.75% colloidal silicon dioxide, and about 0.53% magnesium stearate. The SGLT2 inhibitor composition comprises about 1.7% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% anhydrous lactose, about 61% microcrystalline cellulose 302, about 15% mannitol, about 4% crospovidone, about 1.5% silicon dioxide and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is about 300 mg. The film coating may be Opadry® II coating.

The present invention relates to a bilayer tablet comprising metformin XR compositions (500 mg), SGLT2 inhibitor compositions (2.5, 5.0 or 10.0 mg), and, optionally, a film coating. The metformin XR 500 mg composition comprises metformin hydrochloride (HCl), sodium carboxymethylcellulose, hydroxypropyl methylcellulose, magnesium stearate. The SGLT2 composition comprises SGLT2 inhibitor, anhydrous lactose, microcrystalline cellulose, crospovidone, silicon dioxide, magnesium stearate. For the second layer, pregelatinized starch, hydroxypropyl cellulose EXF or mannitol (pearlitol SD 200) can be used to replace part of the microcrystalline cellulose. In addition, the total weight of the second layer is from about 300 mg to about 400 mg. The preferred weight of the second layer is 300 mg. The additional film coating may be an Opadry® II coating. In a preferred embodiment, the SGLT2 inhibitor is dapagliflozin, dapagliflozin (S) PGS or dapagliflozin (R) PGS.

In another aspect, the present invention provides bilayer tablets in which the metformin (500 mg) XR composition comprises about 40-60% metformin hydrochloride (HCl), about 4-6% sodium carboxymethylcellulose, about 30-40% hydroxypropyl methylcellulose 2208, about 0.1-1.5% hydroxypropyl methylcellulose 2910, about 5-15% microcrystalline cellulose, about 0.75-1.25% silicon dioxide or about 0.25-0.75% colloidal silicon dioxide, and about 0.05-5% magnesium stearate. The SGLT2 inhibitor composition comprises about 0.1-10% SGLT2 inhibitor, about 5-30% anhydrous lactose, about 40-90% microcrystalline cellulose, about 0-25% pregelatinized starch, about 0-20% hydroxypropyl cellulose EXF, about 0-25% mannitol (pearlitol SD 200), about 1-10% crospovidone, about 0.1-5% silicon dioxide and about 0.1-5% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is 300 mg. The additional film coating may be Opadry® II coating. In a preferred embodiment, the SGLT2 inhibitor is dapagliflozin or dapagliflozin (S) PGS.

In another aspect, the present invention provides bilayer tablets in which the metformin (500 mg) XR composition comprises about 45-50% metformin hydrochloride (HCl), about 4-6% sodium carboxymethylcellulose, about 30-40% hydroxypropyl methylcellulose 2208, about 0.1-1.5% hydroxypropyl methylcellulose 2910, about 5-15% microcrystalline cellulose, about 0.75-1.25% silicon dioxide or about 0.25-0.75% colloidal silicon dioxide, and about 0.05-5% magnesium stearate. The SGLT2 inhibitor composition comprises about 0.1-10% SGLT2 inhibitor, about 5-30% anhydrous lactose, about 40-90% microcrystalline cellulose, about 0-25% pregelatinized starch, about 0-20% hydroxypropyl cellulose EXF, about 0-25% mannitol (pearlitol SD 200), about 1-10% crospovidone, about 0.1-5% silicon dioxide and about 0.1-5% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is 300 mg. The additional film coating may be Opadry® II coating. In a preferred embodiment, the SGLT2 inhibitor is dapagliflozin or dapagliflozin (S) PGS.

In another aspect, the present invention provides bilayer tablets in which the metformin (500 mg) XR composition comprises about 45-50% metformin hydrochloride (HCl), about 4-6% sodium carboxymethylcellulose, about 30-40% hydroxypropyl methylcellulose 2208, about 0.1-1.5% hydroxypropyl methylcellulose 2910, about 5-15% microcrystalline cellulose, about 0.75-1.25% silicon dioxide or about 0.25-0.75% colloidal silicon dioxide, and about 0.05-5% magnesium stearate. The SGLT2 inhibitor composition comprises about 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 14-18% anhydrous lactose, about 72-80% microcrystalline cellulose 302, about 2-6% crospovidone, about 0.5-2.5% silicon dioxide and about 0.5-1.5% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is 300 mg. The film coating may be Opadry® II coating.

In another aspect, the present invention provides bilayer tablets in which the metformin (500 mg) XR composition comprises about 45-50% metformin hydrochloride (HCl), about 4-6% sodium carboxymethylcellulose, about 30-40% hydroxypropyl methylcellulose 2208, about 0.1-1.5% hydroxypropyl methylcellulose 2910, about 5-15% microcrystalline cellulose, about 0.75-1.25% silicon dioxide or about 0.25-0.75% colloidal silicon dioxide, and about 0.05-5% magnesium stearate. The SGLT2 inhibitor composition comprises about 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 14-18% anhydrous lactose, about 50-70% microcrystalline cellulose 302, about 10-22% pregelatinized starch, about 2-6% crospovidone, about 0.5-2.5% silicon dioxide and about 0.5-1.5% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is 300 mg. The film coating may be Opadry® II coating.

In another aspect, the present invention provides bilayer tablets in which the metformin (500 mg) XR composition comprises about 45-50% metformin hydrochloride (HCl), about 4-6% sodium carboxymethylcellulose, about 30-40% hydroxypropyl methylcellulose 2208, about 0.1-1.5% hydroxypropyl methylcellulose 2910, about 5-15% microcrystalline cellulose, about 0.75-1.25% silicon dioxide or about 0.25-0.75% colloidal silicon dioxide, and about 0.05-5% magnesium stearate. The SGLT2 inhibitor composition comprises about 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 14-18% anhydrous lactose, about 60-70% microcrystalline cellulose 302, about 5-15% hydroxypropyl cellulose EXF, about 2-6% crospovidone, about 0.5-2.5% silicon dioxide and about 0.5-1.5% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is 300 mg. The film coating may be Opadry® II coating.

In another aspect, the present invention provides bilayer tablets in which the metformin (500 mg) XR composition comprises about 45-50% metformin hydrochloride (HCl), about 4-6% sodium carboxymethylcellulose, about 30-40% hydroxypropyl methylcellulose 2208, about 0.1-1.5% hydroxypropyl methylcellulose 2910, about 5-15% microcrystalline cellulose, about 0.75-1.25% silicon dioxide or about 0.25-0.75% colloidal silicon dioxide, and about 0.05-5% magnesium stearate. The SGLT2 inhibitor composition comprises about 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 14-18% anhydrous lactose, about 55-65% microcrystalline cellulose 302, about 10-20% mannitol, about 2-6% crospovidone, about 0.5-2.5% silicon dioxide and about 0.5-1.5% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is 300 mg. The film coating may be Opadry® II coating.

In another aspect, the present invention provides bilayer tablets in which the metformin (500 mg) XR composition comprises about 45-50% metformin hydrochloride (HCl), about 4-6% sodium carboxymethylcellulose, about 30-40% hydroxypropyl methylcellulose 2208, about 0.1-1.5% hydroxypropyl methylcellulose 2910, about 5-15% microcrystalline cellulose, about 0.75-1.25% silicon dioxide or about 0.25-0.75% colloidal silicon dioxide, and about 0.05-5% magnesium stearate. The SGLT2 inhibitor composition comprises about 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% lactose anhydrous, about 74-77% microcrystalline cellulose 302, about 4% crospovidone, about 1.5% silicon dioxide and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is from about 300 mg to about 400 mg, wherein the preferred weight is 300 mg. The film coating may be Opadry® II coating.

The percentages of SGLT2 given above correspond to the active substance. The preferred active substance is dapagliflozin or dapagliflozin (S) propylene glycol hydrate. It should be understood that the percentages (amounts) given above for dapagliflozin in the form of propylene glycol hydrate will be higher compared to dapagliflozin not in the form of solvate/hydrate.

Various forms of the antidiabetic drug metformin are suitable for use in the bilayer tablet compositions of the present invention, including its pharmaceutically acceptable salts such as hydrochloride, hydrobromide, fumarate, succinate, p-chlorophenoxyacetate or embonate. The fumarate and succinate salts of metformin are preferably metformin (2:1) fumarate and metformin (2:1) succinate. Metformin hydrochloride is preferred.

The present invention also provides bilayer film-coated tablets, wherein the coating comprises saxagliptin or a pharmaceutically acceptable salt thereof. Saxagliptin is preferably in the form of a free base, a monohydrate or in the form of a hydrochloride. The film-coated tablet comprises a tablet core, a first coating, a second coating and, optionally, a third coating. The tablet core comprises metformin, preferably metformin hydrochloride. The first and second coatings optionally comprise saxagliptin, wherein at least only the first or the second coating comprises saxagliptin. The third coating is an optional outer protective coating. Saxagliptin, described below, can be prepared as described in U.S. Patent 6,395,767, the disclosure of which is incorporated herein by reference in its entirety. The first and second coatings are prepared in the same manner as the inner insulating layer of the coating or the middle (drug) layer of the coating, as described in WO 2005/117841, the disclosure of which is incorporated herein by reference in its entirety. The third coating is prepared in the same manner as the outer protective layer of the coating, as described in WO 2005/117841.

The first coating comprises up to 95% of the polymer based on the weight of the first coating. The composition comprises at least one polymer for the coating and a solvent for the coating, preferably the solvent is water used for applying the coating and removed during the drying process. The polymer for the first coating can be hydroxypropyl methylcellulose, polyvinyl alcohol (PVA), ethyl cellulose, methacrylic polymer or hydroxypropyl cellulose, preferably PVA. The first coating optionally comprises saxagliptin in the range of from about 0.5% to about 70%, preferably from about 30% to about 50%, based on the weight of the second coating. The first coating can optionally include a plasticizer such as triacetin, diethyl phthalate, tributyl sebacate or polyethylene glycol (PEG), preferably PEG; an anti-adhesive or glidant such as talc, colloidal silicon dioxide or magnesium stearate, and an opacifying agent such as titanium dioxide. The coating layer may also include iron oxide-based colorants. The coating material is commercially available under the trade names Opadry® HP or Opadry® II white.

The second shell is similar in composition to the first shell and preferably includes saxagliptin.

The third shell is similar in composition to the first shell, but does not include saxagliptin.

Thus, in one aspect, the present invention provides bilayer tablets that comprise: (1) a bilayer tablet core comprising two layers, wherein the first layer comprises metformin and the second layer comprises an SGLT2 inhibitor, wherein the weight of the second layer is from about 300 to about 400 mg, (2) a first coating that coats the bilayer tablet core and optionally comprises saxagliptin, (3) a second coating that coats the first coating and optionally comprises saxagliptin, and (4) optionally a third coating that coats the second coating, wherein at least the first coating or the second coating comprises saxagliptin.

Thus, in one aspect, the present invention provides bilayer tablets that comprise: (1) a bilayer tablet core comprising two layers, wherein the first layer comprises about 64-82% metformin hydrochloride, about 3-5% sodium carboxymethylcellulose, about 15-30% hydroxypropyl methylcellulose, about 0.1-0.75% magnesium stearate, and about 0.2% silicon dioxide or 0-1.5% colloidal silicon dioxide, and the second layer comprises about 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 14-18% anhydrous lactose, about 50-80% microcrystalline cellulose, about 0-20% pregelatinized starch, about 0-20% mannitol, about 0-15% hydroxypropyl cellulose, about 2-6% crospovidone, 0.5-2.5% silicon dioxide and about 0.5-2% magnesium stearate, wherein the weight of the second layer is from about 300 mg to about 400 mg (2) a first coating comprising a polyvinyl alcohol-based polymer (3) a second coating comprising saxagliptin and a polyvinyl alcohol-based polymer and (4) a third coating comprising a polyvinyl alcohol-based polymer.

In one aspect, the present invention provides bilayer tablets that comprise:

(1) a bilayer tablet core in which the first layer contains about 67-71% metformin hydrochloride, about 3-5% sodium carboxymethylcellulose, about 25-29% hydroxypropyl methylcellulose 2208, about 0.1-0.75% magnesium stearate, and the second layer contains:

(A) about 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 14-18% lactose anhydrous, about 72-80% microcrystalline cellulose 302, about 2-6% crospovidone, about 0.5-2.5% silicon dioxide, and about 0.5-1.5% magnesium stearate;

(B) about 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 14-18% anhydrous lactose, about 50-70% microcrystalline cellulose 302, about 10-22% pregelatinized starch, about 2-6% crospovidone, about 0.5-2.5% silicon dioxide, and about 0.5-1.5% magnesium stearate;

(C) about 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 14-18% lactose anhydrous, about 60-70% microcrystalline cellulose 302; about 5-15% hydroxypropyl cellulose EXF, about 2-6% crospovidone, about 0.5-2.5% silicon dioxide, and about 0.5-1.5% magnesium stearate, or

(D) about 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 14-18% lactose anhydrous, about 55-65% microcrystalline cellulose 302, about 10-20% mannitol, about 2-6% crospovidone, about 0.5-2.5% silicon dioxide, and about 0.5-1.5% magnesium stearate, wherein the weight of the second layer is from about 300 mg to about 400 mg;

(2) a first coating comprising Opadry® HP, (3) a second coating comprising saxagliptin and Opadry® HP, and (4) a third coating comprising Opadry® HP.

In one aspect, the present invention provides bilayer tablets that comprise:

(1) a bilayer tablet core in which the first layer contains about 69% metformin hydrochloride, about 3.5% sodium carboxymethylcellulose, about 27% hydroxypropyl methylcellulose 2208, and about 0.48% magnesium stearate, and the second layer contains:

(A) about 0.8% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% lactose anhydrous, about 77% microcrystalline cellulose 302, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate;

(B) about 1.7% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% lactose anhydrous, about 76% microcrystalline cellulose 302, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate;

(C) about 3.4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% lactose anhydrous, about 74% microcrystalline cellulose 302, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate;

(D) about 1.7% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% anhydrous lactose, about 64% microcrystalline cellulose 302, about 13% pregelatinized starch, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate;

(E) about 1.7% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% anhydrous lactose, about 57% microcrystalline cellulose 302, about 19% pregelatinized starch, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate;

(F) about 1.7% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% lactose anhydrous, about 66% microcrystalline cellulose 302, about 10% hydroxypropyl cellulose EXF, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate, or

(G) about 1.7% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% lactose anhydrous, about 61% microcrystalline cellulose 302, about 15% mannitol, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate, wherein the weight of the second layer is from about 300 mg to about 400 mg

(2) a first coating comprising Opadry® HP, (3) a second coating comprising saxagliptin and Opadry® HP, and (4) a third coating comprising Opadry® HP.

In one aspect, the present invention provides bilayer tablets that comprise:

(1) a bilayer tablet core in which the first layer comprises about 72-82% metformin hydrochloride, about 3-5% sodium carboxymethylcellulose, about 15-22% hydroxypropyl methylcellulose 2208, about 0.75-1.25% silicon dioxide or about 0.25-0.75% colloidal silicon dioxide and about 0.1-0.6% magnesium stearate, and the second layer comprises:

(A) about 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 14-18% lactose anhydrous, about 72-80% microcrystalline cellulose 302, about 2-6% crospovidone, about 0.5-2.5% silicon dioxide, and about 0.5-1.5% magnesium stearate;

(B) about 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 14-18% anhydrous lactose, about 50-70% microcrystalline cellulose 302, about 10-22% pregelatinized starch, about 2-6.00% crospovidone, about 0.5-2.5% silicon dioxide, and about 0.5-1.5% magnesium stearate;

(C) about 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 14-18% lactose anhydrous, about 60-70% microcrystalline cellulose 302; about 5-15% hydroxypropyl cellulose EXF, about 2-6% crospovidone, about 0.5-2.5% silicon dioxide, and about 0.5-1.5% magnesium stearate, or

(D) about 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 14-18% lactose anhydrous, about 55-65% microcrystalline cellulose 302, about 10-20% mannitol, about 2-6% crospovidone, about 0.5-2.5% silicon dioxide, and about 0.5-1.5% magnesium stearate, wherein the weight of the second layer is from about 300 mg to about 400 mg;

(2) a first coating comprising Opadry® HP, (3) a second coating comprising saxagliptin and Opadry® HP, and (4) a third coating comprising Opadry® HP.

In one aspect, the present invention provides bilayer tablets that comprise:

(1) a bilayer tablet core wherein the first layer comprises about 76.6% metformin hydrochloride, about 3.84% sodium carboxymethylcellulose, about 18% hydroxypropyl methylcellulose 2208, about 0.75-1.25% silicon dioxide or about 0.25-0.75% colloidal silicon dioxide and about 0.53% magnesium stearate, and the second layer comprises:

(A) about 0.8% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% lactose anhydrous, about 77% microcrystalline cellulose 302, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate;

(B) about 1.7% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% lactose anhydrous, about 76% microcrystalline cellulose 302, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate;

(C) about 3.4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% lactose anhydrous, about 74% microcrystalline cellulose 302, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate;

(D) about 1.7% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% anhydrous lactose, about 64% microcrystalline cellulose 302, about 13% pregelatinized starch, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate;

(E) about 1.7% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% anhydrous lactose, about 57% microcrystalline cellulose 302, about 19% pregelatinized starch, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate;

(F) about 1.7% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% lactose anhydrous, about 66% microcrystalline cellulose 302, about 10% hydroxypropyl cellulose EXF, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate, or

(G) about 1.7% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, about 16% lactose anhydrous, about 61% microcrystalline cellulose 302, about 15% mannitol, about 4% crospovidone, about 1.5% silicon dioxide, and about 1% magnesium stearate, wherein the weight of the second layer is from about 300 mg to about 400 mg

(2) a first coating comprising Opadry® HP, (3) a second coating comprising saxagliptin and Opadry® HP, and (4) a third coating comprising Opadry® HP.

In one aspect, the present invention provides a film-coated tablet that comprises a tablet core coated with a first coating optionally comprising saxagliptin, a second coating optionally comprising saxagliptin, and optionally a third coating. The tablet core comprises metformin, wherein metformin hydrochloride is preferred. At least the first and second coating comprises saxagliptin. The first and second coatings are prepared in the same manner as the inner insulating coating layer or the middle (drug) coating layer as described in WO 2005/117841, the disclosure of which is incorporated herein by reference in its entirety. The third coating is prepared in the same manner as the outer protective coating layer as described in WO 2005/117841.

In another aspect, the present invention provides a film-coated tablet comprising: (1) a tablet core that comprises metformin, (2) a first coating that coats the tablet core and optionally includes saxagliptin, (3) a second coating that coats the first coating and optionally includes saxagliptin, and (4) optionally a third coating that coats the second coating, wherein at least the first coating or the second coating comprises saxagliptin.

In another aspect, the present invention provides a film-coated tablet comprising: (1) a tablet core that comprises about 72-82% metformin hydrochloride, about 3-5% sodium carboxymethylcellulose, about 15-22% hydroxypropyl methylcellulose 2208, about 0.75-1.25% silicon dioxide or about 0.25-0.75% colloidal silicon dioxide, and about 0.1-0.6% magnesium stearate, (2) a first coating comprising a polyvinyl alcohol polymer, (3) a second coating comprising saxagliptin and a polyvinyl alcohol polymer, and (4) a third coating comprising a polyvinyl alcohol polymer.

In another aspect, the present invention provides a film-coated tablet comprising: (1) a tablet core that comprises about 76.6% metformin hydrochloride, about 3.84% sodium carboxymethylcellulose, about 18% hydroxypropyl methylcellulose 2208, about 0.75-1.25% silicon dioxide or about 0.25-0.75% colloidal silicon dioxide, and about 0.53% magnesium stearate, (2) a first coating comprising Opadry® HP, (3) a second coating comprising saxagliptin and Opadry® HP, and (4) a third coating comprising Opadry® HP.

In another aspect, the present invention provides a film-coated tablet comprising: (1) a tablet core that comprises about 76.6% metformin hydrochloride, about 3.84% sodium carboxymethylcellulose, about 18% hydroxypropyl methylcellulose 2208, about 1% silicon dioxide, and about 0.53% magnesium stearate, (2) a first coating comprising Opadry® HP, (3) a second coating comprising saxagliptin and Opadry® HP, and (4) a third coating comprising Opadry® HP.

In another aspect, the present invention provides a film-coated tablet comprising: (1) a tablet core that comprises about 76.6% metformin hydrochloride, about 3.84% sodium carboxymethylcellulose, about 18% hydroxypropyl methylcellulose 2208, about 1% silicon dioxide, and about 0.53% magnesium stearate, (2) a first coating comprising about 2% Opadry® HP, (3) a second coating comprising about 1.25% saxagliptin and 10% Opadry® HP, and (4) a third coating comprising about 2% Opadry® HP

In another aspect, the present invention provides a combination therapy that comprises the bilayer tablets of the present invention in combination with one or more drugs selected from: antidiabetic agents, antihyperglycemic agents; hypolipidemic/lipid-lowering agents, antiobesity agents; antihypertensive agents, appetite suppressants; insulin secretagogues, insulin sensitizers, glucokinase activators, glucocorticoid antagonists, fructose-1,6-bis-phosphatase inhibitors, AMP kinase activators, incretin pathway modulators such as incretin secretagogues such as GPR119 or GPR40 agonists, incretin mimics such as Byetta, incretin action enhancers, bile acid sequestrants or bile acid receptor agonists such as TGR5 agonists, dopamine receptor agonists such as Cycloset, aldose reductase inhibitors, PPARγ agonists, PPARα agonists, PPARδ antagonists or agonists, dual PPARα/γ agonists, 11-β-HSD-1 inhibitors, dipeptide peptide IV (DPP4) inhibitors other than saxagliptin, SGLT2 inhibitors other than dapagliflozin, glucagon-like peptide-1 (GLP-1), GLP-1 agonists, and PTP-1B inhibitors. In addition, weight-loss agents that act by decreasing food intake such as sibutramine, CB1 antagonists, 5HT2C agonists, MCHR1 antagonists, as well as agents that decrease nutrient absorption (eg, lipase inhibitors (orlistat)), and agents that increase energy expenditure such as thyromimetics, or that slow gastrointestinal motility such as amylin mimetics or ghrelin antagonists may be used.

Examples of suitable antidiabetic agents for use in combination with the compositions of the present invention include, but are not limited to, alpha-glucosidase inhibitors (acarbose or miglitol), insulin (including insulin secretagogues or insulin sensitizers), meglitinides (repaglinide), sulfonylureas (glimepiride, glibenclamide, gliclazide, chlorpropamide, and glipizide), biguanide/glyburide combinations (Glucovance®), thiazolidinediones (e.g., troglitazone, rosiglitazone, and pioglitazone), PPAR alpha agonists, PPAR gamma agonists, dual PPAR alpha/gamma agonists, glycogen phosphorylase inhibitors, fatty acid binding protein (aP2) inhibitors, GPR-119, GPR 40 modulators, glucokinase inhibitors, glucagon-like peptide-1 (GLP-1) and other GLP-1 receptor agonists, SGLT2 inhibitors other than dapagliflozin, and dipeptidyl peptidase IV (DPP4) inhibitors other than saxagliptin.

Other suitable thiazolidinediones include, but are not limited to, MCC-555 (described in U.S. Patent No. 5,594,016, Mitsubishi), faraglitazone (GI-262,570, Glaxo-Wellcome), englitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer, isaglitazone, MIT/Johnson & Johnson), reglitazone (JTT-501 (JPNT/Pharmacia & Upjohn), rivoglitazone (R-119702, Sankyo/WL), liraglutide (NN-2344, Dr. Reddy/NN), and (Z) 1,4-bis-4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl-methyl)]phenoxybut-2-ene (YM-440, Yamanouchi).

Examples of PPAR alpha agonists, PPAR gamma agonists, and dual PPAR alpha/gamma agonists include, but are not limited to, muraglitazar, peliglitazar, tesaglitazar AR-HO39242 (Astra/Zeneca), GW-501516 (Glaxo-Wellcome), KRP297 (Kyorin Merck), and the agents disclosed by Murakami et al., in "A Novel Insulin Sensitizer Acts As a Coligand for Peroxisome Proliferation - Activated Receptor Alpha (PPAR alpha) and PPAR gamma. Effect on PPAR alpha Activation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats", Diabetes 47, 1841-1847 (1998); in WO 01/21602 and in U.S. Patent No. 6,414,002 and U.S. Patent No. 6,653,314, the disclosures of which are incorporated herein by reference in their entireties, and the dosages given herein may be used. In one embodiment, the compounds cited as preferred in the cited references are preferred for use herein.

Suitable aP2 inhibitors include, but are not limited to, those described in U.S. Application Ser. No. 09/391,053, filed September 7, 1999, and U.S. Pat. No. 6,548,529, the disclosures of which are hereby incorporated by reference in their entireties, and the dosages described therein may be used.

Suitable DPP4 inhibitors include, but are not limited to, sitagliptin and vildagliptin, as well as the agents disclosed in WO 99/38501, WO 99/46272, WO 99/67279 (PROBIODRUG), WO 99/67278 (PROBIODRUG), WO 99/61431 (PROBIODRUG) NVP-DPP728A (1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine) (Novartis), as disclosed by Hughes et al, Biochemistry, 38(36), 11597-11603, 1999, TSL-225 (tryptophyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (disclosed by Yamada et al, Bioorg. & Med. Chem. Lett. 8 (1998) 1537-1540), 2-cyanopyrrolilides and 4-cyanopyrrolilides as disclosed by Ashworth et al, Bioorg. & Med. Chem. Lett., Vol. 6, No. 22, pp 1163-1166 and 2745-2748 (1996), compounds described in U.S. Application Ser. No. 10/899,641, the disclosures of which are hereby incorporated by reference in their entireties, and the dosages given in said references may be used.

Suitable SGLT2 inhibitors for the provided film-coated bilayer tablets of the present invention and for the bilayer tablet combination therapy of the present invention include sergliflozin, remogliflozin, remogliflozin etabonate, canagliflozin, BI-10773 and BI-44847, ASP-1941, P-7201, LX-4211, YM-543, PR 2268, TS-033 or SGL-0100, as well as the compounds disclosed in US 7,589,193, WO 2007007628, EP 2009010, WO 200903596, US 2009030198, US 7,288,528 and US 2007/0197623, the disclosures of which are incorporated herein in their entireties. the present invention by reference. The following SGLT2 inhibitors are preferred

Suitable meglitinides include nateglinide (Novartis) or KAD1229 (PF/Kissei).

Examples of suitable antihyperglycemic agents for use in combination with the compositions of the present invention include, but are not limited to, glucagon-like peptide-1 (GLP-1) such as GLP-1(1-36) amide, GLP-1(7-36) amide, GLP-1(7-37) (as described in U.S. Patent No. 5,614,492, incorporated herein by reference in its entirety), as well as exenatide (Amylin/Lilly), LY-315902 (Lilly), MK-0431 (Merck), liraglutide (NovoNordisk), ZP-10 (Zealand Pharmaceuticals A/S), CJC-1131 (Conjuchem Inc), and the compounds described in WO 03/033671, the disclosure of which is incorporated herein by reference in its entirety.

Examples of hypolipidemic/lipid-lowering agents suitable for use in combination with the compositions of the present invention include one or more agents selected from MTP inhibitors, HMG-CoA reductase inhibitors, squalene synthetase inhibitors, fibric acid derivatives, ACAT inhibitors, lipoxygenase inhibitors, cholesterol uptake inhibitors, ileal Na ⁺ and bile acid cotransporter inhibitors, LDL receptor activators, bile acid excretion enhancers, cholesterol ester transfer protein inhibitors (e.g., CETP inhibitors such as torcetrapib (CP-529414, Pfizer) and JTT-705 (Akros Pharma)), PPAR agonists (as described above) and/or nicotinic acid and derivatives thereof. The hypolipidemic agent may be an LD2 receptor activator such as 3-(13-hydroxy-10-oxotetradecyl)-5,7-dimethoxy-1(3H)-isobenzofuranone (MD-700, Taisho Pharmaceutical Co. Ltd) and 4-(2-propenyl)-(3a,4a,5a)-cholestan-3-ol (LY295427, Eli Lilly). Preferred hypolipidemic agents include, for example, pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, atavastatin and rosuvastatin (ZD-4522).

Examples of MTP inhibitors that can be used as described above include, but are not limited to, those disclosed in U.S. Patent No. 5,595,872, U.S. Patent No. 5,739,135, U.S. Patent No. 5,712,279, U.S. Patent No. 5,760,246, U.S. Patent No. 5,827,875, U.S. Patent No. 5,885,983, and U.S. Patent No. 5,962,440, the disclosures of which are herein incorporated by reference in their entireties.

Examples of HMG-CoA reductase inhibitors that may be used in combination with the compositions of the present invention include, but are not limited to, mevastatin and related compounds as described in U.S. Patent No. 3,983,140, lovastatin (mevinoline) and related compounds as described in U.S. Patent No. 4,231,938, pravastatin and related compounds as described in U.S. Patent No. 4,346,227, simvastatin and related compounds as described in U.S. Patent Nos. 4,448,784 and 4,450,171. Other suitable HMG-CoA reductase inhibitors that may be used herein include, but are not limited to, fluvastatin as disclosed in U.S. Patent No. 5,354,772, cerivastatin as disclosed in U.S. Patents Nos. 5,006,530 and 5,177,080, atorvastatin disclosed in U.S. Patent Nos. 4,681,893, 5,273,995, 5,385,929 and 5,686,104, atavastatin (nisvastatin Nissan/Sankyo (NK-104)), disclosed in U.S. Patent No. 5,011,930, rosuvastatin (Shionogi-Astra/Zeneca (ZD-4522)), disclosed in U.S. Patent No. 5,260,440 and statin-related compounds disclosed in U.S. Patent No. 5,753,675, pyrazole-based mevalonolactone derivative analogs disclosed in U.S. Patent No. 4,613,610, indene-based mevalonolactone derivative analogs disclosed in PCT application WO 86/03488, 6-[2-(substituted pyrrol-1-yl)-alkyl)pyran-2-ones and derivatives thereof disclosed in U.S. Patent No. 4,647,576, Searle's SC-45355 dichloroacetate (a 3-substituted pentanedionic acid derivative), imidazole-based mevalonolactone analogues disclosed in PCT application WO 86/07054, 3-carboxy-2-hydroxypropane-phosphonic acid as described in French Patent No. 2,596,393, 2,3-substituted pyrrole, furan and thiophene derivatives as described in European Patent Application No. 0221025, naphthyl-based mevalonolactone analogues as described in U.S. Patent No. 4,686,237, octahydronaphthalenes as described in U.S. Patent No. 4,499,289, keto analogues of mevinoline (lovastatin) as described in European Patent Application No. 0142146 A2, and quinoline and pyridine derivatives as described in U.S. Patents Nos. 5,506,219 and 5,691,322. All documents incorporated by reference herein are hereby incorporated in their entireties. In addition, phosphinic acids useful for inhibiting HMG-CoA reductase, such as those described in GB 2205837, are suitable for use in combination with the compositions of the present invention.

Examples of squalene synthetase inhibitors suitable for use herein include, but are not limited to, the α-phosphonosulfonates disclosed in U.S. Patent No. 5,712,396, disclosed by Biller et al., J. Med. Chem., 1988, Vol. 31, No. 10, pp. 1869-1871, including isoprenoid (phosphinyl-methyl) phosphonates, as well as other known squalene synthetase inhibitors, such as those disclosed in U.S. Patents 4,871,721 and 4,924,024 and Biller, S. A., Neuenschwander, K., Ponpipom, M. M., Poulter, C. D., Current Pharmaceutical Design, 2, 1-40 (1996). Other squalene synthetase inhibitors suitable for use herein include the terpenoid pyrophosphates disclosed by P. Ortiz de Montellano et al, J. Med. Chem., 1977, 20, 243-249; the farnesyl diphosphate analog A and presqualene pyrophosphate analogs (PSQ-PP) disclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293; the phosphinyl phosphonates disclosed by McClard, RW et al, JACS, 1987, 109, 5544; and the cyclopropanes disclosed by Capson, TL, PhD dissertation, June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp 16, 17, 40-43, 48-51, Summary. All documents referenced herein are incorporated herein in their entireties.

Examples of fibric acid derivatives that may be used in combination with the compositions of the invention include, but are not limited to, fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like, probucol and related compounds as disclosed in U.S. Patent No. 3,674,836, bile acid sequestrants such as cholestyramine, colestipol and DEAE-Sephadex (Secholex®, Policexide®), as well as lipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanolamine derivative), imanixilon (HOE-402), tetrahydrolipstatin (THL), istigmastanylphosphorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (an azulene derivative), melinamide (Sumitomo), Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546 (a disubstituted urea derivative), nicotinic acid, acipimox, acifrane, neomycin, p-aminosalicylic acid, aspirin, poly(diallylmethylamine) derivatives such as those disclosed in U.S. Patent No. 4,759,923, quaternary amines poly(diallyldimethylammonium chloride) and ionenes such as those disclosed in U.S. Patent No. 4,027,009, and other art-known cholesterol-lowering agents. In one embodiment, the fibric acid derivative is probucol or gemfibrozil. All documents incorporated by reference herein are hereby incorporated in their entireties.

Examples of ACAT inhibitors that may be used in combination with the compositions of the present invention include, but are not limited to, those described in Drugs of the Future 24, 9-15 (1999), (Avasimibe); and in the articles "The ACAT inhibitor, Cl-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters", Nicolosi et al., Atherosclerosis (Shannon, Irel) (1998), 137(1), 77-85; "The pharmacological profile of FCE 27677: a novel ACAT inhibitor with potent hypolipidemic activity mediated by selective suppression of the hepatic secretion of ApoB100-containing lipoprotein", Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1), 16-30; "RP 73163: a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor", Smith, S. et al., Bioorg. Med. Chem. Lett. (1996), 6(1), 47-50; "ACAT inhibitors: physiologic mechanisms for hypolipidemic and anti-atherosclerotic activities in experimental animals", Krause et al., edited by Ruffolo, Robert R. Jr.; Hollinger, Mannfred A., Inflammation: Mediators and Pathways (1995), 173-98, Publisher: CRC, Boca Raton, Florida; "ACAT inhibitors: potential anti-atherosclerotic agents", Sliskovic et al., Curr. Med. Chem. (1994), 1(3), 204-25; "Inhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. The first water-soluble ACAT inhibitor with lipid-regulating activity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). Development of a series of substituted N-phenyl-N'-[(1-phenylcyclopentyl)methyl]ureas with enhanced hypocholesterolemic activity", Stout et al., Chemtracts: Org. Chem. (1995), 8(6), 359-62, or TS-962 (Taisho Pharmaceutical Co. Ltd). All of the cited references are herein incorporated by reference in their entireties.

Examples of suitable cholesterol uptake inhibitors for use in combination with the compositions of the present invention include, but are not limited to, SCH48461 (Schering-Plough), as well as the inhibitors disclosed in Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998), which are hereby incorporated by reference in their entireties.

Examples of suitable ileal Na+ and bile acid cotransporter inhibitors for use in combination with the compositions of the present invention include, but are not limited to, the compounds disclosed in Drugs of the Future, 24, 425-430 (1999), which is incorporated herein by reference in its entirety.

Examples of lipoxygenase inhibitors suitable for use in combination with the compositions of the present invention include, but are not limited to, 15-lipoxygenase (15-LO) inhibitors such as benzimidazole derivatives, such as those disclosed in WO 97/12615, 15-LO inhibitors, such as those disclosed in WO 97/12613, isothiazolones, such as those disclosed in WO 96/38144, and 15-LO inhibitors described by Sendobry et al., "Attenuation of diet-induced atherosclerosis in rabbits with a highly selective 15-lipoxygenase inhibitor lacking significant antioxidant properties", Brit. J. Pharmacology (1997) 120, 1199-1206, and Cornicelli et al., "15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target for Vascular Disease," Current Pharmaceutical Design, 1999, 5, 11-20. All references cited herein are hereby incorporated by reference in their entireties.

Examples of suitable antihypertensive agents for use in combination with the compositions of the present invention include, but are not limited to, beta-blockers, calcium channel blockers (L-type and T-type channels, such as diltiazem, verapamil, nifedipine, amlodipine and mibefradil), diuretics (e.g. chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichlormethiazide, polythiazide, benzthiazide, ethacrynic acid, tricrinafen, chlorthalidone, furosemide, muzolimine, bumetanide, triamtrenene, amiloride, spironolactone), renin inhibitors, ACE (e.g. captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists (e.g. losartan, irbesartan, valsartan), ET receptor antagonists (e.g. sitaxentan, atrsentan and the compounds described in U.S. Patent Nos. 5,612,359 and 6,043,265), dual ET/AII antagonists (e.g. the compounds described in WO 00/01389), neutral endopeptidase (NEP) inhibitors, vasopeptidase inhibitors (dual NEP-ACE inhibitors) (e.g. omapatrilat and hemopatrilat) and nitrates. All cited materials are hereby incorporated by reference in their entirety.

Examples of suitable anti-obesity agents for use in combination with the compositions of the present invention include, but are not limited to, beta3-adrenergic receptor agonists, lipase inhibitors, serotonin (and dopamine) reuptake inhibitors, thyroid beta receptor acting drugs, 5HT2C agonists (e.g., Arena APD-356); MCHR1 antagonists such as Synaptic SNAP-7941 and Takeda T-226926, melanocortin receptor (MC4R) agonists, melanin-enriching hormone receptor (MCHR) antagonists (e.g., Synaptic SNAP-7941 and Takeda T-226926), galanin receptor modulators, orexin antagonists, CCK agonists, NPY1 or NPY5 antagonists, NPY2 and NPY4 modulators, corticotropin releasing factor agonists, histamine 3 (H3) receptor modulators, 11-beta-HSD-1 inhibitors, adinopectin receptor modulators, monoamine reuptake inhibitors or monoamine releasing agents, ciliary neurotrophic factors (CNTF, such as AXOKINE® from Regeneron), BDNF (brain-derived neurotrophic factor), leptin and leptin receptor modulators, cannabinoid receptor 1 antagonists (e.g., SR-141716 (Sanofi) or SLV-319 (Solvay)) and anorexigenic agents.

Beta3-adrenergic receptor agonists suitable for use in combination with the compositions of the present invention include, but are not limited to, AJ9677 (Takeda/Dainippon), L750355 (Merck), CP331648 (Pfizer), and other known beta3-agonists, such as those disclosed in U.S. Patent Nos. 5,541,204, 5,770,615, 5,491,134, 5,776,983, and 5,488,064, which are herein incorporated by reference in their entireties.

Examples of lipase inhibitors that may be used in combination with the compositions of the present invention include, but are not limited to, orlistat and ATL-962 (Alizyme).

Serotonin (and dopamine) reuptake inhibitors (or serotonin receptor agonists) that may be used in combination with the compositions of the present invention include, but are not limited to, BVT-933 (Biovitrum), sibutramine, topiramate (Johnson & Johnson), and axokine (Regeneron).

Examples of thyroid receptor beta-active compounds that may be used in combination with the compositions of the present invention include, but are not limited to, thyroid receptor ligands such as those disclosed in WO 97/21993 (The University of California, San Francisco), WO 99/00353 (KaroBio), and WO 00/039077 (KaroBio), the disclosures of which are incorporated herein by reference in their entireties.

Examples of monoamine reuptake inhibitors that may be used in combination with the compositions of the present invention include, but are not limited to, fenfluramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, chlorphentermine, cloforex, clortermine, picilorex, sibutramine, dexamphetamine, phentermine, phenylpropanolamine, and mazindol.

Anorexigenic agents that may be used in combination with the compositions of the present invention include, but are not limited to, topiramate (Johnson & Johnson), dexamphetamine, phentermine, phenylpropanolamine, and mazindol.

The said patents and patent applications are incorporated herein by reference in their entirety.

If any of the compositions of the invention are used in combination with other therapeutic agent(s), the other therapeutic agent(s) may be used in amounts such as those described in the Physician's Desk Reference Encyclopedia of Drugs, or those described in the patents and patent applications cited above, or those known from other sources and used by one of ordinary skill in the art.

The present invention provides bilayer tablets that comprise (1) a reduced weight metformin composition, (2) a canagliflozin composition, and (3), optionally, a coating. Thus, in one aspect, the present invention relates to a bilayer tablet, wherein (1) the first layer comprises about 72-82% metformin hydrochloride, about 3-5% sodium carboxymethylcellulose, about 15-22% hydroxypropyl methylcellulose 2208, about 0.75-1.25% silicon dioxide or about 0.25-0.75% colloidal silicon dioxide, and about 0.1-0.6% magnesium stearate, (2) the second layer comprises canagliflozin, and (3) the optionally present coating comprises Opadry® II.

In another aspect, the present invention provides bilayer tablets, wherein (1) the first layer comprises about 76.6% metformin hydrochloride, about 3.84% sodium carboxymethylcellulose, about 18% hydroxypropyl methylcellulose 2208, about 0.75-1.25% silicon dioxide or about 0.25-0.75% colloidal silicon dioxide and about 0.53% magnesium stearate, (2) the second layer comprises canagliflozin and (3) the optional coating comprises Opadry® II.

In another aspect, the present invention provides bilayer tablets, wherein (1) the first layer comprises about 76.6% metformin hydrochloride, about 3.84% sodium carboxymethylcellulose, about 18% hydroxypropyl methylcellulose 2208, about 0.75-1.25% silicon dioxide or about 0.25-0.75% colloidal silicon dioxide and about 0.53% magnesium stearate, (2) the second layer comprises canagliflozin and (3) the optional coating comprises Opadry® II.

Examples of fillers or filling agents suitable for use in the present invention include, but are not limited to, cellulose derivatives such as microcrystalline cellulose or wood cellulose (including microcrystalline cellulose 302), lactose, anhydrous lactose, sucrose, starch, pregelatinized starch, glucose, mannitol (including mannitol Pearlitol SD 200), fructose, xylitol, sorbitol, corn starch, modified corn starch, inorganic salts such as calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dextrin/dextrates, maltodextrin, compressed sugar and other known fillers or filling agents and/or mixtures of two or more thereof. Several types of microcrystalline cellulose are suitable for use in the compositions described herein, such as microcrystalline cellulose selected from Avicel® type PH101, PH102, PH103, PH105, 112 PH, PH113, PH200, PH301, and other types of microcrystalline cellulose such as silicified microcrystalline cellulose. Several types of lactose are suitable for use in the compositions described herein, such as selected from the group consisting of anhydrous lactose, lactose monohydrate, Fast Flo lactose, direct compression anhydrous lactose, and modified lactose monohydrate.

Examples of suitable binders for use in the present invention include, but are not limited to, carboxymethylcellulose (including sodium carboxymethylcellulose), hydroxypropylcellulose (including hydroxypropylcellulose EXF), corn starch, pregelatinized starch, modified corn starch, polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC) (including hydroxypropyl methylcellulose 2208), lactose, gum arabic, ethylcellulose, cellulose acetate, and wax such as carnauba wax, paraffin, spermaceti, polyethylene or microcrystalline wax, as well as other conventional binders and/or mixtures of two or more thereof.

Examples of suitable disintegrants for use in the present invention include, but are not limited to, croscarmellose sodium, crospovidone, starch, potato starch, pregelatinized starch, corn starch, sodium starch glycolate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and other known disintegrants. Several specific types of disintegrants are suitable for use in the compositions described herein. For example, any type of crospovidone can be used, including, for example, crospovidone XL-10, including a crospovidone selected from the group consisting of Kollidon CL®, Polyplasdone XL®, Kollidon CL-M®, Polyplasdone XL-10®, and Polyplasdone INF-10®. In one embodiment, the disintegrant of the granular mass, if present in the composition, is sodium starch glycolate, sodium croscarmellose and/or crospovidone.

Examples of suitable lubricants for use in the present invention include, but are not limited to, magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, palmitic acid, sodium stearyl fumarate, sodium lauryl sulfate, glyceryl palmitostearate, palmitic acid, myristic acid, and hydrogenated vegetable oils and fats, as well as other known lubricants and/or mixtures of two or more thereof.

Examples of suitable glidants and/or anti-adhesive agents for use in the present invention include, but are not limited to, silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc and other forms of silicon dioxide such as aggregated silicates and hydrated silicon dioxide.

Examples of suitable release modifiers include, but are not limited to, hydroxypropyl methylcellulose, polyvinyl alcohol (PVA), ethyl cellulose, methacrylic polymers, hydroxypropyl cellulose, starch, gums, cellulose ethers, protein-derived materials, nylon, acrylic resins, polylactic acid, polyvinyl chloride, polyvinylpyrrolidone, and cellulose acetate phthalate.

In one aspect, the present invention relates to methods for treating diseases or disorders associated with SGLT2 activity, comprising administering to a mammal, preferably a human, in need of such treatment, a therapeutically effective amount of a bilayer tablet comprising a metformin XR composition or a reduced weight metformin XR composition, an SGLT2 inhibitor composition and, optionally, a film coating. The bilayer tablets of the present invention as described herein can be administered to mammals, preferably humans, for the treatment of diabetes (including type I and type II diabetes), impaired glucose tolerance, insulin resistance and diabetic complications such as nephropathy, retinopathy, neuropathy and cataract, hyperglycemia, hyperinsulinemia, hypercholesterolemia, dyslipidemia, elevated levels of free fatty acids and glycerol in the blood, hyperlipidemia, hypertriglyceridemia, obesity, wound healing, treatment of tissue ischemia, atherosclerosis and hypertension. In a preferred embodiment, the bilayer tablet composition of the present invention is administered to humans for the treatment of type II diabetes mellitus.

In another aspect, the present invention provides the use of a bilayer tablet comprising a metformin XR composition or a reduced weight metformin XR composition, an SGLT2 inhibitor composition and, optionally, a film coating, for the preparation or for the manufacture of a medicament for the treatment of diabetes mellitus (including type I and type II diabetes), impaired glucose tolerance, insulin resistance and diabetic complications such as nephropathy, retinopathy, neuropathy and cataract, hyperglycemia, hyperinsulinemia, hypercholesterolemia, dyslipidemia, increased levels of free fatty acids and glycerol in the blood, hyperlipidemia, hypertriglyceridemia, obesity, for wound healing, treatment of tissue ischemia, atherosclerosis and hypertension.

Definitions

The term "about" as used herein means a deviation within 10%, more preferably within 5%, even more preferably within 2% of the stated number.

The term "dapagliflozin" as used herein means the compound of Example 1 and includes pharmaceutically acceptable salts thereof.

The term "dapagliflozin (S) PGS" as used herein means the compound of Example 2 dapagliflozin (S) propylene glycol hydrate (1:1:1).

The term "dapagliflozin (R) PGS" as used herein means the compound of Example 3 dapagliflozin (R) propylene glycol hydrate (1:1:1).

The term "metformin extended release" or "metformin XR" as used herein refers to a quantity of metformin HCl that is present in a dosage form that allows for controlled release oral delivery, releasing the drug (metformin HCl) over an extended period of time after administration while maintaining the desired plasma drug level.

The term "Opadry® II" as used herein means a film coating for tablets, including bilayer tablets, which comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol (PEG) and talc. Opadry® II white 85F18422 comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc. Opadry® II Yellow 85F92582 comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc and yellow iron oxide.

The term "Opadry® HP" as used herein refers to a film-coated tablet composition comprising 40% polyvinyl alcohol, 20% polyethylene glycol, 15% talc and 25% titanium dioxide.

Human studies

In a 24-week phase 3 clinical trial, the combination of metformin and dapagliflozin, an SGLT2 inhibitor, reduced glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG) in patients with type 2 diabetes. HbA1c and FPG were not adequately controlled with metformin monotherapy, as demonstrated by placebo plus metformin. The study also showed that patients receiving dapagliflozin experienced statistically greater mean weight loss compared to patients receiving placebo.

The study was conducted to evaluate the efficacy and safety of dapagliflozin as an add-on to metformin for 24 weeks in patients with poorly controlled type 2 diabetes. Data are from a randomized, double-blind, placebo-controlled trial of 546 patients with type 2 diabetes whose HbA1c was greater than or equal to 7.0 percent and less than or equal to 10 percent at baseline. After a two-week run-in period, patients were randomly assigned to one of four separate treatment groups: dapagliflozin 2.5 mg (n=137), dapagliflozin 5 mg (n=137), dapagliflozin 10 mg (n=135), or placebo (n=137). Patients in all groups also received metformin (at a dose greater than or equal to 1500 mg/day). The primary endpoint of the study compared the change in HbA1c from baseline for each group after 24 weeks of treatment with dapagliflozin compared with placebo. Secondary endpoints included change in FPG from baseline and change in body weight at week 24 compared with placebo, and the adjusted percentage of dapagliflozin-treated patients who achieved an HbA1c of less than 7 percent at 24 weeks. Exploratory endpoints included weight reduction greater than or equal to 5 percent or greater than or equal to 10 percent, and percent change in body weight from baseline.

After 24 weeks, patients receiving dapagliflozin 2.5 mg, 5 mg, and 10 mg plus metformin demonstrated statistically significant adjusted mean changes from baseline in HbA1c of 0.67 percent, 0.70 percent, and 0.84 percent, respectively, compared with 0.30 percent in the placebo group. Patients receiving dapagliflozin demonstrated statistically significant adjusted mean changes from baseline in FPG, a secondary endpoint, at week 24: -17.8 mg/dL for 2.5 mg dapagliflozin, -21.5 mg/dL for 5 mg dapagliflozin, and -23.5 mg/dL for 10 mg dapagliflozin, compared with -6.0 mg/dL for placebo.

The study also assessed the potential effect of dapagliflozin on weight loss. Observations included measuring changes in total body weight over the 24-week study period. At week 24, the change in total body weight in kg, a secondary endpoint, was 2.21 kg for 2.5 mg dapagliflozin, 3.04 kg for 5 mg dapagliflozin, and 2.86 kg for 10 mg dapagliflozin, compared with 0.89 kg in the placebo group. Overall, more patients receiving dapagliflozin achieved a weight loss of greater than or equal to 5 percent, the exploratory endpoint, compared with the placebo group.

These results indicate that the combination of an SGLT2 inhibitor, specifically dapagliflozin or dapagliflozin (S) propylene glycol hydrate, with metformin effectively treats hyperglycemia in patients with type 2 diabetes without causing weight gain.

Example 1

Dapagliflozin (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

Dapagliflozin can be prepared using procedures similar to those described in US Patent No. 6,515,117 or International Applications WO 03/099836 and WO 2008/116179, the disclosures of which are incorporated herein by reference in their entireties. SGLT2 EC ₅₀ = 1.1 nM.

Example 2

Dapagliflozin (S) PGS (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(S)-propane-1,2-diol hydrate (1:1:1)

Dapagliflozin (S) propylene glycol hydrate (1:1:1) can be prepared using procedures similar to those described in International Applications WO 08/002824 and WO 2008/116179, the disclosures of which are incorporated herein by reference in their entireties. SGLT2 EC ₅₀ = 1.1 nM.

Example 3

Dapagliflozin (R) PGS (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(R)-propane-1,2-diol hydrate (1:1:1)

Dapagliflozin (R) propylene glycol hydrate (1:1:1) can be prepared using procedures similar to those described in International Applications WO 08/002824 and WO 2008/116179, the disclosures of which are incorporated herein by reference in their entireties. SGLT2 EC ₅₀ = 1.1 nM.

Example 4

Bilayer tablets containing a sustained-release formulation of metformin (1000 mg) and an immediate-release formulation of dapagliflozin (S) PGS (5.00 mg) were prepared as described below.

Granulation of metformin (1000 mg)

Metformin HCl, 0.5% magnesium stearate, and sodium carboxymethylcellulose were combined and mixed in a high shear granulator for one minute. Purified water was added through a spray nozzle with mixing for one minute. The wet granulation was passed through a mill and then dried to a moisture content of 1.0% or less. The dry material containing metformin HCl, 0.5% magnesium stearate, and sodium carboxymethylcellulose was passed through a mill and dispensed into polyethylene-lined drums to yield a 1 g metformin milled granulation mass.

Hydroxypropyl methylcellulose 2208 USP (100,000 centipoise) (Methocel K100M Premium) was transferred to a bin mixer and mixed for 60 revolutions. The material was passed through a mill and distributed to yield ground hydroxypropyl methylcellulose 2208 USP.

Metformin (1 g of milled granulation mass), hydroxypropyl methylcellulose 2208 USP (milled), hydroxypropyl methylcellulose 2208 USP (undrilled) and magnesium stearate were added to a bin mixer and mixed for 60 revolutions. The prepared material was dispensed into polyethylene-lined drums to yield 1 g of metformin sustained-release granulation mass.

Dapagliflozin Granulations (2.5, 5.0, 10.0 mg)

Dapagliflozin (S) PGS was mixed with microcrystalline cellulose, anhydrous lactose, part of the crospovidone and part of the silicon dioxide in a suitable tumble blender and passed through a suitable conical mill. Part of the magnesium stearate (screened) was mixed with the resulting mixture, which was then compacted using a suitable roller compactor. The compacted mixture was milled to form granules. The granules were mixed with the remaining amount of silicon dioxide and crospovidone in a suitable tumble blender. The granules were then mixed with the remaining amount of magnesium stearate in a suitable tumble blender.

Pressing of bilayer tablets

The first hopper of the bilayer tablet press was filled with the metformin XR formulation or the reduced-weight metformin XR formulation and the second hopper was filled with the SGLT2 inhibitor formulation, which was dapagliflozin (S) PGS granulated mass (2.5 mg, 5 mg, or 10 mg strength). The tablet press was set to produce the first layer of the desired weight (metformin XR or metformin XR). The second hopper was opened and the tablet press was set to produce the desired weight of dapagliflozin and metformin XR or dapagliflozin and metformin XR reduced-weight bilayer tablets. After setting the desired weight, the press was set to produce the desired hardness. After setting the desired hardness, the manufactured tablets were periodically checked for the weight of the first layer, as well as the weight, hardness, size, and friability of the entire tablet. The resulting bilayer tablets were coated with Opadry® II PVA (polyvinyl alcohol) film.

Example 5

Bilayer tablets containing a sustained release formulation of metformin (1000 mg) and an immediate release formulation of dapagliflozin (S) PGS (2.5 mg) were prepared in the same manner as described in Example 4.

Example 6

Bilayer tablets containing a sustained release formulation of metformin (1000 mg) and an immediate release formulation of dapagliflozin (S) PGS (10.00 mg) were prepared in the same manner as described in Example 4.

Example 7

Bilayer tablets containing a reduced weight sustained release formulation of metformin (1000 mg) and an immediate release formulation of dapagliflozin (S) PGS (5.00 mg) were prepared as described below.

Metformin HCl, 0.5% magnesium stearate, and sodium carboxymethylcellulose were combined and mixed in a high shear granulator for one minute. Purified water was added through a spray nozzle with mixing for one minute. The wet granulation was passed through a mill and then dried to a moisture content of 1.0% or less. The dry material containing metformin HCl, 0.5% magnesium stearate, and sodium carboxymethylcellulose was passed through a mill and dispensed into polyethylene-lined drums to yield a 1 g metformin milled granulation mass.

Metformin (1 g of milled granulation mass), hydroxypropyl methylcellulose 2208 USP (100,000 centipoise) (Methocel K100M Premium) and silicon dioxide were added to a bin mixer and mixed for 120 revolutions. Magnesium stearate was then added and after 60 revolutions the prepared material was dispensed into polyethylene-lined drums to obtain a reduced weight, sustained release granulation mass of metformin 1 g.

Granulation of dapagliflozin (S) PGS and the bilayer tablet compression procedure were performed as described in Example 4.

Example 8

Bilayer tablets containing a reduced weight sustained release formulation of metformin (1000 mg) and an immediate release formulation of dapagliflozin (S) PGS (2.5 mg) were prepared as described in Example 7.

Example 9

Bilayer tablets containing a reduced weight sustained release formulation of metformin (1000 mg) and an immediate release formulation of dapagliflozin (S) PGS (10.00 mg) were prepared as described in Example 7.

Other IR SGLT2 inhibitor compositions described in Table 2 may be used to prepare the bilayer tablets of the present invention. The compositions listed in Table 2 are compatible with the metformin XR compositions or the reduced weight metformin XR compositions described herein. Bilayer tablets prepared from the IR SGLT2 inhibitor composition described in Table 2 are characterized by reduced or no cracking, separation, and/or cross-contamination with the metformin XR layer and the reduced weight metformin XR layer.

Example 10

Bilayer tablets containing a reduced weight sustained release formulation of metformin (500 mg) and an immediate release formulation of dapagliflozin (S) PGS (5.00 mg) were prepared as described in Example 13, except that silicon dioxide was not added to the metformin layer.

Example 11

Bilayer tablets containing a sustained release formulation of metformin (500 mg) and an immediate release formulation of dapagliflozin (S) PGS (10.0 mg) were prepared as described in Example 13, except that silicon dioxide was not added to the metformin layer.

Example 12

Bilayer tablets containing a sustained release formulation of metformin (500 mg) and an immediate release formulation of dapagliflozin (S) PGS (2.50 mg) were prepared as described in Example 13, except that silicon dioxide was not added to the metformin layer.

Example 13

Bilayer tablets containing a sustained-release formulation of metformin (500 mg) and an immediate-release formulation of dapagliflozin (S) PGS (5.0 mg) were prepared as described below.

Metformin HCl, 0.5% magnesium stearate, and sodium carboxymethylcellulose were combined and mixed in a high shear granulator for one minute. Purified water was added via a spray nozzle with mixing for one minute. The wet granulation was passed through a mill and then dried to a moisture content of 1.0% or less. The dry material containing metformin HCl, 0.5% magnesium stearate, and sodium carboxymethylcellulose was passed through a mill and dispensed into polyethylene-lined drums to yield a milled metformin 500 mg granulation mass.

The crushed metformin 500 mg granule mass, hydroxypropyl methylcellulose 2208, hydroxypropyl methylcellulose 2910 and silicon dioxide were added to a bin mixer and mixed for 240 revolutions. Then magnesium stearate was added and after 60 revolutions the prepared material was distributed into polyethylene-lined drums, obtaining metformin 500 mg delayed-release granule mass.

Granulation of dapagliflozin (S) PGS and the bilayer tablet compression procedure were performed as described in Example 4.

Example 14

Bilayer tablets containing metformin composition (500 mg)

sustained release and immediate release dapagliflozin (S) PGS (10.0 mg) formulation were prepared as described in Example 13.

Example 15

Bilayer tablets containing a sustained release formulation of metformin (500 mg) and an immediate release formulation of dapagliflozin (S) PGS (2.50 mg) were prepared as described in Example 13.

Based on the above, the invention provides the following variants.

Embodiment 1. A bilayer tablet comprising (1) a first layer, wherein the first layer is a sustained release formulation of metformin hydrochloride, (2) a second layer, wherein the second layer is a formulation of a sodium-dependent glucose transporter type 2 inhibitor (SGLT2 inhibitor) comprising dapagliflozin, dapagliflozin (S) propylene glycol hydrate or dapagliflozin (R) propylene glycol hydrate or canagliflozin, and (3) optionally a film coating comprising polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc, which covers the first layer and the second layer.

Option 2. A two-layer tablet according to option 1, in which the total weight of the second layer is from 300 mg to 400 mg.

Embodiment 3. A bilayer tablet according to embodiment 1, wherein (1) the first layer comprises metformin hydrochloride, a binder, a release modifier, a lubricant and optionally a glidant, and (2) the second layer comprises dapagliflozin or dapagliflozin (S) propylene glycol hydrate, two or three fillers, a disintegrant, a glidant and a lubricant.

Embodiment 4. A bilayer tablet comprising (1) a first layer, wherein the first layer is a metformin hydrochloride sustained release composition comprising metformin hydrochloride, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, magnesium stearate and optionally silicon dioxide or colloidal silicon dioxide, (2) a second layer, wherein the second layer is a sodium-dependent glucose transporter type 2 inhibitor (SGLT2 inhibitor) composition comprising dapagliflozin, dapagliflozin (S) propylene glycol hydrate, two or three fillers selected from anhydrous lactose, microcrystalline cellulose, pregelatinized starch, mannitol and hydroxypropyl cellulose, a disintegrant which is crospovidone, a glidant which is silicon dioxide and a lubricant which is stearate magnesium, and (3) an optional film coat that covers the first layer and the second layer, comprising polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc.

Embodiment 5. A bilayer tablet according to embodiment 4, wherein (1) the first layer comprises 40-82% metformin hydrochloride, 3-5% sodium carboxymethylcellulose, 15-40% hydroxypropyl methylcellulose, 0.1-0.75% magnesium stearate and 0-2% silicon dioxide or 0-1.5% colloidal silicon dioxide, (2) the second layer comprises 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, 14-18% lactose anhydrous, 50-80% microcrystalline cellulose, 2-6% crospovidone, 0.5-2.5% silicon dioxide and 0.5-2% magnesium stearate, (3) an optionally present film coating containing polyvinyl alcohol, dioxide titanium, polyethyleneglycol and talc.

Option 6. A bilayer tablet according to option 4, wherein (1) the first layer contains 40-87% metformin hydrochloride, 1-10% sodium carboxymethylcellulose, 10-40% hydroxypropyl methylcellulose, 0.1-0.75% magnesium stearate and 0-2% titanium dioxide, and (2) the weight of the second layer is from 300 mg to 400 mg.

Option 7. A two-layer tablet according to option 4, in which the first layer additionally contains microcrystalline cellulose.

Option 8. A two-layer tablet according to option 6, in which the first layer additionally contains 5-15% microcrystalline cellulose.

Option 9. A two-layer tablet according to option 6, in which the second layer contains:

(A) 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, 14-18% anhydrous lactose, 72-80% microcrystalline cellulose; 2-6% crospovidone, 0.5-2.5% silicon dioxide, and 0.5-1.5% magnesium stearate;

(B) 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, 14-18% anhydrous lactose, 50-70% microcrystalline cellulose, 10-22% pregelatinized starch, 2-6% crospovidone, about 0.5-2.5% silicon dioxide, and 0.5-1.5% magnesium stearate;

(C) 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, 14-18% anhydrous lactose, 60-70% microcrystalline cellulose; 5-15% hydroxypropyl cellulose, 2-6% crospovidone, 0.5-2.5% silicon dioxide, and 0.5-1.5% magnesium stearate, or

(D) 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, 14-18% anhydrous lactose, 55-65% microcrystalline cellulose, 10-20% mannitol, 2-6% crospovidone, 0.5-2.5% silicon dioxide, and 0.5-1.5% magnesium stearate.

Option 10. A two-layer tablet according to option 9, which has a film coating, and the film coating contains polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc.

Option 11. A two-layer tablet according to option 3, in which the first layer additionally contains a filler.

Option 12. A two-layer tablet according to option 11, in which the filler is microcrystalline cellulose.

Variant 13. A bilayer tablet according to variant 3, in which (1) the first layer contains 42-82% metformin hydrochloride, 3-5% sodium carboxymethylcellulose, 15-40% hydroxypropyl methylcellulose, 0.75-1.25% silicon dioxide or 0.25-0.75% colloidal silicon dioxide and 0.1-0.75% magnesium stearate, and (2) the weight of the second layer is from 300 mg to 400 mg.

Option 14. A two-layer tablet according to option 13, in which the first layer additionally contains 5-15% microcrystalline cellulose.

Option 15. A two-layer tablet according to option 13, in which the second layer contains:

(A) 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, 14-18% anhydrous lactose, 72-80% microcrystalline cellulose; 2-6% crospovidone, 0.5-2.5% silicon dioxide, and 0.5-1.5% magnesium stearate;

(B) 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, 14-18% anhydrous lactose, 50-70% microcrystalline cellulose, 10-22% pregelatinized starch, 2-6.0% crospovidone, about 0.5-2.5% silicon dioxide, and 0.5-1.5% magnesium stearate;

(C) 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, 14-18% anhydrous lactose, 60-70% microcrystalline cellulose; 5-15% hydroxypropyl cellulose, 2-6% crospovidone, 0.5-2.5% silicon dioxide, and 0.5-1.5% magnesium stearate, or

(D) 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, 14-18% anhydrous lactose, 55-65% microcrystalline cellulose, 10-20% mannitol, 2-6% crospovidone, 0.5-2.5% silicon dioxide, and 0.5-1.5% magnesium stearate.

Option 16. A two-layer tablet according to option 13, which has a film coating, and the film coating contains polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc.

Embodiment 17. A pharmaceutical combination comprising a bilayer tablet according to embodiment 4 and an antidiabetic drug, wherein the antidiabetic drug is a sulfonylurea, a thiazolidinedione, an alpha-glucosidase inhibitor, meglitinide, a glucagon-like peptide (GLP) agonist, insulin, an amylin agonist, a fructose-1,6-bisphosphatase inhibitor, an insulin secretagogue, an insulin action-enhancing substance, a glucokinase activator, a glucocorticoid antagonist, an AMP kinase activator, an incretin secretagogue, an incretin mimic, an incretin action-enhancing substance, a TGR5 agonist, a dopamine receptor agonist, an aldose reductase inhibitor, a PPARγ agonist, a PPARα agonist, an antagonist or PPARδ agonist, dual PPARα/γ agonist, 11-β-HSD-1 inhibitor, dipeptidyl peptidase IV (DPP4) inhibitor, SGLT2 inhibitor other than dapagliflozin, glucagon-like peptide-1 (GLP-1), GLP-1 agonist, or PTP-1B inhibitor.

Option 18. A pharmaceutical combination comprising a bilayer tablet according to option 4 and a weight loss inducing agent, wherein the weight loss inducing agent is sibutramine, a CB1 antagonist, a 5HT2C agonist, an MCHR1 antagonist, orlistat, a thyromimetic, an amylin mimetic or a ghrelin antagonist.

Variant 19. A bilayer tablet according to variant 1, wherein (1) the first layer contains 72-82% metformin hydrochloride, 3-5% sodium carboxymethylcellulose, 15-22% hydroxypropyl methylcellulose, 0.75-1.25% silicon dioxide or 0.25-0.75% colloidal silicon dioxide and 0.1-0.6% magnesium stearate, and (2) the second layer contains canagliflozin.

Option 20. A two-layer tablet according to option 19, which has a film coating, and the film coating contains polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc.

Variant 21. A bilayer tablet according to variant 1, wherein (1) the first layer contains 76.6% metformin hydrochloride, 3.84% sodium carboxymethylcellulose, 18% hydroxypropyl methylcellulose, 0.75-1.25% silicon dioxide or 0.25-0.75% colloidal silicon dioxide and 0.53% magnesium stearate, and (2) the second layer contains canagliflozin.

Option 22. A two-layer tablet according to option 21, which has a film coating, and the film coating contains polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc.

Embodiment 23. A method for treating a disorder or disease selected from diabetes, impaired glucose tolerance, insulin resistance, nephropathy, retinopathy, neuropathy and cataracts, hyperglycemia, hyperinsulinemia, hypercholesterolemia, dyslipidemia, elevated levels of free fatty acids or glycerol in the blood, hyperlipidemia, hypertriglyceridemia, obesity, wound healing, tissue ischemia, atherosclerosis and hypertension in a mammal, comprising administering to a mammal in need of such treatment a bilayer tablet according to embodiment 1.

Embodiment 24. The method according to embodiment 23, wherein the disorder is type II diabetes and the mammal is a human.

Embodiment 25. The method according to embodiment 23, wherein (1) the first layer comprises metformin hydrochloride, a binder, a release modifier, a lubricant, and optionally a glidant, and (2) the second layer comprises dapagliflozin or dapagliflozin (S) propylene glycol hydrate, two or three fillers, a disintegrant, a glidant, and a lubricant.

Embodiment 26. The method according to embodiment 25, wherein (1) the binder is sodium carboxymethylcellulose, the release modifier is hydroxypropyl methylcellulose, the lubricant is magnesium stearate, and the optionally present glidant is silicon dioxide or colloidal silicon dioxide, (2) the SGLT2 inhibitor is dapagliflozin or dapagliflozin (S) propylene glycol hydrate, two or three excipients are selected from anhydrous lactose, microcrystalline cellulose, pregelatinized starch, mannitol, hydroxypropyl cellulose, the disintegrant is crospovidone; the glidant is silicon dioxide, and the lubricant is magnesium stearate, (3) the optionally present film coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc.

Embodiment 27. The method according to embodiment 23, wherein (1) the first layer comprises 40-87% metformin hydrochloride, 1-10% sodium carboxymethylcellulose, 10-40% hydroxypropyl methylcellulose, 0.1-0.75% magnesium stearate and 0-2% silicon dioxide or 0-1.5% colloidal silicon dioxide, (2) the second layer comprises 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, 14-18% lactose anhydrous, 50-80% microcrystalline cellulose, 2-6% crospovidone, 0.5-2.5% silicon dioxide and 0.5-2% magnesium stearate, (3) the optionally present film coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc.

Option 28. The method according to option 25, wherein the first layer additionally contains a filler.

Option 29. The method according to option 28, wherein the filler is microcrystalline cellulose.

Option 30. The method according to option 27, wherein the first layer additionally contains 5-15% microcrystalline cellulose.

Embodiment 31. A method of treating a disorder or disease selected from diabetes, impaired glucose tolerance, insulin resistance, nephropathy, retinopathy, neuropathy and cataracts, hyperglycemia, hyperinsulinemia, hypercholesterolemia, dyslipidemia, elevated levels of free fatty acids or glycerol in the blood, hyperlipidemia, hypertriglyceridemia, obesity, wound healing, tissue ischemia, atherosclerosis and hypertension in a mammal, comprising administering to a mammal in need of such treatment a bilayer tablet according to embodiment 4.

Embodiment 32. The method according to embodiment 31, wherein the disorder is type II diabetes and the mammal is a human.

Claims (16)

1. A bilayer tablet for the treatment of type II diabetes, comprising (1) a first layer, wherein the first layer is a sustained release formulation of metformin hydrochloride, (2) a second layer, wherein the second layer is a formulation of a sodium-dependent glucose transporter type 2 inhibitor (SGLT2 inhibitor) comprising dapagliflozin, dapagliflozin (S) propylene glycol hydrate or dapagliflozin (R) propylene glycol hydrate, and (3) optionally a film coating comprising polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc that covers the first layer and the second layer, wherein (1) the first layer contains 42-82% metformin hydrochloride, 3-5% sodium carboxymethylcellulose, 15-40% hydroxypropyl methylcellulose and 0.1-0.75% magnesium stearate, where the ratio of the first layer to the second layer is about 3.4:1, and and the total weight of the second layer is from 300 to 400 mg. 2. A bilayer tablet for the treatment of type II diabetes, comprising (1) a first layer, wherein the first layer is a sustained release composition of metformin hydrochloride, (2) a second layer, wherein the second layer is a composition of a sodium-dependent glucose transporter type 2 inhibitor (SGLT2 inhibitor) comprising dapagliflozin, dapagliflozin (S) propylene glycol hydrate or dapagliflozin (R) propylene glycol hydrate, and (3) optionally a film coating comprising polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc that covers the first layer and the second layer, wherein (1) the first layer contains 42-82% metformin hydrochloride, 3-5% sodium carboxymethylcellulose, 15-40% hydroxypropyl methylcellulose and 0.1-0.75% magnesium stearate, and where the ratio of the first layer to the second layer is about 4.8:1, and and the total weight of the second layer is from 300 to 400 mg. 3. A bilayer tablet according to any one of claims 1 or 2, wherein the second layer comprises: (A) 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, 14-18% anhydrous lactose, 72-80% microcrystalline cellulose; 2-6% crospovidone, 0.5-2.5% silicon dioxide, and 0.5-1.5% magnesium stearate; (B) 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, 14-18% anhydrous lactose, 50-70% microcrystalline cellulose, 10-22% pregelatinized starch, 2-6.0% crospovidone, about 0.5-2.5% silicon dioxide, and 0.5-1.5% magnesium stearate; (C) 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, 14-18% anhydrous lactose, 60-70% microcrystalline cellulose; 5-15% hydroxypropyl cellulose, 2-6% crospovidone, 0.5-2.5% silicon dioxide, and 0.5-1.5% magnesium stearate, or (D) 0.5-4% dapagliflozin or dapagliflozin (S) propylene glycol hydrate, 14-18% anhydrous lactose, 55-65% microcrystalline cellulose, 10-20% mannitol, 2-6% crospovidone, 0.5-2.5% silicon dioxide, and 0.5-1.5% magnesium stearate. 4. A bilayer tablet according to any one of claims 1-3, which has a film coating, and the film coating contains polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc. 5. A method for treating type II diabetes in a mammal, comprising administering to a mammal in need of such treatment a bilayer tablet according to any one of claims 1-4. 6. The method according to claim 5, wherein the mammal is a human.