two-layer tablets, their use, and their pharmaceutical combinations

专利摘要:
two-layer tablets, their use, and their pharmaceutical combinations the present invention relates to two-layer tablet formulations comprising extended-release metformin (xr) formulation or reduced-mass metformin xr as the first layer, a formulation of the sglt2 inhibitor as the second layer, and optionally a film coating. the present invention provides methods of preparing two-layer tablet formulations and methods of treating diseases or disorders associated with sglt2 activity using two-layer tablet formulations.
公开号:BR112012011726A2
申请号:R112012011726
申请日:2010-11-12
公开日:2020-05-19
发明作者:Abebe Admassu；Desai Divyakant；M Patel Jatin；Martin Kyle；Timmins Peter
申请人:Astrazeneca Uk Ltd；Squibb Bristol Myers Co；
IPC主号:

专利说明:

Invention Patent Descriptive Report for TWO-LAYER TABLETS, THEIR USE, AND THEIR PHARMACEUTICAL COMBINATIONS.
FIELD OF THE INVENTION
The present invention relates to two-layer tablet formulations comprising extended-release metformin (XR) formulations or reduced-mass metformin XR formulations as the first layer, sodium-dependent glucose transporter inhibitor (SGLT2) formulations as the second layer, and optionally a film coating. The present invention provides methods of preparing two-layer tablet formulations and methods of treating diseases or disorders associated with SGLT2 activity using two-layer tablet formulations.
BACKGROUND OF THE INVENTION
Type II diabetes is the most common form of diabetes responsible for 90% of diabetes cases. More than 100 million people worldwide have type-2 diabetes (almost 17 million in the United States) and the prevalence is increasing dramatically in both the developed and the developing world. Type-II diabetes is a lifelong disease that usually begins in middle age or later in life, but can begin at any age. Patients with type-2 diabetes do not respond properly to insulin, the hormone that normally lets the body convert blood glucose into energy or store it in cells for later use. The problem in type-2 diabetes is a condition called insulin resistance in which the body produces insulin, in normal or even high amounts, but certain mechanisms prevent insulin from changing glucose in cells. Because the body does not use insulin properly, glucose rises to unsafe levels in the blood, a condition known as hyperglycemia.
Over time, sustained hyperglycemia leads to glucotoxicity, which worsens insulin resistance and contributes to dysfunction in the pancreatic beta cells. The degree of sustained hyperglycemia is directly related to microvascular diabetic complications and can also
2/70 may also contribute to macro vascular complications. In this way, hyperglycemia perpetuates a cycle of harmful effects that exacerbate the control and complications of type 2 diabetes.
It is now widely accepted that glycemic control makes a difference in patients with type II diabetes. The goal of diabetes therapy today is to achieve and maintain blood glucose as close to normal as possible to prevent long-term microvascular and macrovascular complications associated with high blood glucose. Oral therapeutic options for the treatment of type II diabetes mellitus include compounds known as: sulfonylureas, biguanides (metformin), thiazolidinediones, and alpha-glucosidase inhibitors. The active agents in each class are generally administered to patients alone. However, once monotherapy becomes inadequate, combination therapy is an attractive and rational course of action to treat hyperglycemia despite the known side effect of weight gain associated with sulfonylurea and thiazolidinone therapies.
Recently, a new class of antidiabetics has been discovered known as sodium-glucose transporter-2 inhibitors (SGLT2). SGLT2 inhibitors prevent the reabsorption of glucose in the blood through the kidney. The kidney continuously filters glucose through the glomerulus in the bladder, however, almost all of that glucose is reabsorbed. SGLT2 is the protein responsible for most of the glucose reabsorption and helps the body retain glucose for its energy needs. For patients with diabetes, the retention of excess glucose by this route contributes to persistent hyperglycemia. Suppressing SGLT2 activity inhibits the reabsorption of renal glucose in the body, thereby leading to the excretion of glucose in the urine.
Accordingly, the present invention provides two-layer tablet formulations consisting of metformin and an SGLT2 inhibitor for oral administration in the treatment of diseases or disorders associated with SGLT2 activity without weight gain associated with other therapies. The first layer of the two-layer tablet is metformin prolonged release (XR) or metformin XR in a formulation
3/70 reduced mass. The second layer is an SGLT2 inhibitor formulation. The two-layer metformin / SGLT2 tablet of the present invention provides an antidiabetic therapy for patients that is convenient and effective for controlling blood glucose levels.
SUMMARY OF THE INVENTION
The present invention provides two-layer tablets comprising (1) a metformin XR formulation or a reduced mass metformin XR formulation as the first layer, (2) an SGLT2 inhibitor formulation as the second layer, and (3) optionally a film coating covering both layers. Metformin can be in the form of a pharmaceutically acceptable salt in which metformin hydrochloride (HCl) is preferred. A preferred SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt of the same, dapagliflozin propylene glycol hydrate (S) (1: 1: 1), or dapagliflozin propylene glycol hydrate (R) (1: 1: 1). The most preferred SGLT2 inhibitor is dapagliflozin or dapagliflozin (S) (1: 1: 1). The SGLT2 inhibitor formulation is an immediate release formulation or prolonged deliberation, in which an immediate release formulation is preferred.
The metformin XR layer (1000 mg) comprises metformin, a binder, a release modifier, a lubricant, and optionally the glidant. A preferred binder is carboxymethyl cellulose. Hydroxypropyl methylcellulose 2208 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, hurts or three fillers, a disintegrant, a glidant, and a lubricant. Preferred fillers are anhydrous lactose, microcrystalline cellulose 302, pregelatinized starch, and mannitol. A 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, an
4/70 chimento, a lubricant, and optionally a glidant. A preferred binder is sodium carboxymethyl cellulose. Preferred release modifiers are hydroxypropyl methylcellulose 2208 in combination with hydroxypropyl methylcellulose 2910. Microcrystalline cellulose is a preferred filler. 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. A 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 of treating diseases or disorders associated with SGLT2 activity comprising administering to a mammal in need of such treatment a therapeutically effective amount of a two-layer tablet comprising metformin XR or metformin XR of reduced mass, a SGLT2 inhibitor, and optionally a film coating. The two-layer tablet formulations of the present invention can be administered to ammiferous, preferably humans, for the treatment of a variety of conditions and disorders associated with SGLT2 activity including, but not limited to, treating or delaying progress or onset diabetes (including Type I and Type II Diabetes), impaired glucose tolerance, insulin resistance, and diabetic complications such as nephropathy, retinopathy, neuropathy and cataracts, hyperglycemia, hyperinsulinemia, hypercholesterolemia, dyslipidemia, high blood levels of free fatty acids or glycerol, hyperlipidemia, hypertriglyceridemia, obesity, wound healing, tissue ischemia, atherosclerosis and hypertension. The formulations of the present invention can also be used to increase blood levels of high density lipoprotein (HDL). In addition, conditions, diseases, and illnesses collectively referred to as Syndrome X or Metabolic Syndrome as detailed in Johannsson, J.
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Clin. Endocrinol. Metab., 82, 727-34 (1997), can be treated using the formulations of the present invention.
In another aspect, the present invention provides methods for preparing a two-layer tablet comprising metformin XR or metformin XR of reduced mass, an SGLT2 inhibitor, and optionally a film coating.
DETAILED DESCRIPTION OF THE INVENTION
Preparing two-layer tablets with significantly different weight ratios between the two layers can lead to fractionation at the layer interface, separation of the layers, or even cross-contamination of the two layers. The large difference in weight ratio between the metformin layers and the SGLT2 inhibitor of Examples 4-15 provides challenges with respect to the maintenance potency and content uniformity of the lower weight layer, the SGLT2 inhibitor layer. Furthermore, it was discovered that a number of test formulations showed a fractionation in the SGLT2 layers on the tablet surface in an area adjacent to, but separate from, the interface between the layers and parallel to that interface. Formulations of the SGLT2 layer with increased levels of microcrystalline cellulose, for example, reduced or eliminated fractionation, separation, and cross-contamination of the two layers while maintaining potency and uniformity of the second layer. In addition, pregelatinized starch, hydroxypropyl cellulose EXF, or mannitol, can be used as a substitute for a portion of microcrystalline cellulose. Finally, a total weight of about 300 mg to about 400 mg for the second layer contributed to reduce or eliminate fractionation, separation, and cross-contamination of the two layers. The preferred weight of the second layer is 300 mg. Accordingly, the present invention provides two-layer tablet formulations that reduce or eliminate fractionation, separation, and cross-contamination of metformin and SGLT2 layers, and maintain or improve the potency and uniformity of the SGLT2 layer.
The present invention provides a two-layer tablet
6/70 comprising metformin XR formulations (1000 mg), SGLT2 inhibitor formulations (2.5, 5.0, or 10.0 mg), and optionally a film coating. The metformin XR formulation comprises metformin hydrochloride (HCl), sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, and magnesium stearate. The SGLT2 inhibitor formulation comprises an SGLT2 inhibitor, anhydrous lactose, microcrystalline cellulose, crospovidone, silicon dioxide, and magnesium stearate. For the second layer, pregelatinized starch, hydroxypropyl cellulose EXF, or mannitol (pearlitol SD 200) can be used to replace a portion of the microcrystalline cellulose. In addition, the second layer has a total weight of about 300 mg to about 400 mg. The preferred weight of the second layer is 300 mg. The optional film coating can be Opadry® II. In a preferred embodiment, the SGLT2 inhibitor is dapagliflozin, dapagliflozin (S) PGS, or dapagliflozin (R) PGS.
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (1000 mg) comprises about 50-87% metformin hydrochloride (HCl), about 1-10% sodium carboxymethyl cellulose , about 10-40%) hydroxypropyl methylcellulose, about 0.1-75% magnesium stearate, and about 0-2% silicon dioxide or about 0-1.5% colloidal silicon dioxide. The SGLT2 inhibitor formulation comprises about 0.1-10% SGLT2 inhibitor, about 5-30% anhydrous lactose, about 40-90% microcrystalline cellulose, about 0-25% pre-starch gelatinized, 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 optional film coating can be Opadry® II. In a preferred embodiment, the SGLT2 inhibitor is dapagliflozin or dapagliflozin (S) PGS.
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (1000 mg) comprises about 64-82% metformin hydrochloride (HCl), about 3-5% sodium carboxymethyl cellulose , about 15-30% hydroxypropyl methyl cell
7/70 if, about 0.1-75% magnesium stearate, and about 0-2% silicon dioxide or about 0-1.5% colloidal silicon dioxide. The SGLT2 inhibitor formulation comprises about 0.5-4% SGLT2 inhibitor, about 14-18% anhydrous lactose, about 50-80% microcrystalline cellulose, about 0-20% pre-starch gelatinized, 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 optional film coating can be Opadry® II. In a preferred embodiment, the SGLT2 inhibitor is dapagliflozin or dapagliflozin (S) PGS.
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (1000 mg) comprises about 67-71% metformin hydrochloride (HCl), about 3-5% carboxymethyl cellulose. sodium, about 25-29% hydroxypropyl methylcellulose 2208, and about 0.1-0.75% magnesium stearate. The SGLT2 inhibitor formulation comprises about 0.5-4% dapagliflozin or dapagliflozin (S) PGS, about 14-18% anhydrous lactose, about 72-80% microcrystalline cellulose 302, about 2-6 % of 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 about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (1000 mg) comprises about 67-71% metformin hydrochloride (HCl), about 3-5% sodium carboxymethyl cellulose , about 25-29% hydroxypropyl methylcellulose 2208, and about 0.1-0.75% magnesium stearate. The SGLT2 inhibitor formulation comprises about 0.5-4% dapagliflozin or dapagliflozin propylene glycol hydrate (S); 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
8/70 of the SGLT2 inhibitor layer is about 300 mg to about 400 mg where the preferred weight is about 300 mg.
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (1000 mg) comprises about 67-71% metformin hydrochloride (HCl), about 3-5% sodium carboxymethyl cellulose , about 25-29% hydroxypropyl methylcellulose 2208, and about 0.1-0.75% magnesium stearate. The SGLT2 inhibitor formulation comprises about 0.5-4% dapagliflozin or dapagliflozin propylene glycol hydrate (S); about 14-18% anhydrous lactose; about 60-70% microcrystalline cellulose 302; about 5-15% hydroxypropyl cellulose EXF; about 2-6% crospovidone; about 0.52.5% silicon dioxide; and about 0.5-1.5% magnesium stearate. The total weight of the SGLT2 inhibitor layer is about 300 mg to about 400 mg where the preferred weight is about 300 mg.
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (1000 mg) comprises about 67-71% metformin hydrochloride (HCl), about 3-5% sodium carboxymethyl cellulose , about 25-29% hydroxypropyl methylcellulose 2208, 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% 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 about 300 mg to about 400 mg where the preferred weight is about 300 mg.
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (1000 mg) comprises about 69% metformin hydrochloride (HCl), about 3.5% sodium carboxymethyl cellulose, about 27% hydroxypropyl methylcellulose 2208, and about 0.49% magnesium stearate. The SGLT2 inhibitor formulation comprises about 0.5-4% dapagliflozin (S) PGS, about
9/70
16% anhydrous lactose, about 57-77% microcrystalline cellulose 302, about 0-19% pregelatinized starch, 0-10% hydroxypropyl cellulose EXF, about 0-15% mannitol, about 4 % of crospovidone, about 1.5% of silicon dioxide, and about 1% of magnesium stearate. The total weight of the SGLT2 inhibitor layer is about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® IL
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (1000 mg) comprises about 69% metformin hydrochloride (HCl), about 3.5% sodium carboxymethyl cellulose, about 27% hydroxypropyl methiiceiulose 2208, and about 0.49% magnesium stearate. The SGLT2 inhibitor formulation comprises about 0.8% dapagliflozin or dapagliflozin (S) propylene glycol hydrate; about 16% anhydrous lactose; 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 about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (1000 mg) comprises about 69% metformin hydrochloride (HCl), about 3.5% sodium carboxymethyl cellulose, about 27% hydroxypropyl methiiceiulose 2208, and about 0.49% magnesium stearate. The SGLT2 inhibitor formulation comprises about 1.7% dapagliflozin or dapagliflozin (S) propylene glycol hydrate; about 16% anhydrous lactose; 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 about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a tablet of
10/70 two layers in which the metformin XR formulation (1000 mg) comprises about 69% metformin hydrochloride (HCl), about 3.5% sodium carboxymethyl cellulose, 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% anhydrous lactose; 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 about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (1000 mg) comprises about 69% metformin hydrochloride (HCl), about 3.5% sodium carboxymethyl cellulose, about 27% hydroxypropyl methylcellulose 2208, and about 0.49% magnesium stearate. The SGLT2 inhibitor formulation comprises about 1.7% dapagliflozin or dapagliflozin propylene glycol (S); about 16% anhydrous lactose; about 64% microcrystalline cellulose 302; about 13% pre-gelatinized starch; about 4% crospovidone; about 1.5% silicon dioxide; and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (1000 mg) comprises about 69% metformin hydrochloride (HCl), about 3.5% sodium carboxymethyl cellulose, about 27% hydroxypropyl methylcellulose 2208, and about 0.49% magnesium stearate. The SGLT2 inhibitor formulation comprises about 1.7% dapagliflozin or dapagliflozin (S) proylene glycol hydrate; about 16% anhydrous lactose; about 57% microcrystalline cellulose 302; about 19% of pregelatinized starch; about 4% crospovidone; about 1.5% carbon dioxide
11/70 silicon; and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry®
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (1000 mg) comprises about 69% metformin hydrochloride (HCl), about 3.5%) sodium carboxymethyl cellulose, 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% anhydrous lactose; 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 about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (1000 mg) comprises about 69% metformin hydrochloride (HCl), about 3.5% sodium carboxymethyl cellulose, about 27% hydroxypropyl methylcellulose 2208, and about 0.49% magnesium stearate. The SGLT2 inhibitor formulation comprises about 1.7% of dapagliflozin or dapagliflozin (S) depropylene 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 about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a two-layer tablet formulation in which the metformin XR formulation (1000 mg) comprises about 67-73% metformin hydrochloride (HCl), about 3-5% carboxymethyl cellulose sodium, about 25-30% hydro
12/70 xipropyl 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 about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (1000 mg) comprises about 69% metformin hydrochloride (HCl), about 3.5% sodium carboxymethyl cellulose, 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 about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a two-layer formulation tablet in which the metformin XR formulation (1000 mg) comprises about 67-73% metformin hydrochloride (HO), about 3-5% carboxymethyl cellulose sodium, 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 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 about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
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In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (1000 mg) comprises about 69% metformin hydrochloride (HCl), about 3.5% sodium carboxymethyl cellulose, 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 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 about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (1000 mg) comprises about 67-73% metformin hydrochloride (HCl), about 3-5% sodium carboxymethyl cellulose , 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 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 about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (1000 mg) comprises about 69% metformin hydrochloride (HCl), about 3.5% sodium carboxymethyl cellulose, 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 61% microcrystalline cellulose 302, about 15% mannitol, about 4% crospovidone , about 1.5% dioxide
14/70 silicon, and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
The present invention also provides a two-layer tablet comprising formulations of metformin XR (500 mg), formulations of the SGLT2 inhibitor (2.5, 5.0, or 10.0 mg), and optionally a film coating. The metformin XR formulation comprises metformin hydrochloride (HCl), sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, and magnesium stearate. The SGLT2 inhibitor formulation comprises an SGLT2 inhibitor, anhydrous lactose, microcrystalline cellulose, crospovidone, silicon dioxide, and magnesium stearate. For the second layer, pregelatinized starch, hydroxypropyl cellulose EXF, or mannitol (pearlitol SD 200) can be used to replace a portion of the microcrystalline cellulose. In addition, the second layer has a total weight of about 300 mg to about 400 mg. The preferred weight of the second layer is 300 mg. The optional film coating can be Opadry® II. In a preferred embodiment, the SGLT2 inhibitor is dapagliflozin, dapagliflozin (S) PGS, or dapagliflozin (R) PGS.
In another aspect, the present invention provides a two-layer tablet in which the formulation of metformin XR (500 mg) comprises about 40-60% metformin hydrochloride (HCl), about 1-10% sodium carboxymethyl cellulose , about 20-45% hydroxypropyl methylcellulose, 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 formulation comprises about 0.1-10% SGLT2 inhibitor, about 5-30% anhydrous lactose, about 40-90% microcrystalline cellulose, about 0-25% pre-starch gelatinized, 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 optional film coating can be Opadry® II. In a preferred embodiment, the inhibitor
15/70 SGLT2 is dapagliflozin or dapagliflozin (S) PGS.
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (500 mg) comprises about 42-55% metformin hydrochloride (HCl), about 4-6% sodium carboxymethyl cellulose , about 30-40% hydroxypropyl methylcellulose, 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 formulation comprises about 0.5-4% SGLT2 inhibitor, about 14-18% anhydrous lactose, about 65-80% microcrystalline cellulose, about 0-20% pre-starch gelatinized, 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 optional film coating can be Opadry® II. In a preferred embodiment, the SGLT2 inhibitor is dapagliflozin or dapagliflozin (S) PGS.
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (500 mg) comprises about 46-50% metformin hydrochloride (HCl), about 4-6% sodium carboxymethyl cellulose , about 30-40% hydroxypropyl methylcellulose 2208, about 0.1-1.5% hydroxypropyl methylcellulose 2910, 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) PGS, about 14-18% anhydrous lactose, about 72-80% microcrystalline cellulose 302, about 2-6 % of crospovidone, about 0.5-2.5% silicon dioxide, and about 0.5-1.5% magnesium stearate. The total weight layer of the SGLT2 inhibitor is about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (500 mg) comprises about 46-50% metformin hydrochloride (HCl), about 4-6% sodium carboxymethyl cellulose , about 30-40% hydroxypropyl methyl cell
16/70 if 2208, 0.1-1.5% hydroxypropyl methylcellulose 2910, 5-15% microcrystalline cellulose, and about 0.1-0.75% magnesium stearate. The SGLT2 inhibitor formulation comprises about 0.5-4% dapagliflozin propylene glycol hydrate or dapagliflozin (S); about 14-18% anhydrous lactose; about 50-70% microcrystalline cellulose 302; about 10-22% pregelatinized starch; about 2-6% crospovidone; about 0.52.5% silicon dioxide; and about 0.5-1.5% magnesium stearate. The total weight of the SGLT2 inhibitor layer is about 300 mg to about 400 mg where the preferred weight is about 300 mg.
In another aspect, the present invention provides a two-layer tablet in which the formulation of metformin XR (500 mg) comprises about 46-50% metformin hydrochloride (HCl), about 4-6% sodium carboxymethyl cellulose , about 30-40% hydroxypropyl methylcellulose 2208, 0.1-1.5% hydroxypropyl methylcellulose 2910, 5-15% microcrystalline cellulose, and about 0.1-0.75% magnesium stearate. The SGLT2 inhibitor formulation comprises about 0.5-4% dapagliflozin or dapagliflozin propylene glycol hydrate (S); about 14-18% anhydrous lactose; about 60-70% microcrystalline cellulose 302; about 5-15% hydroxypropyl cellulose EXF; about 2-6% crospovidone; about 0.52.5% silicon dioxide; and about 0.5-1.5% magnesium stearate. The total weight of the SGLT2 inhibitor layer is about 300 mg to about 400 mg where the preferred weight is about 300 mg.
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (500 mg) comprises about 46-50% metformin hydrochloride (HCl), about 4-6% sodium carboxymethyl cellulose , about 30-40% hydroxypropyl methylcellulose 2208, 0.1-1.5% hydroxypropyl methylcellulose 2910, 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% anhydrous lactose; about 55-65% microcrystalline cellulose 302; about 1020% mannitol; about 2-6% crospovidone; about 0.5-2.5% diode
17/70 silicon oxide; and about 0.5-1.5% magnesium stearate. The total weight of the SGLT2 inhibitor layer is about 300 mg to about 400 mg where the preferred weight is about 300 mg.
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (500 mg) comprises about 48-49% metformin hydrochloride (HCl), about 4.5-5% carboxymethyl cellulose sodium, about 34.5-35% hydroxypropyl methylcellulose 2208, 0.8-1.2% hydroxypropyl methylcellulose 2910, about 9.7510.25% microcrystalline cellulose, and about 0.34% stearate magnesium. The SGLT2 inhibitor formulation comprises about 0.5-4% dapaglifiozine (S) PGS, about 16% anhydrous lactose, about 72-77% microcrystalline cellulose 302, about 0-19% pre-starch gelatinized, 010% 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 about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (500 mg) comprises about 48-49% metformin hydrochloride (HCl), about 4.5-5% carboxymethyl cellulose sodium, about 34.5-35% hydroxypropyl methylcellulose 2208, 0.8-1.2% hydroxypropyl methylcellulose 2910, about 9.7510.25% microcrystalline cellulose, and about 0.34% stearate magnesium. The SGLT2 inhibitor formulation comprises about 0.5-4% dapaglifiozine (S) PGS, about 16% anhydrous lactose, about 72-77% microcrystalline cellulose 302, about 4% crospovidone, about 0.51.5% silicon dioxide, and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
Formulations that reduce the mass of the metformin XR layer when compared to known or currently formulations
18/70 available metformin XR, without affecting the amount of active ingredient are desirable because these formulations provide lower weight differentials between the two layers in this way reducing or eliminating problems associated with preparing a two-layer tablet (fractionation, separation , cross contamination). In addition, the two-layer tablets are considered smaller and more suitable for oral delivery to patients. The present invention provides reduced mass formulations of metformin XR which comprise silicon dioxide or colloidal silicon dioxide with reduced amounts of hydroxypropyl methylcellulose. Hydroxypropyl methylcellulose is reduced from about 27% to about 18%. These formulations improve compactability and reduce the weight proportions of the layer from about 4.8: 1 to about 4.4: 1 while maintaining similar rates and metformin release.
Accordingly, the present invention provides a two-layer tablet comprising reduced mass formulations of metformin XR (1000 mg), SGLT2 inhibitor formulations (2.5, 5.0, 10.0 mg), and optionally a film coating . The reduced mass formulations of metformin XR comprise metformin HCl, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, silicon dioxide or colloidal silicon dioxide, and magnesium stearate. The SGLT2 inhibitor formulation comprises the SGLT2 inhibitor, anhydrous lactose, microcrystalline cellulose, crospovidone, silicon dioxide, and magnesium stearate. For the second layer, pregelatinized starch, hydroxypropyl cellulose, or mannitol can be used to replace a portion of the microcrystalline cellulose. The total weight of the SGLT2 inhibitor layer is about 300 mg to about 400 mg where the preferred weight is about 300 mg. The optional film coating can be Opadry® II. In a preferred embodiment, the SGLT2 inhibitor is dapagliflozin, dapagliflozin (S) PGS, or dapagliflozin (R) PGS.
In another aspect, the present invention provides a two-layer tablet in which the reduced mass formulations of metformin XR (1000 mg) comprise about 70-85% metformin hydrochloride (HCl), about 2-6% carboxymethyl sodium cellulose, about 15-27%
19/70 hydroxypropyl methylcellulose 2208, about 0.75-1.25% silicon dioxide or about 0.25% -0.75% colloidal silicon dioxide, and about 0.05-5% stearate magnesium. The SGLT2 inhibitor formulation comprises about 0.1-10% SGLT2 inhibitor, about 5-30% anhydrous lactose, about 40-90% microcrystalline cellulose 302, about 0-25% pre-starch gelatinized, about 0-20% hydroxypropyl cellulose EXF, about 025% 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 about 300 mg to about 400 mg where the preferred weight is about 300 mg. The optional film coating can be Opadry® II. In a preferred embodiment, the SGLT2 inhibitor is dapagliflozin or dapagliflozin (S) PGS.
In another aspect, the present invention provides a two-layer tablet in which the reduced mass formulation of metformin XR (1000 mg) comprises about 72-82% metformin hydrochloride (HCl); about 3-5% sodium carboxymethyl cellulose; 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. The SGLT2 inhibitor formulation comprises about 0.1-10% SGLT2 inhibitor, about 5-30% anhydrous lactose, about 40-90% microcrystalline cellulose 302, about 0-25% pre-starch gelatinized, about 0-20% hydroxypropyl cellulose EXF, about 025% 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 about 300 mg to about 400 mg where the preferred weight is about 300 mg. The optional film coating can be Opadry® II. In a preferred embodiment, the SGLT2 inhibitor is dapagliflozin or dapagliflozin (S) PGS.
In another aspect, the present invention provides a two-layer tablet in which the reduced mass metformin XR (1000 mg) formulation comprises about 72-82% metformin hydrochloride (HCl); about 3-5% sodium carboxymethyl cellulose; about 15-22% of
20/70 hydroxypropH 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. The SGLT2 inhibitor formulation comprises about 0.5-4% dapagliflozin or dapagliflozin propylene glycol hydrate (S); 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 about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a two-layer tablet in which the reduced mass metformin XR (1000 mg) formulation comprises about 72-82% metformin hydrochloride (HCl); about 3-5% sodium carboxymethyl cellulose; about 15-22% hydroxypropyl methyl cellulose 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. The SGLT2 inhibitor formulation comprises about 0.5-4% dapagliflozin or dapagliflozin propylene glycol hydrate (S); about 14-18% anhydrous lactose; about 50-70% microcrystalline cellulose 302; about 10-22% pregelatinized starch; about 26% crospovidone; about 0.5-2.5% silicon dioxide; and about 0.51.5% magnesium stearate. The total weight of the SGLT2 inhibitor layer is about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a two-layer tablet in which the reduced mass metformin XR (1000 mg) formulation comprises about 72-82% metformin hydrochloride (HCl); about 3-5% sodium carboxymethyl cellulose; about 15-22% hydroxypropyl methyl cellulose 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. The SGLT2 inhibitor formulation comprises about 0.5-4% dapagliflozin or dapagli propylene glycol hydrate
21/70 flozina (S); 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 about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a two-layer tablet in which the reduced mass metformin XR (1000 mg) formulation comprises about 72-82% metformin hydrochloride (HCl); about 3-5% sodium carboxymethyl cellulose; 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. The SGLT2 inhibitor formulation comprises about 0.5-4% dapagliflozin or dapagliflozin propylene glycol hydrate (S); 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 about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a two-layer tablet in which the reduced mass metformin XR (1000 mg) formulation comprises about 72-82% metformin hydrochloride (HCl); about 3-5% sodium carboxymethyl cellulose; 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. 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 about 300 mg to about 400 mg where the weight
Preferred 22/70 is about 300 mg. The film coating can be Opadry®
In another aspect, the present invention provides a two-layer tablet in which the reduced mass metformin XR (1000 mg) formulation comprises about 72-82% metformin hydrochloride (HCl); about 3-5% sodium carboxymethyl cellulose; 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. The SGLT2 inhibitor formulation comprises about 1.7% dapagliflozin (S) PGS, 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 about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a two-layer tablet in which the reduced mass metformin XR (1000 mg) formulation comprises about 72-82% metformin hydrochloride (HCl); about 3-5% sodium carboxymethyl cellulose; 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. The SGLT2 inhibitor formulation comprises about 1.7% dapagliflozin (S) PGS, 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 about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.5
In another aspect, the present invention provides a two-layer tablet in which the reduced mass metformin XR (1000 mg) formulation comprises about 76.6% metformin hydrochloride (HCl); about 3.84% sodium carboxymethyl cellulose; about 18% hydroxy
23/70 propyl methylthiulose 2208; about 0.75-1.25% silicon dioxide or 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% anhydrous lactose; 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 about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a two-layer tablet in which the reduced mass metformin XR (1000 mg) formulation comprises about 76.6% metformin hydrochloride (HCl); about 3.84% sodium carboxymethyl cellulose; about 18% hydroxypropyl methylthiulose 2208; about 0.75-1.25% silicon dioxide or 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% anhydrous lactose; about 76% microcrystalline cellulose 302; about 4% and crospovidone; about 1.5% silicon dioxide; and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a two-layer tablet in which the reduced mass metformin XR (1000 mg) formulation comprises about 76.6% metformin hydrochloride (HCl); about 3.84% sodium carboxymethyl cellulose; about 18% hydroxypropyl methylthiulose 2208; about 0.75-1.25% silicon dioxide or 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% anhydrous lactose; about 74% microcrystalline cellulose 302; about 4% crospovidone; about 1.5% silicon dioxide; and
24/70 about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a two-layer tablet in which the reduced mass metformin XR (1000 mg) formulation comprises about 76.6% metformin hydrochloride (HCl); about 3.84% sodium carboxymethyl cellulose; 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. The SGLT2 inhibitor formulation comprises about 1.7% dapagliflozin or dapagliflozin (S) propylene glycol hydrate; about 16% anhydrous lactose; about 64% microcrystalline cellulose 302; about 13% pre-gelatinized starch; about 4% crospovidone; about 1.5% silicon dioxide; and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a two-layer tablet in which the reduced mass metformin XR (1000 mg) formulation comprises about 76.6% metformin hydrochloride (HCl); about 3.84% sodium carboxymethyl cellulose; 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. The SGLT2 inhibitor formulation comprises about 1.7% dapagliflozin or dapagliflozin (S) propylene glycol hydrate; about 16% anhydrous lactose; about 57% microcrystalline cellulose 302; about 19% pre-gelatinized starch; about 4% crospovidone; about 1.5% silicon dioxide; and about 1% magnesium stearate. The total weight of the SGLT2 inhibitor layer is about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a tablet of
25/70 two layers in which the formulation metformin XR of reduced mass (1000 mg) comprises about 76.6% of metformin hydrochloride (HCl); about 3.84% sodium carboxymethyl cellulose; 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. The SGLT2 inhibitor formulation comprises about 1.7% dapagliflozin or dapagliflozin (S) propylene glycol hydrate; about 16% anhydrous lactose; 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 about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a two-layer tablet in which the reduced mass metformin XR (1000 mg) formulation comprises about 76.6% metformin hydrochloride (HCl); about 3.84% sodium carboxymethyl cellulose; 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. The SGLT2 inhibitor formulation 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 about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
The present invention also provides a two-layer tablet comprising metformin XR formulations (500 mg), SGLT2 2.5, 5.0, 10.0 mg inhibitor formulations, and optionally a film coating. The metformin XR 500 mg formulations comprise metformin HCl, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, cellulose
26/70 lose microcrystalline, magnesium stearate, and optionally silicon dioxide or colloidal silicon dioxide. The SGLT2 inhibitor formulation comprises the SGLT2 inhibitor, anhydrous lactose, microcrystalline cellulose, crospovidone, silicon dioxide, and magnesium stearate. For the second layer, pregelatinized starch, hydroxypropyl cellulose, or mannitol can be used to replace a portion of the microcrystalline cellulose. The total weight of the SGLT2 inhibitor layer is about 300 mg to about 400 mg where the preferred weight is about 300 mg. The optional film coating can be Opadry® II. In a preferred embodiment, the SGLT2 Inhibitor is dapagliflozin, dapagliflozin (S) PGS, or dapagliflozin (R) PGS.
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (500 mg) comprises about 40-60% metformin hydrochloride (HCl), about 4-6% sodium carboxymethyl cellulose , about 30-40% hydroxypropyl methylcellulose 2208, about 0.1-1.5% hydroxypropyl methylcellulose 2910, about 515% 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 formulation comprises about 0.1-10% SGLT2 inhibitor, about 5-30% anhydrous lactose, about 40-90% microcrystalline cellulose 302, about 0-25% pre-starch gelatinized, about 20% hydroxypropyl cellulose EXF, about 025% mannitol (pearlitol SD 200), about 10% crospovidone, about 0.1-5% silicon dioxide, and about 0.1-5 % magnesium stearate. The total weight of the SGLT2 inhibitor layer is about 300 mg to about 400 mg where the preferred weight is about 300 mg. The optional film coating can be Opadry® II. In a preferred embodiment, the SGLT2 inhibitor is dapagliflozin or dapagliflozin (S) PGS.
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (500 mg) comprises about 45-50% metformin hydrochloride (HCl), about 4-6% sodium carboxymethyl cellulose , about 30-40% hydroxypropyl methylcellulose 2208, about 0.1-1.5% hydroxypropyl methylcellulose 2910, about 5
27/70
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 formulation comprises about 0.1-10% SGLT2 inhibitor, about 5-30% anhydrous lactose, about 40-90% microcrystalline cellulose 302, about 0-25% pre-starch gelatinized, about 0-20% hydroxypropyl cellulose EXF, about 025% 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 about 300 mg to about 400 mg where the preferred weight is about 300 mg. The optional film coating can be Opadry® II. In a preferred embodiment, the SGLT2 inhibitor is dapagliflozin or dapagliflozin (S) PGS.
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (500 mg) comprises about 45-50% metformin hydrochloride (HCl), about 4-6% sodium carboxymethyl cellulose , about 30-40% hydroxypropyl methylcellulose 2208, about 0.1-1.5% hydroxypropyl methylcellulose 2910, about 515% 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 formulation comprises about 0.5-4% dapagliflozin or dapagliflozin propylene glycol hydrate (S); 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 about 300 mg and about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (500 mg) comprises about 45-50% metformin hydrochloride (HCl), about 4-6% sodium carboxymethyl cellulose , about 30-40% hydroxypropyl methylcellulose 2208, about 0.1-1.5% hydroxypropyl methylcellulose 2910, about 5
28/70
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 formulation comprises about 0.5-4% dapagliflozin or dapagliflozin propylene glycol hydrate (S); about 14-18% anhydrous lactose; about 50-70% microcrystalline cellulose 302; about 10-22% pregelatinized starch; about 26% crospovidone; about 0.5-2.5% silicon dioxide; and about 0.51.5% magnesium stearate. The total weight of the SGLT2 inhibitor layer is about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (500 mg) comprises about 45-50% metformin hydrochloride (HCl), about 4-6% sodium carboxymethyl cellulose , about 30-40% hydroxypropyl methylcellulose 2208, about 0.1-1.5% hydroxypropyl methylcellulose 2910, about 515% 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 formulation comprises about 0.5-4% dapagliflozin or dapagliflozin propylene glycol hydrate (S); 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% and magnesium stearate. The total weight of the SGLT2 inhibitor layer is about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a two-layer tablet in which the metformin XR formulation (500 mg) comprises about 45-50% metformin hydrochloride (HCl), about 4-6% sodium carboxymethyl cellulose , about 30-40% hydroxypropyl methylcellulose 2208, about 0.1-1.5% hydroxypropyl methylcellulose 2910, about 515% microcrystalline cellulose, about 0.75-1.25% silicon dioxide or about 0.25% -0.75% colloidal silicon dioxide, and about 0.05-5%
29/70 magnesium stearate. The SGLT2 inhibitor formulation comprises about 0.5-4% dapagliflozin or dapagliflozin propylene glycol hydrate (S); 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 about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
In another aspect, the present invention provides a two-layer tablet in which the formulation of metformin XR (500 mg) comprises about 45-50% metformin chlorohydrate (HCl), about 4-6% sodium carboxymethyl cellulose , about 30-40% hydroxypropyl methylcellulose 2208, about 0.1-1.5% hydroxypropyl methylcellulose 2910, about 515% 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 formulation comprises about 0.5-4% dapagliflozin (S) PGS, about 16% anhydrous lactose, 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 about 300 mg to about 400 mg where the preferred weight is about 300 mg. The film coating can be Opadry® II.
The percentages of SGLT2 listed above correspond to the active ingredient. The preferred active ingredient is dapagliflozin or dapagliflozin (S) propylene glycol hydrate. It is to be understood that the percentages (amounts) above will be higher for dapagliflozin as propylene glycol hydrate than as non-solvate / hydrate.
Different forms of antidiabetic agent metformin are suitable for use in the two-layer tablet formulations of the present invention including pharmaceutically acceptable salts thereof such as hydrochloride, hydrobromide, fumarate, succinate, p-chlorophenoxy acetate or embonate. The fumarate and succinate salts are preferably fumarate
30/70 metformin (2: 1), and metformin succinate (2: 1). Metformin hydrochloride is preferred.
The present invention also contemplates coated two-layer tablets in which the coating comprises Saxagliptin or a pharmaceutically acceptable salt thereof. Saxagliptin as the free base, as the monohydrate, or as the hydrochloride is preferred. The 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 in which at least one of the first and second coatings comprises Saxagliptin. The third coating is an optional external protective coating. Saxagliptin, shown below, can be prepared as described in U.S. 6395767, hereby incorporated by reference in its entirety for any purpose. The first and second coatings are prepared in a manner similar to the preparation of the inner seal coating layer or the middle coat layer (drug) described in WO 2005/117841, hereby incorporated by reference in its entirety for any purpose . The third coating is prepared in a manner similar to the preparation of the external protective coating layer described in WO 2005/117841.
Saxagliptin
The first coating includes up to 95% polymer based on the weight of the first coating layer. The formulation will contain at least one coating layer polymer and a coating solvent, preferably the solvent is water used for processing and removed by drying. The polymer of the first coating layer can be hydroxypropyl methylcellulose, polyvinyl alcohol (PVA), ethyl cellulose, methacrylic polymers or hydroxypropyl cellulose, preferably PVA. The first coat
31/70 optionally includes Saxagliptin without the range of about 0.5 to about 70%, preferably from about 30 to about 50% by weight based on the weight of the second coating layer. The first coating can include: optionally a plasticizer such as triacetin, diethyl phthalate, tributyl sebacate or polyethylene glycol (PEG), preferably PEG; a non-stick or glidant such as talc, smoked silica or magnesium stearate; and an opacifying agent such as titanium dioxide. The coating layer can also include dye based iron oxide. The coating material is commercially available under the trade name Opadry® HP or Opadry® II white.
The second coating is similar in composition to the first coating and preferably includes Saxagliptin.
The third coating is similar in composition to the first coating, only without Saxagliptin.
Accordingly, in one aspect, the present invention provides a coated two-layer tablet comprising: (1) a two-layer core tablet comprising two layers wherein the first layer comprises metformin; and the second layer comprises an SGLT2 inhibitor; wherein the second layer is about 300 to about 400 mg; (2) a first coating that coats the core of the two-layer tablet 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 one of the first coating and the second coating comprises Saxagliptin.
In one aspect, the present invention provides a coated two-layer tablet comprising: (1) a two-layer tablet core in which the first layer comprises about 64-82% metformin hydrochloride, about 3-5% sodium carboxymethyl cellulose; 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% of
32/70 dapagliflozin or dapagliflozin propylene glycol hydrate (S); 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; about 0.5-2.5% silicon dioxide; and about 0.5-2% magnesium stearate; wherein the second layer is about 300 to about 400 mg; (2) the first coating comprises a polyvinyl alcohol based on polymer; (3) the second coating comprises Saxagliptin and a polymer-based polyvinyl alcohol; and (4) the third coating comprises a polymer-based polyvinyl alcohol.
In one aspect, the present invention provides a coated two-layer tablet comprising: (1) a two-layer core tablet in which the first layer comprises about 67-71% metformin hydrochloride, about 3-5% sodium carboxymethyl cellulose, about 25-29% hydroxypropyl methylcellulose 2208, and about 0.1-0.75% magnesium stearate; and the second layer comprises:
(A) about 0.5-4% dapagliflozin or dapagliflozin propylene glycol hydrate (S): about 14-18% anhydrous lactose: about 7280% 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 propylene glycol hydrate (S); about 14-18% anhydrous lactose; about 5070% microcrystalline cellulose 302; about 10-22% of 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% propylene glycol hydrate of dapagliflozin or dapagliflozin (S); about 14-18% anhydrous lactose; about 6070% 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% dapagliflo propylene glycol hydrate
33/70 zine or dapagliflozin (S); about 14-18% anhydrous lactose; about 5565% 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 second layer is about 300 to about 400 mg; (2) the first coating comprises Opadry® HP; (3) the second coating comprises Saxagliptin and Opadry® HP; and (4) the third coating comprises Opadry® HP.
In one aspect, the present invention provides a coated two-layer tablet comprising: (1) a two-layer core tablet in which the first layer comprises about 69% metformin hydrochloride, about 3.5% carboxymethyl sodium cellulose, about 27% hydroxypropyl methylcellulose 2208, and about 0.48% magnesium stearate and second layer comprises:
(A) about 0.8% dapagliflozin or dapagliflozin propylene glycol hydrate (S); about 16% anhydrous lactose; about 77% microcrystalline cellulose 302; about 4% crospovidone; about 1.5% silicon dioxide; and about 1% magnesium stearate;
(B) about 1.7% of propylene glycol hydrate of dapagliflozin or dapagliflozin (S); about 16% anhydrous lactose; about 76% microcrystalline cellulose 302; about 4% crospovidone; about 1.5% silicon dioxide; and about 1% magnesium stearate;
(C) about 3.4% of propylene glycol hydrate of dapagliflozin or dapagliflozin (S); about 16% anhydrous lactose; about 74% microcrystalline cellulose 302; about 4% crospovidone; about 1.5% silicon dioxide; and about 1% magnesium stearate;
(D) about 1.7% of dapagliflozin or dapagliflozin propylene glycol hydrate (S); about 16% anhydrous lactose; about 64% microcrystalline cellulose 302; about 13% pre-gelatinized starch; about 4% crospovidone; about 1.5% silicon dioxide; and about 1% magnesium stearate;
(E) about 1.7% dapagliflozin or dapagliflozin propylene glycol hydrate (S); about 16% anhydrous lactose; about 57% of
34/70 microcrystalline cellulose 302; about 19% pre-gelatinized starch; about 4% crospovidone; about 1.5% silicon dioxide; and about 1% magnesium stearate;
(F) about 1.7% of propylene glycol hydrate of dapaglifiozine or dapaglifiozine (S); about 16% anhydrous lactose; 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% propylene glycol hydrate of dapaglifiozine or dapaglifiozine (S); 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; wherein the second layer is about 300 to about 400 mg;
(2) the first coating comprises Opadry® HP; (3) the second coating comprises Saxagliptin and Opadry® HP; and (4) the third coating comprises Opadry® HP.
In one aspect, the present invention provides a two-layer coated tablet which comprises: (1) a two-layer core tablet in which the first layer comprises about 72-82% metformin hydrochloride; about 3-5% sodium carboxymethyl cellulose; 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; the second layer comprises:
(A) about 0.5-4% dapaglifiozine or dapaglifiozine propylene glycol hydrate (S); about 14-18% anhydrous lactose; about 7280% 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% dapaglifiozine or dapaglifiozine propylene glycol hydrate (S); about 14-18% anhydrous lactose; about 5070% microcrystalline cellulose 302; about 10-22% of pregelatinized starch; about 2-6.00% crospovidone; about 0.5-2.5% of
35/70 silicon oxide; and about 0.5-1.5% magnesium stearate;
(C) about 0.5-4% propylene glycol hydrate of dapagliflozin or dapagliflozin (S); about 14-18% anhydrous lactose; about 6070% 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%) of propylene glycol hydrate of dapagliflozin or dapagliflozin (S); about 14-18% anhydrous lactose; about 5565% 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 second layer is about 300 to about 400 mg;
(2) the first coating comprises Opadry® HP; (3) the second coating comprises Saxagliptin and Opadry® HP; and (4) the third coating comprises Opadry® HP.
In one aspect, the present invention provides a coated two-layer tablet comprising: (1) a two-layer tablet core in which the first layer comprises about 76.6% metformin hydrochloride; about 3.84% sodium carboxymethyl cellulose; 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; the second layer comprises:
(A) about 0.8%) of dapagliflozin or dapagliflozin propylene glycol hydrate (S); about 16% anhydrous lactose; about 77% microcrystalline cellulose 302; about 4% crospovidone; about 1.5% silicon dioxide; and about 1% magnesium stearate;
(B) about 1.7% of propylene glycol hydrate of dapagliflozin or dapagliflozin (S); about 16% anhydrous lactose; 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 propylene glycol hydrate (S), about 16% anhydrous lactose; about 74% cellulose
36/70 lose microcrystalline 302; about 4% crospovidone; about 1.5% silicon dioxide; and about 1% magnesium stearate;
(D) about 1.7% dapagliflozin or dapagliflozin propylene glycol hydrate (S); about 16% anhydrous lactose; about 64% microcrystalline cellulose 302; about 13% pre-gelatinized starch; about 4% crospovidone; about 1.5% silicon dioxide; and about 1% magnesium stearate;
(E) about 1.7% dapagliflozin or dapagliflozin propylene glycol hydrate (S); about 16% anhydrous lactose; about 57% microcrystalline cellulose 302; about 19% pre-gelatinized starch; about 4% crospovidone; about 1.5% silicon dioxide; and about 1% magnesium stearate;
(F) about 1.7% dapagliflozin or dapagliflozin propylene glycol hydrate (S); about 16% anhydrous lactose; 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 propylene glycol hydrate (S); 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; wherein the second layer is about 300 to about 400 mg;
(2) the first coating comprises Opadry® HP; (3) the second coating comprises Saxagliptin and Opadry® HP; and (4) the third coating comprises Opadry® HP.
In one aspect, the present invention provides a coated tablet comprising a tablet core coated with a first coating optionally containing Saxagliptin, the second coating optionally containing Saxagliptin, and an optional third coating. The tablet core comprises metformin in which metformin hydrochloride is preferred. At least one of the first and second coatings contains Saxagliptin. The first and second coatings are pre
37/70 stopped in a similar manner to the preparation of the inner seal coating layer or coating layer of the medium (drug) described in WO 2005/117841. The third coating is prepared in a manner similar to the preparation of the internal protective coating layer described in WO 2005/117841.
In another aspect, the present invention provides a coated tablet comprising: (1) a tablet core comprising metformin; (2) a first coating that coats the 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 one of the first coating and the second coating comprises Saxagliptin.
In another aspect, the present invention provides a coated tablet comprising: (1) a tablet core which comprises about 72-82% metformin hydrochloride; about 3-5% sodium carboxymethyl cellulose; 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 first coating comprising a polymer based polyvinyl alcohol;
(3) a second coating comprising Saxagliptin and a polymer-based polyvinyl alcohol; and (4) a third coating comprising a polymer based polyvinyl alcohol.
In another aspect, the present invention provides a coated tablet comprising: (1) a tablet core which comprises about 76.6% metformin hydrochloride; about 3.84% sodium carboxymethyl cellulose; 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 first coating comprising Opadry® HP; (3) a second coating comprising saxagliptin and Opadry® HP; and (4) a third coating comprising Opadry® HP.
38/70
In another aspect, the present invention provides a coated tablet comprising: (1) a tablet core which comprises about 76.6% metformin hydrochloride; about 3.84% sodium carboxymethyl cellulose; 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 coated tablet comprising: (1) a tablet core which comprises about 76.6% metformin hydrochloride; about 3.84% sodium carboxymethyl cellulose; 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 about 10% Opadry® HP; and (4) a third coating comprising about 2% Opadry® HP.
In another aspect, the present invention provides combination therapies that comprise the two-layer tablet of the present invention in combination with one or more: antidiabetics; antihyperglycemic agents: hypolipidemic / lipid-lowering agents; anti-obesity agents: appetite-suppressing anti-hypertensive agents; insulin secretagogue, insulin sensitizers, glucocinase activators, glucocorticoid antagonist, fructose 1,6-bi phosphatase inhibitors, AMP kinase activators, incretin pathway modulators such as GPR119 or GPR40 agonists, incretin mimics like Byetta , and incretin enhancers, bile acid repressors or bile acid receptor agonists such as TGR5 agonists, dopamine receptor agonists such as Cycloset, PPARy agonists, aldose reductase inhibitors, PPARa agonists, PPARone agonists or antagonists , PPARa / y dual agonists, 11 -β-HSD-1 inhibitors, dipeptidyl peptidase IV (DPP4) inhibitors instead of saxagliptin, SGLT2s inhibitor
39/70 instead of dapagliflozin, glucagon-like peptide-1 (GLP-1), GLP-1 agonists, and PTP-1B inhibitors. Also as weight loss agents acting to decrease food intake such as sibutrimine, CB1 antagonists, 5HT2C agonists, MCHR1 antagonists, and agents that decrease nutrient absorption (such as lipase inhibitors (Orlistat)), and agents that they increase energy expenditure as thymomimetics, or decrease the motility of Gl as amylin mimetics or ghrelin antagonists.
Examples of antidiabetic agents suitable for use in combination with the formulations of the present invention include, but are not limited to, alpha glucosidase inhibitors (acarbose or miglitol), insulins (including insulin secretagogues or insulin sensitizers), meglitinides (repaglinide), sulfonylureas (glimepiride, glyburide, gliclazide, chloropropamide and glipizide), biguanide / glyburide combinations (Glucovance®), thiazolidinediones (for example, troglitazone, rosiglitazone and pioglitazone), PPAR-alpha agonists, PPAR-gamma agonists, PPAR-agonists alpha / gamma, glycogen phosphorylase inhibitors, fatty acid binding protein (aP2) inhibitors, GPR-119 modulators, GPR40 modulators, glucokinase inhibitors, glucagon-like peptide-1 (GLP-1) and other receptor agonists of GLP-1, SGLT2 inhibitor instead of dapagliflozin, and dipeptidyl peptidase IV (DPP4) inhibitors instead of saxagliptin.
Other suitable thiazolidinediones include, but are not limited to, MCC-555 (described in US Patent No. 5,594,016, Mitsubishi), faraglitazar (GI-262570, Glaxo-Wellcome), englitazone (CP-68722, Pfizer) or darglitazone ( CP-86325, Pfizer; isaglitazone, MIT / Johnson & Johnson), reglitazar (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-1,2,4oxadiazolidin-2-ylmethyl)] phenoxybibut-2-ene (YM-30 440, Yamanouchi).
Examples of PPAR-alpha agonists, PPARgama agonists, and PPAR alpha / gamma dual agonists include, but are not limited to, muraglitazar, peliglitazar, tesaglitazar AR-H039242 (Astra / Zeneca), GW501516 (Glaxo-Wellcome), KRP297 (Kyorin Merck), as well as those
40/70 described by Murakami et al., 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); WO 01/21602 and 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, employing dosages as set forth in that regard. In one embodiment, the compounds designated as preferred in the cited references are preferred for use herein.
Suitable aP2 inhibitors include, but are not limited to, those described in US application Serial No. 09 / 391,053, filed September 7, 1999, and in US Patent No. 6,548,529, the descriptions of which are incorporated herein by reference in its entirety, using dosages as established for this purpose.
Suitable DPP4 inhibitors include, but are not limited to, sitagliptin and vildagliptin, as well as those described in WO99 / 38501, W099 / 46272, W099 / 67279 (PROBIODRUG), W099 / 67278 (PROBIODRUG), W099 / 61431 (PROBIODRUG), ΝνΡ-ϋΡΡ728Α (Ι - [[[2 - [(5-cyanopyridin-2-yl) amino] ethyl] amino] acetyl] -2-cyano- (S) ~ pyrrolidine) (Novartis) as described by Hughes et al., Biochemistry, 38 (36), 11597-11603, 1999, TSL-225 acid (triptofill-1,2,3,4-tetrahydroisoquinoline-3-carboxylic (described by Yamada et al., Bioorg. & Med. Chem. Lett. 8 (1998 ) 1537-1540), 2-cyanopyrrolidides and 4-cyanopyrrolidides, as described by Ashworth et al., Bioorg. & Med. Chem. Lett., Vol. 6, No. 22, pp 1163-1166 and 2745-2748 (1996) , the compounds described in US application Serial No. 10 / 899,641, all of which are incorporated herein by reference in their entirety, employing dosages as set out in the references above.
Appropriate SGLT2 inhibitors considered by the bilayer tablet of the present invention and combination therapy with the two-layer tablet and combination therapy of the present invention include sergliflozin, remogliflozin, remogliflozin etabonate, canagliflozin, BI-10773 and BI-44847, ASP-1941 , R-7201, LX-4211, YM-543, AVE 2268, TS41 / 70
033 or SGL-0100, and the compounds described in US 7,589,193,
W02007007628, EP2009010, W0200903596, US2009030198, US
7,288,528 and US 2007/0197623, hereby incorporated by reference in their entirety for any purpose. The following SGLT2 Inhibitors
Suitable meglitinides include nateglinide (Novartis) or KADI229 (PF / Kissei).
Examples of anti-hyperglycemic agents suitable for use in combination with the formulations of the present invention include, but are not limited to, glucagon-like peptide-1 (GLP-1) such as GLP-1 (l-36) amide,
42/70
GLP-1 (7-36) amide, GLP-1 (7-37) (as described in US 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, incorporated herein in the present by reference in its entirety.
Examples of hypolipidemic / lipid-lowering agents suitable for use in combination with the formulations of the present invention include one or more MTP inhibitors, HMG Coa reductase inhibitors, squalene synthase inhibitors, fibric acid derivatives, ACAT inhibitors, inhibitors lipoxygenase inhibitors, cholesterol absorption inhibitors, ileal acid cotransporter inhibitors Na7bile, supraregulators of LDL receptor activity, bile acid separators, cholesterol ester transfer protein (eg, 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 a supra-regulator of LD2 receptor activity, such as 1 (3H) -isobenzofuranone, 3- (13-hydroxy-10oxotetradecyl) -5,7-dimethoxy- (MD-700, Taisho Pharmaceutical Co. Ltd ) and cholestan-3-ol, 4- (2-propenyl) - (3a, 4a, 5a) - (LY295427, Eli Lilly). Preferred hypolipidemic agents include pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, atavastatin and rosuvastatin (ZD-4522), for example.
Examples of MPT inhibitors that can be employed as described above include, but are not limited to, those described in US Patent No. 5,595,872, US Patent No. 5,739,135, US Patent No. 5,712,279, US Patent No. 5,760 .246, US Patent No. 5,827,875, US Patent No. 5,885,983 and US Patent No. 5,962,440, all of which are hereby incorporated by reference in their entirety.
Examples of HMG CoA reductase inhibitors that can be used in combination with the formulations of the invention include, but are not limited to, mevastatin and related compounds, such as des
43/70 as described in US Patent No. 3,983,140, lovastatin (mevinoline) and related compounds, as described in US Patent No. 4,231,938, pravastatin and related compounds, as described in US Patent No. 4,346,227, simvastatin and related compounds, as described in US Patent Nos. 4,448,784 and 4,450,171. Other suitable HMG CoA reductase inhibitors that can be employed herein include, but are not limited to, fiuvastatin, described in U.S. Patent No. 5,354,772, cerivastatin, as described in U.S. Patent Nos. 5,006,530 and 5,177,080, atorvastatin, as described in U.S. Patent Nos. 4,681,893, 5,273,995, 5,385,929 and 5,686,104, atavastatin (Nissan / Sankyo nivastatin (NK-104)), as described in US Patent No. 5,011,930, rosuvastatin (ShionogiAstra / Zeneca (ZD-4522) )), as described in US Patent No. 5,260,440, and related statin compounds described in US Patent No. 5,753,675, pyrazole analogs of mevalonolactone derivatives, as described in US Patent No. 4,613,610, analogs of indene mevalonolactone derivatives, as described in PCT application WO 86/03488, 6- [2 (substituted-pyrrol-1-yl) -alkyl) pyran-2-ones and derivatives thereof, as described in US Patent No. 4,647 .576, Searle's SC-45355 (a 3-substituted pentanedioic acid derivative) dichloroacetate, mevalonolactone imidazole analogs, as described in PCT application WO 86/07054, 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives , as described in French Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan and thiophene derivatives, as described in the European Patent Application No. 0221025, mevalonolactone naphthyl analogs, as described in US Patent No. 4,686,237, octahydronaphthalenes, as described in US Patent No. 4,499,289, mevinolin keto analogs (lovastatin), as described in the European Patent Application No. 0142146 A2, and quinoline and pyridine derivatives, as described in US Patent Nos. 5,506,219 and 5,691,322. All references cited are hereby incorporated by reference in their entirety. In addition, phosphonic acid compounds useful in inhibiting HMG CoA reductase, such as those described in GB 2205837, are suitable for use in combination with the formulations of the present invention.
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Examples of squalene synthase inhibitors suitable for use herein herein include, but are not limited to, α-phosphonosulfonates described in US Patent No. 5,712,396, those described by Biller et al., J. Med. Chem., 1988, Vol. 31, No. 10, pp. 1869-1871, including isoprenoid (phosphinylmethyl) phosphonates, as well as other known squalene synthase inhibitors, for example, as described in US Patent No. 4,871,721 and 4,924,024 and in Biller, SA, Neuenschwander, K. , Ponpipom, MM, and Poulter, CD., Current Pharmaceutical Design, 2, 1-40 (1996). Other squalene synthase inhibitors suitable for use herein include the terpenoid pyrophosphates described by P. Ortiz de Montellano et al., J. Med. Chem., 1977, 20, 243-249; farnesyl diphosphate analog A and presqualene pyrophosphate analogs (PSQ-PP) as described by Corey and Volante, J. Am. Chem. Soc, 1976, 98, 1291-1293; phosphinylphosphonates reported by McCIard, R.W. and others, J.A.C.S., 1987,709, 5544; and cyclopropanes reported by Capson, T.L., PhD dissertation, June 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp 16, 17, 40-43, 48-51, Summary. All references cited are hereby incorporated by reference in their entirety.
Examples of fibric acid derivatives that can be used in combination with the formulations of the invention include, but are not limited to, fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like, probucol, and related compounds, as described in the US Patent. No. 3,674,836, bile acid separators, such as cholestyramine, colestipol and DEAE-Sephadex (Secholex®, Policexide®), as well as lipostabil (Rhone-Poulenc), Eisai E-5050 (an unsubstituted ethanolamine derivative), imanixyl ( HOE-402), tetrahydrolipstatin (THL), istigmastanylphosphorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide (Sumitomo), Sandoz 58-035, American Cyanamid CL-277,082 and CL-2778282 -283,546 (disubstituted urea derivatives), nicotinic acid, acipimox, acifran, neomycin, paminosalicylic acid, aspirin, poly (diallylmethylamine) derivatives, as described in US Patent No. 4,759,923, poly quaternary amine (diallyl chloride dimethi
45/70 lamonium) and ionenes, as described in U.S. Patent No. 4,027,009, and other known serum cholesterol lowering agents. In one embodiment, the fibric acid derivative is probucol or gemfibrozil. All references cited are hereby incorporated by reference in their entirety.
Examples of ACAT inhibitors that can be used in combination with the formulations of the invention include, but are not limited to, those described in Drugs of the Future 24, 9-15 (1999), (Avasimibe); The AC AT inhibitor, CI-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters, Nicolosi and others, Atherosclerosis (Shannon, Irel). (1998), 137 (1), 77-85; The pharmacological profile of FCE 27677: a novel AC AT inhibitor with potent hypolipidemic activity mediated by selective suppression of the hepatic secretion of ApoBIOO-containing lipoprotein, Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16 (1), 16-30; RP 73163: a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor, Smith, C, and others, Bioorg.
Med. Chem. Lett. (1996), 6 (1), 47-50; ACAT inhibitors: physiologic mechanisms for hypolipidemic and anti-atherosclerotic activities in experimental animals, Krause and others, Editor (s): Ruffolo, Robert FL, Jr .; Hollinger, Mannfred A., Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, Boca Raton, Fla .; 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 '- [(l-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 references cited are hereby incorporated by reference in their entirety.
Examples of cholesterol absorption inhibitors suitable for use in combination with the formulations of the invention include, but are not limited to,
46/70 are limited to, SCH48461 (Schering-Plow), as well as those described in Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41,973 (1998), incorporated herein by reference in its entirety.
Examples of Na7bile ileal acid cotransporter inhibitors for use in combination with the formulations of the invention include, but are not limited to, compounds as described in Drugs of the Future, 24, 425430 (1999), incorporated herein by reference in its wholeness.
Examples of lipoxygenase inhibitors that can be used in combination with the formulations of the invention include, but are not limited to, 15-lipoxygenase (15-LO) inhibitors, such as benzimidazole derivatives, as described in WO 97/12615, inhibitors 15-LO, as described in WO 97/12613, isothiazolones, as described in WO 96/38144, and 15-LO inhibitors, as described by Sendobry and others Attenuation of diet-induced atherosclerosis in rabbits with a highly selective 15lipoxygenase 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 are hereby incorporated by reference in their entirety.
Examples of antihypertensive agents suitable for use in combination with the formulations of the present invention include, but are not limited to, beta-adrenergic blockers, calcium channel blockers (Le type T- type; for example diltiazem, verapamil, nifedipine, amlodipine and mibefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumetiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichlorometiazide, politiazide, benzthiazide, ethacrine, trichloride, ammonium, trichloride, trichloride, trichloride, trichloride, trichloride, trichloride, ACE inhibitors (eg, captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists (eg, losartan, irbesartan, valsartan), antagonists ET receptor (for example,
47/70 sitaxsentan, atrsentan and compounds described in U.S. Patent Nos. 5,612,359 and 6,043,265), ET / AII Dual antagonist (for example, compounds described in WO 00/01389), neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACE inhibitors) (for example , omapatrilat and gemopatrilat), and nitrates. All references cited are hereby incorporated by reference in their entirety.
Examples of antiobesity agents suitable for use in combination with the formulations of the present invention include, but are not limited to, beta 3 adrenergic agonists, lipase inhibitors, serotonin (and dopamine) reabsorption inhibitors, thyroid beta receptor drugs, agonists 5HT2C, (as Arena APD-356); MCHR1 antagonists, such as Synaptic SNAP-7941 and Takeda T-226926, melanocortin receptor agonists (MC4R), melanin concentrating hormone receptor (MCHR) antagonists (such as Synaptic SNAP-7941 and Takeda T226926), galanine receptor modulators , orexin antagonists, CCK agonists, NPY1 or NPY5 antagonists, NPY2 and NPY4 modulators, corticotropin releasing factor agonists, histamine receptor 3 (H3) modulators, 11-beta-HSD-1 inhibitors, adinopectin receptor modulators, monoamine reabsorption inhibitors or release agents, ciliary neurotrophic factors (CNTF, such as AXOKINE® by Regeneron), BDNF (brain-derived neurotrophic factor), leptin and leptin receptor modulators, receptor antagonists cannabinoid-1 (such as SR-141716 (Sanofi) or SLV-319 (Solvay)), and anoretic agents.
Beta 3 adrenergic agonists that can optionally be used in combination with formulations of the present invention include, but are not limited to, AJ9677 (Takeda / Dainippon), L750355 (Merck), CP331648 (Pfizer,) or other known beta 3 agonists as described in US Patent Nos. 5,541,204, 5,770,615, 5,491,134, 5,776,983 and 5,488,064, all of which are incorporated herein by reference in their entirety.
Examples of lipase inhibitors that can be used in combination with formulations of the present invention include, but are not limited to,
48/70 are limited to, orlistat and ATL-962 (Alizyme).
Serotonin (and dopamine) reabsorption inhibitors (or serotonin receptor agonists) that can be used in combination with the formulations of the present invention include, but are not limited to, BVT-933 (Biovitrum), sibutramine, topiramate (Johnson & Johnson) and axocin (Regeneron).
Examples of beta thyroid receptor compounds that can be used in combination with formulations of the present invention include, but are not limited to, thyroid receptor ligands, such as those described in WO 97/21993 (U. Cal SF), WO 99 / 00353 (KaroBio) and WO 00/039077 (KaroBio), incorporated herein by reference in their entirety.
Examples of monoamine reabsorption inhibitors that can be used in combination with the formulations of the present invention include, but are not limited to, fenfluramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, sertraline, chlorophentermine, chloroforex, chlortermin, picylorex, sibutramine, dexamfetamine , phentermine, phenylpropanolamine and mazindol.
Anoretic agents that can be used in combination with the formulations of the present invention include, but are not limited to, topiramate (Johnson & Johnson), dexamfetamine, phentermine, phenylpropanolamine and mazindole.
The patents and patent applications mentioned above are hereby incorporated by reference.
Where any of the formulations of the invention are used in combination with other therapeutic agent (s), the other therapeutic agent (s) can be used , for example, in the quantities indicated in the Physician's Desk Reference, as in the aforementioned patents and patent applications set out above, or otherwise known and used by the person of ordinary skill in the art.
The present invention considers a two-layer tablet comprising (1) a reduced mass metformin formulation;
49/70 (2) a formulation with canagliflozin; and (3) optionally a coating. Therefore, in one aspect, the present invention provides a two-layer tablet in which (1) the first layer comprises about 72-82% metformin hydrochloride; about 3-5% sodium carboxymethyl cellulose; 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 optional coating comprises Opadry® II.
In another aspect, the present invention provides a two-layer tablet in which (1) the first layer comprises about 76.6% metformin hydrochloride; about 3.84% sodium carboxymethyl cellulose; 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 a two-layer tablet in which (1) the first layer comprises about 76.6% metformin hydrochloride; about 3.84% sodium carboxymethyl cellulose; 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 bulking agents or fillers suitable for use herein herein 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, dextrose, mannitol (including Pearlitol SD 200 mannitol), fructose, xylitol, sorbitol, corn starch, modified isle starch, inorganic salts such as calcium carbonate, calcium phosphate, calcium diphosphate, calcium sulfate, dextrin / dextrates, maltodextrin, compressible sugars, and other bulking agents or fillers known
50/70 dos, and / or mixtures of two or more of the same. Several types of microcrystalline cellulose are suitable for use in the formulations described herein, for example, microcrystalline cellulose selected from the group consisting of Avicel® types: PH101, PH102, PH103, PH105, PH 112, PHI 13, PH200, PH301, and other types microcrystalline cellulose, such as salicified microcrystalline cellulose. Several types of lactose are suitable for use in the formulations described herein, for example, lactose selected from the group consisting of anhydrous lactose, lactose monohydrate, fast-flowing lactose, directly compressible anhydrous lactose, and modified lactose monohydrate.
Examples of binders suitable for use herein herein include, but are not limited to, carboxymethyl cellulose (including sodium carboxymethyl cellulose), hydroxypropyl cellulose (including hydroxypropyl cellulose EXF), corn starch, pregelatinized starch, modified corn starch, polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC) (including hydroxypropyl methylcellulose 2208), lactose, acacia gum, ethyl cellulose, cellulose acetate, as well as an agglutinating wax such as carnauba wax, paraffin, spermaceti, polyethylene or microcrystalline wax. also other conventional binding agents and / or mixtures of two or more of them.
Examples of disintegrants suitable for use herein herein include, but are not limited to, croscarmellose sodium, crospovidone, starch, potato starch, pregelatinized starch, corn starch, sodium starch glycolate, microcrystalline cellulose, substituted hydroxypropyl cellulose and other known disintegrants. Several types of specific disintegrants are suitable for use in the formulations described herein. For example, any degree of crospovidone can be used, including for example crospovidone XL-10, and includes selected members of the group consisting of Kollidon CL®, Poliplasdone XL®, Kollidon CLM®, Poliplasdone XL-10®, and Poliplasdone INF-10 ®. In one embodiment, the disintegrant, if present, of the stock granulation is sodium starch glycolate, croscarmellose sodium and / or crospovidone.
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Examples of lubricants suitable for use herein herein include, but are not limited to, magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, palmitic acid, sodium stearyl fumarate, sodium laurel sulfate , glyceryl palmitostearate, palmitic acid, myristic acid and hydrogenated vegetable fats and oils, as well as other known lubricants, and / or mixtures of two or more of them.
Examples of glidants and / or nonstick suitable for use herein herein include, but are not limited to, silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc, and other forms of silicon dioxide, such as aggregates of silicates and hydrated silica.
Examples of suitable release modifiers include, but are not limited to, hydroxypropyl methylcellulose, polyvinyl alcohol (PVA), ethyl cellulose, methacrylic polymers, hydroxypropyl cellulose, starches, gums, cellulose ethers, protein derived materials, nylon, acrylic resins , polylactic acid, polyvinylchloride, polyvinylpyrrolidones, and cellulose acetate phthalate.
In one aspect, the present invention provides methods of 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 two-layer tablet comprising a formulation of metformin XR or a reduced mass metformin XR formulation, an SGLT2 inhibitor formulation, and optionally a film coating. The two-layer tablet of the present invention, as described herein, can be administered to mammals, preferably humans, to treat diabetes (including type I diabetes and type II diabetes), impaired glucose tolerance, insulin resistance, and complications diabetics, such as nephropathy, retinopathy, neuropathy and cataracts, hyperglycemia, hyperinsulinemia, hypercholesterolemia, dyslipidemia, high blood levels of free fatty acids or glycerol, hyperiipidemia, hypertriglyceridemi52 / 70a, obesity, wound healing, tissue ischemia, atherosclerosis and hypertension . In a preferred embodiment, the two-layer tablet formulations of the present invention are administered to humans to treat type II diabetes.
In another aspect, the present invention provides a use of a two-layer tablet comprising a metformin XR formulation or a reduced mass metformin XR formulation, an SGLT2 inhibitor formulation, and optionally a film coating to prepare, or to the manufacture of a medication to treat diabetes (including type I diabetes and type II diabetes), impaired glucose tolerance, insulin resistance, and diabetic complications such as nephropathy, retinopathy, neuropathy and cataracts, hyperglycemia, hyperinsulinemia, hypercholesterolemia, dyslipidemia, elevated blood levels of free fatty acids or glycerol, hyperlipidemia, hypertriglyceridemia, obesity, wound healing, tissue ischemia, atherosclerosis and hypertension.
Definitions
The term about, as used herein, means a deviation within 10%, more preferably within 5%, and even more preferably within 2% of the reported numbers.
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 propylene glycol hydrate compound (1: 1: 1) dapagliflozin (S) of Example 2.
The term dapagliflozin (R) PGS as used herein means propylene glycol hydrate (1: 1: 1) dapagliflozin (R) from Example 3.
The term extended release of metformin or metformin XR as used herein, refers to an amount of metformin HCl that is present in a dosage form that allows for the delivery of oral controlled release that works by releasing drug-producing charge (metformin HC1) over a period of time
53/70 prolonged after administration, while maintaining the desired plasma levels of the drug.
The term Opadry® II as used herein means a film coating for a tablet, including a two-layer tablet, which comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol (PEG), and talc. Opadry® II white 85F18422 is comprised of polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc. Opadry® II Yellow 85F92582 is comprised of polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and yellow iron dioxide.
The term Opadry® HP as used herein means a film coating for a tablet comprising 40% polyvinyl alcohol, 20% polyethylene glycol, 15% talc, and 25% titanium dioxide.
Human Beings Studies
In a 24-week phase 3 clinical study, the combination of metformin and dapagliflozin, an SGLT2 inhibitor, reduced levels of glycosylated hemoglobin (HbAlc) and fasting plasma glucose (FPG) levels in type II diabetic patients. The levels of glycosylated hemoglobin and fasting plasma deglycosis were inadequately controlled with metformin alone, when compared to placebo plus metformin. The study also showed that subjects receiving dapagliflozin had statistically greater mean reductions in body weight compared to subjects taking placebo.
The study was designed to assess the efficacy and safety of dapagliflozin as a 24-hour metformin aid in patients with inadequately controlled type 2 diabetes. The data represent findings from a randomized, double-blind, placebo-controlled study of 546 individuals with type 2 diabetes whose HbAlc was greater than 5 or equal to 7.0 percent and less than or equal to 10 percent in the reference. After a two-week descent phase, subjects were randomized to separate treatment subdivisions from one to four: dapagliflozin 2.5 mg (n = 137), dapagliflozin 5 mg (n = 137),
54/70 dapagliflozin 10 mg (n = 135), or placebo (n = 137). Patients in all subdivisions also received metformin (more or equal to 1500 mg / d). The study's primary endpoint compared the HbAlc mean exchange rate for each class of dapagliflozin treatment compared to placebo after 24 weeks. Secondary evaluation reference points included change in body weight and FPG in ^§ 24 weeks compared to placebo, and adjusted the percentage of individuals treated with dapagliflozin that achieved HbAlc of less than 7 percent at 24 weeks. Exploratory assessment points included a decrease in body weight of more than or equal to 5 percent or more than or equal to 10 percent as well as a change in the percentage of reference body weight.
After 24 weeks, subjects receiving 2.5 mg, 5 mg and 10 mg of dapagliflozin plus metformin demonstrated a statistically significant change in mean change in HbAlc from the reference of 0.67 percent, -0.70 percent and -0.84 percent, respectively, compared to -0.30 percent for placebo. Subjects treated with dapagliflozin demonstrated a statistically significant adjusted mean change in FPG, a secondary assessment, from the 24-week reference: -17.8 mg / dL to dapagliflozin 2.5 mg -21.5 mg / dL to dapagliflozin 5 mg and 23 , 5 mg / dL / dl for dapagliflozin 10 mg, compared to -6.0 mg / dL for placebo.
The study also assessed the potential impact of dapagliflozin on weight loss. These findings included data measuring changes in total body weight over the 24-week study period. At 24 weeks, the change in total body weight in kg, a secondary endpoint, was -2.21 kg for dapagliflozin 2.5 mg, -3.04 kg for dapaglifiozine 5 mg and -2.86 kg for dapagliflozin from 10 mg, compared to -0.89 kg for placebo. In total, more patients taking dapagliflozin achieved weight losses greater than or equal to 5 percent compared to placebo, an exploratory assessment point.
These results indicate that the combination of an inhibitor of
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SGLT2, in particular propylene glycol hydrate of dapagliflozin or dapagliflozin (S), with metformin effectively treats hyperglycemia in type II diabetic patients without inducing weight gain .________
Example 1
Dapagliflozm - (2S, 3R, 4R ₅ 5S ₅ 6R) “2 (4Cloro3“ (4 ”ethoxybenzyl) feml)“ 6 (hydroxymetH) tetrahydro ~ 2H ~ pkan3,4,54nol
Dapagliflozin can be prepared using similar procedures as described in U.S. Patent No. 6,515,117 or published international applications from nos. WO 03/099836 and WO 2008/116179, the descriptions of which are hereby incorporated by reference in their entirety for any purpose. SGLT2 EC50 = 1.1 nM ._________________
Example 2
Dapagliflozin (S) PGS - (2S, 3R, 4R, 5S, 6R) 2 “(4 ~ chlorO“ 3 ~ (4 “ethoxybenzyl) phenyl) -6“ (hydroxymethyl) tetrahydrO “2H“ piran-3,4 ₅ 5triol iSf-oropane-12-dtol hydrate (1: 1
Propylene glycol hydrate (1: 1: 1) dapagliflozin (S) can be prepared using similar procedures as described in published applications WO 08/002824 and WO 2008/116179, the descriptions of which are hereby incorporated by reference in their entirety to any purpose. SGLT2 EC ₅ o = 1-1 nM.
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Example 3
Dapagliflozin (R) PGS - (2S, 3R, 4R ₅ 5S ₅ 6R) ~ 2- (4 ~ chloro-3 ~ (4 ~ ethoxybenzyl) phenll) “6 ~ (hydroxymethyl) tetraldro ~ 2H ~ pyran3,4,5triol
(R) propane-i, 2-dlol hydrate (1: 1: 1)
Propylene glycol hydrate (1: 1: 1) dapagliflozin (R) can be prepared using similar procedures as described in WO 08/002824 and WO 2008/116179, the descriptions of which are hereby incorporated by reference in their entirety for any purpose .
SGLT2 EC ₅₀ = 1.1 nM.
Example 4
Two-layer tablet containing metformin prolonged-release formulation (1000 mg) and immediate release formulation of dapagliflozin (S) PGS (5.00 mg) were prepared as described below.
First Layer % w / w quantity (m «) Metformin HC1 68.97 1000 Sodium carboxymethyl cellulose 3.45 50.01 Purified water or water for injectionwhat ^(a) Hydroxypropyl Methylcellulose 2208 27.10 393 Magnesium stearate 0.48 7.00 Total Metformin XR 100 1450 Second Layer Dapagliflozin 1.67 5.00 Anhydrous lactose 16.00 48.00 Microcrystalline cellulose 302 75.83 227.5 Crospovidone 4.00 12.00 Silicon dioxide 1.50 4.50 Magnesium stearate 1.00 3.00 Total Dapagliflozin IR 100 300 Full double-layer core1750
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Film Coating
Opadry® I! (2.5% weight gain) 43.75
Total of the 1793.75 film-coated tablet
Granulation of Metformin (1000 mg)
Metformin HC1.0.5% magnesium stearate, and sodium carboxymethyl cellulose were combined and mixed in a high shear granulator for one minute. Purified water, using a spout, was added with stirring for one minute. The wet granulated material was passed through a crusher and then dried until the moisture content was 1.0% or less. The dry material containing metformin HC1.0.5% magnesium stearate, and sodium carboxymethyl cellulose was passed through a crusher and discharged into polyethylene coated drums to provide granulation of 1 g of crushed metformin mass.
Hydroxypropyl methylcellulose 2208 USP (100,000 centipoise) (K100M Premium metocel) was added to a bin mixer and mixed for 60 revolutions. The material was passed through a mill and discharged to provide crushed hydroxypropyl methylcellulose 2208 USP.
Metformin (crushed Ig granulation), hydroxypropyl methylcellulose 2208 USP (ground), hydroxypropyl methylcellulose 2208 USP (unground), and magnesium stearate were added to a bin mixer and mixed for 60 revolutions. The mixed material was discharged into polyethylene coated drums to provide granulation of 1 g of extended release metformin mass.
Granulation of Dapagliflozin (2.5, 5.0, 10.0 mg)
Dapagliflozin (S) PGS was mixed with microcrystalline cellulose, anhydrous lactose, a portion of crospovidone, and a portion of silicon dioxide in a rotary drum mixer and passed through an appropriate cone crusher. A portion of magnesium stearate (screened) was mixed into the mixture and then compacted using an appropriate roller compactor. The compacted mixture was reduced to form granules. The granules were mixed with the remaining amount of crospovidone and silicon dioxide in an appropriate rotary drum mixer. The granules
58/70 were then mixed with the remaining amount of magnesium stearate in an appropriate rotary drum mixer.
Two Layer Compression
A two-layer tablet pressed with the metformin XR formulation or the reduced mass metformin XR formulation in the first cooper and the SGLT2 inhibitor formulation which is granulation of dapagliflozin (S) PGS (2.5 mg, 5 mg or 10 mg of resistance) in the second cooper. The pressed tablet was placed to obtain the object weight for the first layer (metformin XR or metformin XR of reduced mass). The second cooper was opened and the pressed tablet was adjusted to obtain the object-length weight of dapagliflozin and the two-layer tablet of metformin XR or dapagliflozin and metformin XR of reduced mass. Once the target weight was obtained, the press was adjusted to obtain the target hardness. Once the target hardness was obtained, the prepared tablets were periodically monitored for the weight of the first layer, and the weight, hardness, standard measure and friability of the whole tablet. The collected two-layer tablet was coated with Opadry® II PVA (polyvinyl alcohol).
Example 5
Two-layer tablet containing extended-release metformin formulation (1000 mg) and immediate-release dapagliflozin (S) GS formulation (2.5 mg) were prepared in a similar manner as described in Example 4.
First Layer % P / P quantity (mo) Metformin HCI 68.97 1000 Sodium carboxymethyl cellulose 3.45 5001 Purified water or water for injection - qs ^<a) Hydroxypropyl Methylcellulose 2208 27.10 393 Magnesium stearate 0.48 7 Total Metformin XR 100 1450 Second Layer Dapagliflozin 0.83 2.50
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Anhydrous lactose 16.00 48.00 Microcrystalline cellulose 302 76.67 230.00 Crospovidone 4.00 12.00 Silicon dioxide 1.50 4.50 Magnesium stearate 1.00 3.00 Total Dapagliflozin IR 100 300 Total Two Layer Core1750
Example 6
Two-layer tablets containing extended-release metformin formulation (1000 mg) and immediate-release dapagliflozin (S) PGS (10.00 mg) formulation were prepared in a
5 similar as described in Example 4. First Layer % w / w quantity (ms) Metformin HCI 68.97 1000 Sodium carboxymethyl cellulose 3.45 50.01 Purified water or water for injectionqs '' ^a) Hydroxypropyl Methylcellulose 2208 27.10 393 Magnesium stearate 0.48 7 Metformin XR Total 100 1450 Second Layer Dapagliflozin 3.33 10.00 Anhydrous lactose 16.00 48.00 Microcrystalline cellulose 302 74.17 222.50 Crospovidone 4.00 12.00 Silicon dioxide 1.50 4.50 Magnesium stearate 1.00 3.00 Dapagliflozin IR Total 100 300 Two layers of total mutual1750
Example 7
Two-layer tablet containing reduced-mass extended-release metformin formulation (1000 mg) and immediate-release dapagliflozin (S) PGS formulation (5.00 mg) were prepared
60/70 as described below.
First Layer % w / w amount (mg) Metformin HCI 76.62 1000 Sodium carboxymethyl cellulose 3.84 50.01 Purified water or water for injection - qs / ^A Hydroxypropyl Methylcellulose 2208 18.01 ^(b) 235 Silicon dioxide 1.00 ^{,; c)} 13 Magnesium stearate 0.53 7 Total Metformin XR 100 1305 Second Layer Dapagliflozin 1.67 5 Anhydrous lactose 16 48 Microcrystalline cellulose 302 75.84 227.5 Crospovidone 4 12 Silicon dioxide 1.5 4.5 Magnesium stearate 1 3 Dapagliflozin IR Total 100 300
Two layers of total mutual 1605
Film Coating
Opadry® II (2.5% weight gain) 40.13
Whole Film Coated Tablet 1645.13 ^(a) refers to the amount sufficient to make the granulation composition
100% w / w ^{b) The range is 15% - 27% ^{c) The range is 0.75 & - 1.25%
Metformin HC1.0.5% magnesium stearate, and sodium carboxymethyl cellulose were combined and mixed in a high shear granulator for one minute. Purified water, using a spout, was added with action for one minute. The wet granulated material was passed through a crusher and then dried until the moisture content was 1.0% or less. The dry material containing metformin HC1.0.5% magnesium stearate, and sodium carboxymethyl cellulose was passed through a crusher and
61/70 unloaded in polyethylene coated drums to provide a 1 g mass granulation of crushed metformin.
Metformin (crushed Ig granulation), hydroxypropyl methylcellulose 2208 USP (100,000 centipoise) (metocel K100M Premium), and 5 silicon dioxide were added to a bin mixer and mixed for 120 revolutions. Magnesium stearate was added, and after 60 revolutions, the material was discharged into polyethylene coated drums to provide granulation of 1 g of metformin mass for prolonged deliberation.
The granulation of dapagliflozin (S) PGS and the two-layer compression procedures were conducted as described in Example 4.
Example 8
Two-layer tablets containing an extended formulation of metformin (1000 mg) of reduced mass and immediate release formulation of dapagliflozin (S) PGS (2.5 mg) were prepared in a
15 similarly as described in Example 7. amount (mg) First Layer % P / P Metformin HCI 76.62 1000 Sodium carboxymethyl cellulose 3.84 50.01 Purified water or water for injection - what ^(a) Hydroxypropyl methylcellulose 2208 18.01 ^(b) 235 Silicon dioxide 1.00 ^(c) 13 Magnesium stearate 0.53 7 Total Metformin XR 100 1305 Second layer Dapagliflozin 0.83 2.50 Lactose Andira 16.00 48.00 Microcrystalline cellulose 302 76.67 230.00 Crospovidone 4.00 12.00 Silicon dioxide 1.50 4.50 Magnesium stearate 1.00 3.00 Total Dapagliflozin IR 100 300 Total Core in both layers1605
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Example 9
Two-layer tablets containing a reduced-mass extended metformin (1000 mg) formulation and dapagliflozin (S) PGS immediate-release formulation (10.00 mg) were prepared in a similar manner as described in Example 7.
First Layer % P / P amount (mg) Metformin HCI 76.62 1000 Sodium carboxymethyl cellulose 3.84 50.01 Purified water or water for injection - what ^(a) Hydroxypropyl methylcellulose 2208 18.01 ^(b) 235 Silicon dioxide 1.00 ^(c) 13 Magnesium stearate 0.53 7 Total Metformin XR 100 1305 Second layer Dapagliflozin 0.83 2.50 Anhydrous Lactose 16.00 48.00 Microcrystalline cellulose 302 76.67 230.00 Crospovidone 4.00 12.00 Silicon dioxide 1.50 4.50 Magnesium stearate 1.00 3.00 Total Dapagliflozin IR 100 300 Total core in both layers1605
Other IR formulations of the SGLT2 inhibitor, described in Table 2, can be used to prepare two-layer tablets of the present invention. The formulations in Table 2 are compatible with the metformin XR or reduced mass metformin XR formulations described herein. The two-layer tablets prepared from IR formulations of the SGLT2 inhibitor in Table 2 reduced or eliminated cracking, separation, and / or cross-contamination with the metformin XR layer and the reduced mass metformin XR layer.
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Table 2
% w / w % w / w % w / w % w / w % w / w Dapagliflozin (S) PGS 1.66 1.66 1.66 1.66 1.66 Microcrystalline cellulose 302 59.83 63.83 56.83 65.83 60.83 Anhydrous Lactose 16.00 16.00 16.00 16.00 16.00 Pre-gelatinized starch 16.00 13.00 19.00 - - Hydroxypropyl Cellulose EXF - - - 10.00 - Mannitol - - - - 15.00 Crospovidone 4.00 4.00 4.00 4.00 4.00 Silicon dioxide 1.50 1.50 1.50 1.50 1.50 Magnesium stearate 1.00 1.00 1.00 1.00 1.00
Example 10
Two-layer tablets containing metformin extended release formulation (500 mg) and dapagliflozin (S) PGS immediate release formulation (5.00 mg) were prepared in a similar manner as described in Example 13 except that silicon dioxide has not been added to the metformin layer.
Component Occupation % w / w per layer Quantity per layer (mg) Metformin HCI XR Layer (1 ^â Layer) Metformin Hydrochloride Active 48.85 500.00 Sodium carboxymethyl cellulose Binder 4.89 50.03 Purified water or water for injection Granulation fluid - q.S ' ⁽¹⁾ Hydroxypropyl methylcellulose 2208 Release modifier 34.98 357.98 Hydroxypropyl methylcellulose 2910 Release modifier 0.97 9.92 Microcrystalline cellulose Filler 9.97 102.03 Magnesium stearate Lubricant 0.34 3.53 Total Metformin Layer HCI XR100.00 1023.49 Dapagliflozin layer (2 ^â Layer) Dapagliflozin Active 1.67 5.00 Anhydrous lactose Filler 16.00 48.00
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Microcrystalline cellulose 302 Filler 75.83 227.50 Crospovidone Disintegrating 4.00 12.00 Silicon dioxide Non-stick 1.50 ² 4.50 Magnesium stearate Lubricant 1.00 3.00 Total dapagliflozin Layer - 100.00 300.00 Total double layer core - - 1323.49 Opadry® II film coating component (2.5% weight gain) Coating material - 33.09 Total film-coated tablet - - 1356.58
¹ Purified water is used only for processing and is removed during drying ² The range is 0.5% to 1.5%
Example 11
Two-layer tablets containing metformin extended release formulation (500 mg) and dapagliflozin (S) PGS immediate release formulation (10.0 mg) were prepared in a similar manner as described in Example 13 except that silicon dioxide was not added to the metformin layer.
Component Occupation % w / w per layer Quantity per layer (mg) Metformin XR Layer (1 ^â Layer) Metformin Hydrochloride Active 48.85 500.00 Sodium carboxymethyl cellulose Binder 4.89 50.03 Purified water or water for injection G ran ul uction fluid - q.s' ⁽¹⁾ Hydroxypropyl methylcellulose 2208 Release modifier 34.98 357.98 Hydroxypropyl methylcellulose 2910 Release modifier 0.97 9.92 Microcrystalline cellulose Filler 9.97 102.03 Magnesium stearate Lubricant 0.34 3.53
65/70
Total Metformin XR Layer100.00 1023.49 Dapaglifiozine layer (2 ^â Layer) Dapaglifiozine Active 3.33 10.00 Anhydrous lactose Filler 16.00 48.00 Microcrystalline cellulose 302 Filler 74.17 222.50 Crospovidone Disintegratedyou 4.00 12.00 Silicon dioxide Non-stick 1.50 ⁽²⁾ 4.50 Magnesium stearate Lubricant 1.00 3.00 Total dapaglifiozine layer - 100.00 300.00 Total double layer core - - 1323.49 Film coating componentOpadry® II (2.5% weight gain) Coating material - 33.09 Total length coated with film - - 1356.58
¹ Purified water is used only for processing and is removed during drying ² The range is 0.5% to 1.5%
Example 12
Two-layer tablets containing metformin extended release formulation (500 mg) and dapaglifiozine (S) PGS immediate release formulation (2.50 mg) were prepared in a similar manner as described in Example 13 except that silicon dioxide was not added to the metformin layer.
Component Occupation % w / w per layer Quantity per layer (mg) Metformin XR Layer (1 ^â Layer) Metformin Hydrochloride Active 48.85 500.00 Sodium carboxymethyl cellulose Binder 4.89 50.03
66/70
Purified water or water for injection Fluidg ran ul action - q.S ' ⁽¹⁾ Hydroxypropyl methylcellulose 2208 Release modifier 34.98 357.98 Hydroxypropyl methylcellulose 2910 Release modifier 0.97 9.92 Microcrystalline cellulose Filler 9.97 102.03 Magnesium stearate Lubricant 0.34 3.53 Total Metformin XR Layer100.00 1023.49 Dapagliflozin layer (2 ^â Layer) Dapagliflozin Active 0.83 2.50 Anhydrous lactose Filler 16.00 48.00 Microcrystalline cellulose 302 Filler 76.67 230.00 Crospovidone Disintegrating 4.00 12.00 Silicon dioxide Non-stick 1.50 ⁽²⁾ 4.50 Magnesium stearate Lubricant 1.00 3.00 Total dapagliflozin layer - 100.00 300.00 Total core of the two layers - - 1323.49 Film coating componentOpadry® II (2.5% weight gain) Coating material - 33.09 Total film-coated tablet - - 1356.58
¹ Purified water is used only for processing and is removed during drying ² The range is 0.5% to 1.5%
Example 13
Two-layer tablets containing extended-release formulation of metformin (500 mg) and immediate-release formulation
dapagliflozin (S) PGS (5.0 mg) were prepared as described below. Component Occupation % w / w per layer Quantity per layer
67/70
(mg) Metformin XR Layer (1 ^â Layer) Metformin Hydrochloride Active 48.37 500.00 Sodium carboxymethyl cellulose Binder 4.84 50.03 Purified water or water for injection G ran ul uction fluid - q.S ' ⁽¹⁾ Hydroxypropyl methylcellulose 2208 Release modifier 34.63 357.98 Hydroxypropyl methylcellulose 2910 Release modifier 0.96 9.92 Microcrystalline cellulose Filler 9.87 102.03 Silicon dioxide Compression aid 0.99 10.24 Magnesium stearate Lubricant 0.34 3.53 Total metformin aXR Layer100.00 1033.73 Dapagliflozin layer (2 ^â Layer) Dapagliflozin Active 1.67 5.00 Anhydrous lactose Filler 16.00 48.00 Microcrystalline cellulose 302 Filler 75.83 227.50 Crospovidone Disintegratedyou 4.00 12.00 Silicon dioxide Non-stick 1.50 ² 4.50 Magnesium stearate Lubricant 1.00 3.00 Total dapagliflozin Layer a - 100.00 300.00 Total core of the two layers - - 1333.73 Film coating componentOpadry® II (2.5% weight gain) Coating material - 33.34 Total film-coated tablet - - 1367.07
¹ Purified water is used only for processing and is removed during drying ² The range is 0.5% to 1.5%
68/70
Metformin HCI, 0.5% magnesium stearate, and sodium carboxymethyl cellulose were combined and mixed in a high shear granulator for one minute. Purified water, using a spout, was added with stirring for one minute. The wet granulated material was passed through a mill and then dried until the moisture content was 1.0% or less. The dry material containing HCI metformin, 0.5% magnesium stearate, and sodium carboxymethyl cellulose was passed through a mill and discharged into drums lined with polyethylene to provide bulk granulation of 500 mg of ground metformin.
Bulky granulation of 500 mg of ground metformin, hydroxypropyl methyl cellulose 2208, hydroxypropyl methyl cellulose 2910, microcrystalline cellulose and silicon dioxide were added in a box blender and mixer for 240 rotations. Magnesium stearate was added, and after 60 rotations, the material was discharged into drums lined with polyethylene to provide voluminous granulation of 500 mg extended-release metformin.
The granulation of dapagliflozin (S) PGS and the two layer compression procedures were conducted in a similar manner as described in Example 4.
Example 14
Two-layer tablets containing metformin extended release formulation (500 mg) and dapagliflozin (S) PGS immediate release formulation (10.0 mg) were prepared in a similar manner as described in Example 13.
Component Occupation % w / w per layer Quantity per layer (mg) Metformin XR Layer (1 ^â Layer) metformin hydrochloride Active 48.37 500.00 Sodium carboxymethyl cellulose Binder 4.84 50.03 Purified water or water for injection Granulation fluid - q.S ' ⁽¹⁾ Hydroxypropyl methylcellulose Modifier 34.63 357.98
69/70
2208 release Hydroxypropyl methylthiulose 2910 Release modifier 0.96 9.92 Microcrystalline cellulose Filler 9.87 102.03 Silicon dioxide Compression aid 0.99 10.24 Magnesium stearate Lubricant 0.34 3.53 Total metformin XR layer100.00 1033.73 Dapagliflozin layer (2 ^â Layer) Dapagliflozin Active 3.33 10.00 Anhydrous lactose Filler 16.00 48.00 Microcrystalline cellulose 302 Filler 74.17 222.50 Crospovidone Disintegratedyou 4.00 12.00 Silicon dioxide Non-stick 1.50 ⁽²⁾ 4.50 Magnesium stearate Lubricant 1.00 3.00 Total dapagliflozin layer - 100.00 300.00 Total core of the two layers - - 1333.73 Film coating componentOpadry® II (2.5% weight gain) Coating material - 33.34 Total film-coated tablet - - 1367.07
¹ Purified water is used only for processing and is removed during drying ² The range is 0.5% to 1.5%
Example 15
Two-layer tablets containing extended-release formulation of metformin (500 mg) and immediate-release formulation of dapagliflozin (S) PGS (2.50 mg) were prepared in a similar manner as described in Example 13,
70/70
Component Occupation % w / wper layer Quantity per layer (mg) Metformia Layer XR (1 ^â Layer The) metformin hydrochloride Active 48.37 500.00 Sodium carboxymethyl cellulose Binder 4.84 50.03 Purified water or water for injection Granuating fluid - q.S ' ⁽¹⁾ Hydroxypropyl methylcellulose 2208 Release modifier 34.63 357.98 Hydroxypropyl methylcellulose 2910 Release modifier 0.96 9.92 Microcrystalline cellulose Filler 9.87 102.03 Silicon dioxide Assistant ofcompression 0.99 10.24 Magnesium stearate Lubricant 0.34 3.53 Total Metformin XR Layer100.00 1033.73 Dapagliflozin layer (2 ^â Layer) Dapagliflozin Active 0.83 2.50 Anhydrous lactose Filler 16.00 48.00 Microcrystalline cellulose 302 Filler 76.67 230.00 Crospovidone Disintegrating 4.00 12.00 Silicon dioxide Non-stick 1.50 ⁽²⁾ 4.50 Magnesium stearate Lubricant 1.00 3.00 Total dapagliflozin layer - 100.00 300.00 Total core of the two layers - - 1333.73 Film coating componentOpadry® II (2.5% weight gain) Coating material - 33.34 Total film-coated tablet - - 1367.07
¹ Purified water is used only for processing and is removed during drying ² The range is 0.5% to 1.5%

权利要求:
Claims (10)
[1]
1. Two-layer tablet, characterized by the fact that it comprises: (1) a first layer in which the first layer is an extended-release formulation of metformin, comprising metformin hydrochloride, sodium carboxymethyl cellulose as a binder; hydroxypropyl methylcellulose as a release modifier; magnesium stearate as a lubricant; and optionally silicon dioxide or colloidal silicon dioxide as a nonstick; (2) a second layer where the second layer is a formulation of the SGLT2 inhibitor comprising dapagliflozin or propylene glycol dapagliflozin (S), fillers including microcrystalline cellulose and one or two fillers selected from anhydrous lactose, pregelatinized starch, mannitol and hydroxypropyl cellulose, crospovidone as a disintegrant, silicon dioxide as a nonstick, and magnesium stearate as a lubricant; and (3) optionally a film coating that covers the first layer and the second layer.
[2]
(2) the first coating comprises Opadry® HP; (3) the second coating comprises saxagliptin and Opadry® HP; and (4) the third coating comprises Opadry® HP.
14/16
28. Coated tablet, characterized by the fact that it comprises: (1) a tablet core comprising 72 to 82% metformin hydrochloride; from 3 to 5% sodium carboxymethyl cellulose; 15 to 22% hydroxypropyl methylcellulose 2208; from 0.75 to 1.25% of silicon dioxide or from 0.25 to 0.75% of colloidal silicon dioxide; and from 0.1 to 0.6% of magnesium stearate; (2) a first coating that coats the 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 one of the first coat and the second coat comprises saxagliptin.
29. Coated tablet according to claim 28, characterized in that the first coating comprises a polymer based on polyvinyl alcohol; (3) the second coating comprises saxagliptin and a polymer based on polyvinyl alcohol; and (4) the third coating comprises a polymer based on polyvinyl alcohol.
30. Coated tablet according to claim 28, characterized in that (1) the tablet core comprises 76.6% metformin hydrochloride; 3.84% sodium carboxymethyl cellulose; 18% hydropropyl methylcellulose 2208; from 0.75 to 1.25% of silicon dioxide or from 0.25 to 0.75% of colloidal silicon dioxide; and 0.53% magnesium stearate; (2) the first coating comprises Opadry® HP; (3) the second coating comprises saxagliptin and Opadry® HP; and (4) the third coating comprises Opadry® HP.
31. Coated tablet according to claim 28, characterized in that (1) the tablet core comprises 76.6% metformin hydrochloride; 3.84% sodium carboxymethyl cellulose; 18% hydropropyl methylcellulose 2208; 1% silicon dioxide; and 0.53% magnesium stearate; (2) the first coating comprises Opadry® HP; (3) the second coating comprises saxagliptin and Opadry® HP; and (4) the third coating comprises Opadry® HP.
32. Pharmaceutical combination, characterized by the fact that
15/16 comprises a two-layer tablet, as defined in any of claims 1 to 16, and an antidiabetic, wherein the antidiabetic is a sulfonylurea, thiazolidinedione, alpha glucosidase inhibitor, meglitinide, glucagon-like peptide (GLP) agonist , insulin, amylin agonist, fructose inhibitor 1,6-bis phosphatase, insulin secretagogue, insulin synthesizer, glycokinase activator, glucocorticoid antagonist, AMP kinase activator, incretin pathway modulators such as incretin secretagogue, imitation of incretin, incretin enhancer, bile acid scavenger or bile acid receptor agonist such as TGR5 agonist, dopamine receptor agonist, aldose reductase inhibitor, PPARy agonist, PPARa agonist, PPARõ agonist or antagonist, double agonist PPARa / γ, ΙΙ-β-HSD-1 inhibitor, dipeptidyl peptidase IV (DPP4) inhibitor other than saxagliptin, SGLT2 inhibitor other than dapagliflozin, peptide glucagon-like deo-1 (GLP-1), GLP-1 agonist, or PTP-1B inhibitor.
33. Pharmaceutical combination, characterized in that it comprises a two-layer tablet, as defined in any one of claims 1 to 16, and a weight loss agent, wherein the weight loss agent is sibutrimine, an antagonist of CB1, a 5HT2C agonist, an MCHR1 antagonist, Orlistat, a thyromimetic, a mimetic amylin, or a ghrelin antagonist.
34. Two-layer tablet, characterized by the fact that it comprises from 72 to 82% of metformin hydrochloride; 3 to 5% sodium carboxymethyl cellulose; from 15 to 22% hydroxypropyl methylcellulose 2208; from 0.75 to 1.25% of silicon dioxide or from 0.25 to 0.75% of colloidal silicon dioxide; and from 0.1 to 0.6% of magnesium stearate; and (2) a second layer in which the second layer is a formulation of the SGLT2 inhibitor; and (3) optionally a film coating covering the first layer and the second layer
35. Two-layer tablet according to claim 34, characterized in that the second layer comprises canagliflozin.
16/16
36. Two-layer tablet according to claim 34, characterized in that the second layer comprises dapagliflozin or or propylene glycol dapagliflozin (S) hydrate.
37. Two-layer tablet, according to any one
(2) the first coating comprises Opadry® HP; (3) the second coating comprises saxagliptin and Opadry® HP; and (4) the third coating comprises Opadry® HP.
27. Two-layer coated tablet according to claim 22, characterized in that (1) the first layer comprises 76.6% metformin hydrochloride; 3.84% sodium carboxymethyl cellulose; 18% hydroxypropyl methylcellulose 2208; from 0.75 to 1.25% of silicon dioxide or from 0.25 to 0.75% of colloidal silicon dioxide; and 0.53%
13/16 magnesium stearate; the second layer comprises:
(A) 0.8% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 77% microcrystalline cellulose 302; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(B) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 76% microcrystalline cellulose 302; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(C) 3.4% dapagliflozin or propylene glycol dapagliflozin (S) hydrate, 16% anhydrous lactose; 74% microcrystalline cellulose 302; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(D) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 64% microcrystalline cellulose 302; 13% pre-gelatinized starch; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(E) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 57% microcrystalline cellulose 302; 19% pre-gelatinized starch; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(F) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 66% microcrystalline cellulose 302; 10% hydroxypropyl cellulose EXF; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate; or (G) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 61% microcrystalline cellulose 302; 15% mannitol; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(2) the first coating comprises Opadry® HP; (3) the second coating comprises saxagliptin and Opadry® HP; and (4) the third coating comprises Opadry® HP.
12/16
26. Two-layer coated tablet according to claim 22, characterized in that (1) the first layer comprises from 72 to 82% metformin hydrochloride; 3 to 5% sodium carboxymethyl cellulose; from 15 to 22% hydroxypropyl methylcellulose 2208; from 0.75 to 1.25% of silicon dioxide or from 0.25 to 0.75% of colloidal silicon dioxide; and from 0.1 to 0.6% of magnesium stearate; the second layer comprises:
(A) 0.5 to 4% dapaglifiozine or propylene glycol dapaglifiozine (S) hydrate; 14 to 18% anhydrous lactose; 72 to 80% microcrystalline cellulose 302; from 2 to 6% of crospovidone; from 0.5 to 2.5% silicon dioxide; and from 0.5 to 1.5% magnesium stearate;
(B) 0.5 to 4% dapaglifiozine or propylene glycol dapaglifiozine (S) hydrate; 14 to 18% anhydrous lactose; 50 to 70% microcrystalline cellulose 302; 10 to 22% pregelatinized starch; from 2 to 6.00% of crospovidone; from 0.5 to 2.5% silicon dioxide; and from 0.5 to 1.5% magnesium stearate;
(C) 0.5 to 4% dapaglifiozine or propylene glycol dapaglifiozine (S) hydrate; 14 to 18% anhydrous lactose; 60 to 70% microcrystalline cellulose 302; from 5 to 15% hydroxypropyl cellulose EXF; from 2 to 6% of crospovidone; from 0.5 to 2.5% silicon dioxide; and from 0.5 to 1.5% magnesium stearate; or (D) 0.5 to 4% dapaglifiozine or propylene glycol dapaglifiozine (S) hydrate; 14 to 18% anhydrous lactose; 55 to 65% microcrystalline cellulose 302; 10 to 20% mannitol; from 2 to 6% of crospovidone; from 0.5 to 2.5% silicon dioxide; and from 0.5 to 1.5% magnesium stearate;
2/16
0 to 1.5% colloidal silicon dioxide; (2) the second layer comprises 0.5 to 4% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 14 to 18% anhydrous lactose; 50 to 80% microcrystalline cellulose; from 0 to 20% pregelatinized starch; 0 to 20% mannitol; from 0 to 15% hydroxypropyl cellulose; from 2 to 6% of crospovidone; from 0.5 to 2.5% silicon dioxide; and 0.5 to 2% magnesium stearate; (3) the optional film coating is Opadry® II.
2. Two-layer tablet according to claim 1, characterized in that the total weight of the second layer is from 300 mg to 400 mg.
[3]
3/16
3. Two-layer tablet according to claim 1 or 2, characterized in that the two-layer tablet is coated with film.
[4]
4/16 propylene glycol; 16% anhydrous lactose; 61% microcrystalline cellulose 302; 15% mannitol; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate.
11. Two-layer tablet according to any one of claims 1 to 4, characterized in that (1) the first layer comprises 72 to 82% metformin hydrochloride; 3 to 5% sodium carboxymethyl cellulose; from 15 to 22% hydroxypropyl methylcellulose 2208; from 0.75 to 1.25% of silicon dioxide or from 0.25 to 0.75% of colloidal silicon dioxide; and from 0.1 to 0.6% of magnesium stearate; and (2) the second layer is 300 mg to 400 mg.
12. Two-layer tablet according to claim 11, characterized in that the second layer comprises:
(A) from 0.5 to 4% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 14 to 18% anhydrous lactose; 72 to 80% microcrystalline cellulose 302; from 2 to 6% of crospovidone; from 0.5 to 2.5% silicon dioxide; and from 0.5 to 1.5% magnesium stearate;
(B) 0.5 to 4% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 14 to 18% anhydrous lactose; 50 to 70% microcrystalline cellulose 302; 10 to 22% pregelatinized starch; from 2 to 6.00% of crospovidone; from 0.5 to 2.5% silicon dioxide; and from 0.5 to 1.5% magnesium stearate;
(C) 0.5 to 4% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 14 to 18% anhydrous lactose; 60 to 70% microcrystalline cellulose 302; from 5 to 15% hydroxypropyl cellulose EXF; from 2 to 6% of crospovidone; from 0.5 to 2.5% silicon dioxide; and from 0.5 to 1.5% magnesium stearate; or (D) from 0.5 to 4% dapagliflozin or propylene glycol dapagliflozin hydrate (S); 14 to 18% anhydrous lactose; 55 to 65% microcrystalline cellulose 302; 10 to 20% mannitol; from 2 to 6% of crospovidone; from 0.5 to 2.5% silicon dioxide; and 0.5 to 1.5% magnesium stearate.
13. Two-layer tablet according to claim 12, characterized by the fact that the weight ratio between the first
4. Two-layer tablet according to claim 3, characterized in that the film coating is Opadry® II.
[5]
5 of claims 34 to 36, characterized in that (1) the first layer comprises 76.6% metformin hydrochloride; 3.84% sodium carboxymethyl cellulose; 18% hydroxypropyl methylcellulose 2208; from 0.75 to 1.25% of silicon dioxide or from 0.25 to 0.75% of colloidal silicon dioxide;
and 0.53% magnesium stearate.
5/16 layer and the second layer is 4.4: 1.
14. Two-layer tablet according to any one of claims 1 to 4, characterized in that (1) the first layer comprises 76.6% metformin hydrochloride; 3.84% sodium carboxymethyl cellulose; 18% hydroxypropyl methylcellulose 2208; from 0.75 to 1.25% silicon dioxide or from 0.25 to 0.75% colloidal silicon dioxide; and 0.53% magnesium stearate; and (2) the second layer is 300 to 400 mg.
15. Two-layer tablet according to claim 14, characterized by the fact that the second layer comprises:
(A) 0.8% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 77% microcrystalline cellulose 302; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(B) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 76% microcrystalline cellulose 302; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(C) 3.4% dapagliflozin or propylene glycol dapagliflozin (S) hydrate, 16% anhydrous lactose; 74% microcrystalline cellulose 302; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(D) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 64% microcrystalline cellulose 302; 13% pre-gelatinized starch; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(E) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 57% microcrystalline cellulose 302; 19% pre-gelatinized starch; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(F) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 66% microcrystalline cellulose 302; 10% hydroxypropyl cellulose EXF; 4% crospovidone; 1.5% of
Two-layer tablet according to any one of claims 1 to 4, characterized in that the fillers of the second layer include microcrystalline cellulose in combination with pregelatinized starch, hydroxypropyl cellulose EXF or mannitol.
[6]
6/16 silicon oxide; and 1% magnesium stearate; or (G) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 61% microcrystalline cellulose 302; 15% mannitol; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate.
16. Two-layer tablet according to claim 15, characterized in that the weight ratio between the first layer and the second layer is 4.4: 1,
17. Use of a two-layer tablet, as defined in any one of claims 1 to 16, characterized by the fact that it is to prepare a medication to treat a selected diabetes disorder or disease (including type I and type II diabetes), impaired glucose tolerance, insulin resistance, nephrotia, retinopathy, neuropathy and cataracts, hyperglycemia, hyperinsulinemia, hypercholesterolemia, dyslipidemia, high blood levels of free fatty acids or glycerol, hyperlipidemia, hypertriglyceridemia, obesity, wound healing, ischemic tissue, ischemia and hypertension in a mammal.
18. Use according to claim 17, characterized by the fact that the disorder is type II diabetes and the mammal is a human.
19. Use according to claim 17 or 18, characterized in that the (1) first layer comprises 69% metformin hydrochloride; 3.5% sodium carboxymethyl cellulose; 27% hydroxypropyl methylcellulose 2208; and 0.49% magnesium stearate; (2) the second layer is 300 to 400 mg and comprises (A) 0.8% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 77% microcrystalline cellulose 302; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(B) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 76% microcrystalline cellulose 302; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
6, characterized by the fact that (1) the first layer comprises 67 to 71% metformin hydrochloride, 3 to 5% sodium carboxymethyl cellulose, 25 to 29% hydroxypropyl methyl cellulose 2208, and 0.1 0.75% magnesium stearate; and (2) the second layer is 300 mg to 400 mg.
6. Two-layer tablet according to any one of claims 1 to 4, characterized by the fact that (1) the first layer comprises 64 to 82% metformin hydrochloride, 3 to 5% sodium carboxymethyl cellulose ; 15 to 30% hydroxypropyl methylcellulose; from 0.1 to 0.75% of magnesium stearate; and 0 to 2% silicon dioxide or
[7]
7/16 (C) 3.4% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 74% microcrystalline cellulose 302; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(D) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 64% microcrystalline cellulose 302; 13% pre-gelatinized starch; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(E) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 57% microcrystalline cellulose 302; 19% pre-gelatinized starch; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(F) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 66% microcrystalline cellulose 302; 10% hydroxypropyl cellulose EXF; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate; or (G) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 61% microcrystalline cellulose 302; 15% mannitol; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate; and (3) there is a coating, and the coating is Opadry® II.
20. Use according to claim 17 or 18, characterized in that the (1) first layer comprises 76.6% metformin hydrochloride, 3.84% sodium carboxymethyl cellulose, 18% hydroxypropyl methyl cellulose 2208 , from 0.75 to 1.25% silicon dioxide or from 0.25 to 0.75% colloidal silicon dioxide, and 0.53% magnesium stearate; (2) the second layer is from 300 mg to 400 mg and comprises (A) 0.8% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 76.6% microcrystalline cellulose 302; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(B) 1.7% dapagliflozin or dapagliflozin hydrate (S) of
7, characterized by the fact that the second layer comprises:
(A) from 0.5 to 4% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 14 to 18% anhydrous lactose; 72 to 80% microcrystalline cellulose 302; from 2 to 6% of crospovidone; from 0.5 to 2.5% silicon dioxide; and from 0.5 to 1.5% magnesium stearate;
(B) 0.5 to 4% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 14 to 18% anhydrous lactose; 50 to 70% microcrystalline cellulose 302; 10 to 22% pregelatinized starch; from 2 to 6% of crospovidone; from 0.5 to 2.5% silicon dioxide; and from 0.5 to 1.5% magnesium stearate;
(C) 0.5 to 4% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 14 to 18% anhydrous lactose; 60 to 70% microcrystalline cellulose 302; from 5 to 15% hydroxypropyl cellulose EXF; from 2 to 6% of crospovidone; from 0.5 to 2.5% silicon dioxide; and from 0.5 to 1.5% magnesium stearate; or (D) 0.5 to 4% dapagliflozin or propylene glycol dapagliflozin hydrate (S); 14 to 18% anhydrous lactose; 55 to 65% microcrystalline cellulose 302; 10 to 20% mannitol; from 2 to 6% of crospovidone; from 0.5 to 2.5% silicon dioxide; and 0.5 to 1.5% magnesium stearate.
7. Two-layer tablet according to claim
[8]
8/16 propylene glycol; 16% anhydrous lactose; 76% microcrystalline cellulose 302; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(C) 3.4% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 74% microcrystalline cellulose 302; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(D) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 64% microcrystalline cellulose 302; 13% pre-gelatinized starch; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(E) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 57% microcrystalline cellulose 302; 19% pre-gelatinized starch; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(F) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 66% microcrystalline cellulose 302; 10% hydroxypropyl cellulose EXF; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate; or (G) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 61% microcrystalline cellulose 302; 15% mannitol; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate; and (3) there is a coating, and the coating is Opadry® II.
21. Two-layer coated tablet, characterized in that it comprises (1) a two-layer tablet core as defined in any one of claims 1, 2 or 5 to 16; (2) a first coating that covers the two-layer 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; at least one of the first coat and second coat
8. Two-layer tablet according to claim
[9]
9/16 ment comprises saxagliptin.
22. Two-layer coated tablet, characterized by the fact that it comprises: (1) two-layer tablet core comprising two layers in which the first layer comprises metformin hydrochloride, sodium carboxymethyl cellulose as a binder; hydroxypropyl methylcellulose as a release modifier; magnesium stearate as a lubricant; and optionally silicon dioxide or colloidal silicon dioxide as a nonstick; and the second layer comprises dapagliflozin or propylene glycol dapagliflozin (S) hydrate, fillers including microcrystalline cellulose and one or two fillers selected from anhydrous lactose, pregelatinized starch, mannitol and hydroxypropyl cellulose, crospovidone as a disintegrant, silicon dioxide as an antifreeze , and magnesium stearate as a lubricant; wherein the second layer is 300 to 400 mg; (2) a first coating that covers the core of the two-layer tablet 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 one of the first coat and the second coat comprises saxagliptin.
23. Two-layer coated tablet according to claim 22, characterized in that (1) the first layer comprises 64 to 82% metformin hydrochloride, 3 to 5% sodium carboxymethyl cellulose; 15 to 30% hydroxypropyl methylcellulose; from 0.1 to 0.75% of magnesium stearate; and 0 to 2% silicon dioxide or 0 to 1.5% colloidal silicon dioxide; and the second layer comprises from 0.5 to 4% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 14 to 18% anhydrous lactose; 50 to 80% microcrystalline cellulose; from 0 to 20% pregelatinized starch; 0 to 20% mannitol; from 0 to 15% hydroxypropyl cellulose; from 2 to 6% of crospovidone; from 0.5 to 2.5% silicon dioxide; and 0.5 to 2% magnesium stearate; (2) the first coating comprises a polymer based on polyvinyl alcohol; (3) the second coating comprises saxagliptin and a polymer based on poly alcohol
10/16 vinyl; and (4) the third coating comprises a polymer based on polyvinyl alcohol.
24. Two-layer coated tablet according to claim 22, characterized by the fact that (1) the first layer comprises from 67 to 71% metformin hydrochloride, from 3 to 5% sodium carboxymethyl cellulose, from 25 29% hydroxypropyl methylcellulose 2208, and 0.1 to 0.75% magnesium stearate; and the second layer comprises:
(A) from 0.5 to 4% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 14 to 18% anhydrous lactose; 72 to 80% microcrystalline cellulose 302; from 2 to 6% of crospovidone; from 0.5 to 2.5% silicon dioxide; and from 0.5 to 1.5% magnesium stearate;
(B) 0.5 to 4% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 14 to 18% anhydrous lactose; 50 to 70% microcrystalline cellulose 302; 10 to 22% pregelatinized starch; from 2 to 6% of crospovidone; from 0.5 to 2.5% silicon dioxide; and from 0.5 to 1.5% magnesium stearate;
(C) 0.5 to 4% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 14 to 18% anhydrous lactose; 60 to 70% microcrystalline cellulose 302; from 5 to 15% hydroxypropyl cellulose EXF; from 2 to 6% of crospovidone; from 0.5 to 2.5% silicon dioxide; and from 0.5 to 1.5% magnesium stearate; or (D) from 0.5 to 4% dapagliflozin or propylene glycol dapagliflozin hydrate (S); 14 to 18% anhydrous lactose; 55 to 65% microcrystalline cellulose 302; 10 to 20% mannitol; from 2 to 6% of crospovidone; from 0.5 to 2.5% silicon dioxide; and from 0.5 to 1.5% magnesium stearate; (2) the first coating comprises Opadry® HP; (3) the second coating comprises saxagliptin and Opadry® HP; and (4) the third coating comprises Opadry® HP.
25. Two-layer coated tablet according to claim 22, characterized in that (1) the first layer comprises 69% metformin hydrochloride, 3.5% sodium carboxymethyl cellulose, 27% hydroxypropyl methyl cellulose 2208 , and 0.48% stearate
11/16 magnesium, and the second layer comprises:
(A) 0.8% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 77% microcrystalline cellulose 302; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(B) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 76% microcrystalline cellulose 302; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(C) 3.4% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 74% microcrystalline cellulose 302; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(D) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 64% microcrystalline cellulose 302; 13% pre-gelatinized starch; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(E) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 57% microcrystalline cellulose 302; 19% pre-gelatinized starch; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(F) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 66% microcrystalline cellulose 302; 10% hydroxypropyl cellulose EXF; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate; or (G) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 61% microcrystalline cellulose 302; 15% mannitol; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
9. Two-layer tablet according to any one of claims 1 to 4, characterized in that the (1) first layer comprises 69% metformin hydrochloride, 3.5% sodium carboxymethyl cellulose, 27% hydroxypropyl methylcellulose 2208, and 0.48% magnesium stearate; and (2) the second layer is 300 mg to 400 mg.
10. Two-layer tablet according to claim 9, characterized in that the second layer comprises:
(A) 0.8% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 77% microcrystalline cellulose 302; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(B) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 76% microcrystalline cellulose 302; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(C) 3.4% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 74% microcrystalline cellulose 302; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(D) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 64% microcrystalline cellulose 302; 13% pre-gelatinized starch; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(E) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 57% microcrystalline cellulose 302; 19% pre-gelatinized starch; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate;
(F) 1.7% dapagliflozin or propylene glycol dapagliflozin (S) hydrate; 16% anhydrous lactose; 66% microcrystalline cellulose 302; 10% hydroxypropyl cellulose EXF; 4% crospovidone; 1.5% silicon dioxide; and 1% magnesium stearate; or (G) 1.7% dapagliflozin or dapagliflozin hydrate (S) of
[10]
38. Two-layer tablet according to any one of claims 34 to 37, characterized in that there is a film coating, and the film coating is Opadry® II.

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法律状态:
2020-06-02| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2020-06-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2020-07-21| B25A| Requested transfer of rights approved|Owner name: ASTRAZENECA UK LIMITED (GB) ; ASTRAZENECA AB (SE) |

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2020-08-11| B25G| Requested change of headquarter approved|Owner name: ASTRAZENECA AB (SE) ; ASTRAZENECA UK LIMITED (GB) |

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2021-03-09| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2021-06-01| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|

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2021-09-21| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

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2021-10-19| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US26108709P| true| 2009-11-13|2009-11-13|

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PCT/US2010/056529|WO2011060256A2|2009-11-13|2010-11-12|Bilayer tablet formulations|

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