US20140303098A1 - Pharmaceutical composition, methods for treating and uses thereof - Google Patents
Pharmaceutical composition, methods for treating and uses thereof Download PDFInfo
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- US20140303098A1 US20140303098A1 US14/244,208 US201414244208A US2014303098A1 US 20140303098 A1 US20140303098 A1 US 20140303098A1 US 201414244208 A US201414244208 A US 201414244208A US 2014303098 A1 US2014303098 A1 US 2014303098A1
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- empagliflozin
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- OBWASQILIWPZMG-QZMOQZSNSA-N OC[C@H]1O[C@@H](C2=CC(CC3=CC=C(O[C@H]4CCOC4)C=C3)=C(Cl)C=C2)[C@H](O)[C@@H](O)[C@@H]1O Chemical compound OC[C@H]1O[C@@H](C2=CC(CC3=CC=C(O[C@H]4CCOC4)C=C3)=C(Cl)C=C2)[C@H](O)[C@@H](O)[C@@H]1O OBWASQILIWPZMG-QZMOQZSNSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Definitions
- the present invention relates to certain SGLT-2 inhibitors for treating and/or preventing metabolic disorders, such as type 2 or type 1 diabetes mellitus or pre-diabetes, in patients with renal impairment or chronic kidney disease (CDK).
- metabolic disorders such as type 2 or type 1 diabetes mellitus or pre-diabetes, in patients with renal impairment or chronic kidney disease (CDK).
- CDK chronic kidney disease
- T2DM Type 2 diabetes mellitus
- Nephropathy is a well-established complication of poor glycemic control in patients with diabetes.
- An estimated 10-36% of patients with T2DM have some degree of renal impairment and chronic kidney disease (CKD) is present in approximately 40% of patients with diabetes.
- CKD has been classified into 5 stages, where stage 1 is kidney damage with normal GFR (mL/min/1.73 m 2 ) of 90; stage 2 is kidney damage with a mild decrease in GFR (GFR 60-89); stage 3 is a moderate decrease in GFR (GFR 30-59); stage 4 is a severe decrease in GFR (GFR 15-29); and stage 5 is kidney failure (GFR ⁇ 15 or dialysis).
- stage 1 kidney damage with normal GFR (mL/min/1.73 m 2 ) of 90
- stage 2 is kidney damage with a mild decrease in GFR (GFR 60-89)
- stage 3 is a moderate decrease in GFR (GFR 30-59)
- stage 4 is a severe decrease in GFR (GFR 15-29)
- Metformin is contraindicated in patients with renal dysfunction due to the risk of accumulation and lactic acidosis. Caution is advised with the use of insulin secretagogues in renally impaired patients.
- the DPP-4 inhibitors saxagliptin, sitagliptin and vildagliptin (but not linagliptin) are predominantly excreted renally, so dose reduction is necessary in patients with advanced chronic kidney disease.
- the present invention relates to certain SGLT-2 inhibitors, in particular empagliflozin, for treating and/or preventing metabolic disorders, such as type 2 diabetes mellitus, in patients with renal impairment or chronic kidney disease (CDK).
- metabolic disorders such as type 2 diabetes mellitus, in patients with renal impairment or chronic kidney disease (CDK).
- the present invention provides a method for using empagliflozin in one or more of the following methods:
- the method comprises treating prediabetes, type 1 or type 2 diabetes mellitus. In one embodiment, the method comprises improving glycemic control in a patient with prediabetes, type 1 or type 2 diabetes mellitus.
- the present invention provides a method of treating prediabetes, type 1 or type 2 diabetes mellitus in patient comprising administering empagliflozin to the patient, wherein the patient has moderate renal impairment.
- the patient has moderate A renal impairment.
- the patient has moderate B renal impairment.
- the present invention further provides a method for improving glycemic control in a patient with prediabetes, type 1 or type 2 diabetes mellitus comprising administering empagliflozin to the patient, wherein the patient has moderate renal impairment.
- the patient has moderate A renal impairment.
- the patient has moderate B renal impairment.
- the present invention further provides a method of treating prediabetes, type 1 or type 2 diabetes mellitus in patient comprising administering empagliflozin to the patient, wherein the patient has stage 3 chronic kidney disease (CKD).
- the patient has stage 3A chronic kidney disease (CKD).
- the patient has stage 3B chronic kidney disease (CKD).
- the present invention further provides a method for improving glycemic control in a patient with prediabetes, type 1 or type 2 diabetes mellitus comprising administering empagliflozin to the patient, wherein the patient has stage 3 chronic kidney disease (CKD).
- the patient has stage 3A chronic kidney disease (CKD).
- the patient has stage 3B chronic kidney disease (CKD).
- the present invention further provides a method of treating prediabetes, type 1 or type 2 diabetes mellitus or improving glycemic control in a patient with prediabetes, type 1 or type 2 diabetes mellitus, said method comprising:
- the method further comprises treating a patient having mild renal impairment or normal renal function with empagliflozin.
- the present invention further provides a method comprising:
- the method further comprises treating a patient having mild renal impairment or normal renal function with empagliflozin.
- the present invention further provides a method of treating prediabetes, type 1 or type 2 diabetes mellitus or improving glycemic control in a patient with prediabetes, type 1 or type 2 diabetes mellitus, said method comprising:
- the method further comprises treating a patient having mild renal impairment or normal renal function with empagliflozin.
- the present invention further provides a method comprising:
- the method further comprises treating a patient having mild renal impairment or normal renal function with empagliflozin.
- the present invention further provides a method of treating type 2 diabetes comprising:
- empagliflozin is administered if the eGFR of the patient is between ⁇ 30 ml/min/1.73 m 2 and ⁇ 60 ml/min/1.73 m 2 . In one embodiment, the method further comprises discontinuing empagliflozin if the eGFR of the patient falls below 30 ml/min/1.73 m 2 . In one embodiment, empagliflozin is administered if the eGFR of the patient is between ⁇ 45 ml/min/1.73 m 2 and ⁇ 60 ml/min/1.73 m 2 . In one embodiment, the method further comprises discontinuing empagliflozin if the eGFR of the patient falls below 45 ml/min/1.73 m 2 .
- the present invention further provides a method comprising:
- empagliflozin is administered if the eGFR of the patient is between ⁇ 30 ml/min/1.73 m 2 and ⁇ 60 ml/min/1.73 m 2 .
- the present invention further provides a method comprising:
- empagliflozin is administered if the eGFR of the patient is between ⁇ 45 ml/min/1.73 m 2 and ⁇ 60 ml/min/1.73 m 2 .
- the present invention further provides a method of treating prediabetes, type 1 or type 2 diabetes mellitus comprising:
- the method further comprises discontinuing empagliflozin if the eGFR of the patient falls below 30 ml/min/1.73 m 2 .
- the present invention further provides a method of treating prediabetes, type 1 or type 2 diabetes mellitus comprising:
- the method further comprises discontinuing empagliflozin if the eGFR of the patient falls below 45 ml/min/1.73 m 2 .
- the present invention further provides a method of treating prediabetes, type 1 or type 2 diabetes mellitus in a patient having an estimated glomerular filtration rate (eGFR) between 30 ml/min/1.73 m 2 and ⁇ 60 ml/min/1.73 m 2 comprising:
- the patient has a glomerular filtration rate (eGFR) between ⁇ 45 ml/min/1.73 m 2 and ⁇ 60 ml/min/1.73 m 2 .
- eGFR glomerular filtration rate
- the effectiveness of empagliflozin is for example measured by determining the % HbA1c of the free plasma glucose (FPG) in the patient.
- the present invention further provides a method of treatment comprising:
- step b) comprises determining that the patient's estimated glomerular filtration rate (eGFR) is ⁇ 30 ml/min/1.73 m 2 and ⁇ 90 ml/min/1.73 m 2 . In one embodiment, step b) comprises determining that the patient's estimated glomerular filtration rate (eGFR) is ⁇ 30 ml/min/1.73 m 2 and ⁇ 60 ml/min/1.73 m 2 .
- the present invention further provides a method of treatment comprising:
- step b) comprises determining that the patient's estimated glomerular filtration rate (eGFR) is ⁇ 30 ml/min/1.73 m 2 and ⁇ 90 ml/min/1.73 m 2 . In one embodiment, step b) comprises determining that the patient's estimated glomerular filtration rate (eGFR) is ⁇ 30 ml/min/1.73 m 2 and ⁇ 60 ml/min/1.73 m 2 .
- the present invention further provides a method of treatment comprising:
- the present invention further provides a method of treatment comprising:
- the present invention further provides a method of treatment comprising:
- the present invention further provides a method of treatment comprising:
- the present invention further provides a method of treatment comprising:
- the present invention further provides a method of treatment comprising:
- the present invention further provides a method of treatment comprising:
- the present invention further provides a method of treatment comprising:
- the present invention further provides a method of treatment comprising:
- empagliflozin is administered as a pharmaceutical composition, for example a tablet.
- the pharmaceutical composition comprises 10 mg or 25 mg of empagliflozin.
- empagliflozin is administered once daily.
- the present invention further provides a method of improvement of glycemic control in a patient with prediabetes, type 1 or type 2 diabetes mellitus, wherein the patient's estimated glomerular filtration rate (eGFR) is ⁇ 30 ml/min/1.73 m 2 comprising the administration of a pharmaceutical composition comprising empagliflozin to the patient.
- the patient's estimated glomerular filtration rate (eGFR) is ⁇ 45 ml/min/1.73 m 2 .
- the present invention further provides a method of improvement of glycemic control in a type 2 diabetes mellitus patient with moderate renal impairement comprising the administration of a pharmaceutical composition comprising empagliflozin to the patient.
- the patient is with moderate A renal (CKD stage 3A) impairement.
- the patient is with moderate B renal (CKD stage 3B) impairement.
- the pharmaceutical composition comprises 10 mg or 25 mg of empagliflozin.
- empagliflozin is administered once daily.
- the present invention further provides empagliflozin for use in the treatment of prediabetes, type 1 or type 2 diabetes mellitus in a patient wherein the patient's estimated glomerular filtration rate (eGFR) is ⁇ 30 ml/min/1.73 m 2 .
- eGFR estimated glomerular filtration rate
- the present invention further provides a pharmaceutical composition comprising empagliflozin for use in the treatment of prediabetes, type 1 or type 2 diabetes mellitus in a patient wherein the patient's estimated glomerular filtration rate (eGFR) is ⁇ 30 ml/min/1.73 m 2 .
- eGFR estimated glomerular filtration rate
- the present invention further provides empagliflozin for use in the improvement of glycemic control in a patient with prediabetes, type 1 or type 2 diabetes mellitus wherein the patient's estimated glomerular filtration rate (eGFR) is ⁇ 30 ml/min/1.73 m 2 .
- eGFR estimated glomerular filtration rate
- the present invention further provides a pharmaceutical composition comprising empagliflozin for use in the improvement of glycemic control in a patient with prediabetes, type 1 or type 2 diabetes mellitus wherein the patient's estimated glomerular filtration rate (eGFR) is ⁇ 30 ml/min/1.73 m 2 .
- eGFR estimated glomerular filtration rate
- the patient's estimated glomerular filtration rate is ⁇ 30 ml/min/1.73 m 2 and ⁇ 90 ml/min/1.73 m 2 . In one embodiment, the patient's estimated glomerular filtration rate (eGFR) is ⁇ 30 ml/min/1.73 m 2 and ⁇ 60 ml/min/1.73 m 2 . In one embodiment, the patient's estimated glomerular filtration rate (eGFR) is ⁇ 45 ml/min/1.73 m 2 .
- the patient's estimated glomerular filtration rate is ⁇ 45 ml/min/1.73 m 2 and ⁇ 90 ml/min/1.73 m 2 . In one embodiment, the patient's estimated glomerular filtration rate (eGFR) is ⁇ 45 ml/min/1.73 m 2 and ⁇ 60 ml/min/1.73 m 2 .
- the present invention further provides empagliflozin for use in the treatment of prediabetes, type 1 or type 2 diabetes mellitus in a patient with moderate renal impairement.
- the present invention provides a pharmaceutical composition comprising empagliflozin for use in the treatment of prediabetes, type 1 or type 2 diabetes mellitus in a patient with moderate renal impairement.
- the present invention provides empagliflozin for use in the improvement of glycemic control in a prediabetes, type 1 or type 2 diabetes mellitus patient with moderate renal impairement.
- the present invention provides a pharmaceutical composition comprising empagliflozin for use in the improvement of glycemic control in a prediabetes, type 1 or type 2 diabetes mellitus patient with moderate renal impairement.
- the patient in any use of empagliflozin or a pharmaceutical composition above, is with moderate A renal impairement or with moderate B renal impairment. In one embodiment, the use is as an adjunct to diet and exercise. In one embodiment, the patient is an adult patient. In one embodiment, the use is once daily. In one embodiment, the use is 10 mg or 25 mg once daily.
- empagliflozin is administered orally, for example in a total daily amount of 10 mg or 25 mg.
- empagliflozin is administering as a pharmaceutical composition comprising 10 mg or 25 mg of empagliflozin, for example as a tablet.
- a patient in a method or use disclosed herein is patient with type 2 diabetes mellitus (or type 2 diabetes mellitus patient), a patient treated for type 2 diabetes mellitus, a patient diagnosed with type 2 diabetes mellitus or a patient in need of treatment for type 2 diabetes mellitus.
- a patient is a patient with pre-diabetes.
- empagliflozin is administered to a patient at a starting dose of 10 mg daily, for example to a patient as described herein.
- the dose of empagliflozin is increased to 25 mg daily, for example if the patient requires additional glycemic control.
- the present invention provides a method or use as described herein comprising a) administering to a patient 10 mg of empagliflozin daily, b) determining that the patient requires additional glycemic control and c) administering to the patient 25 mg of empagliflozin daily.
- the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus, said method comprising a) administering to a patient 10 mg of empagliflozin daily, b) determining that the patient requires additional glycemic control and c) administering to the patient 25 mg of empagliflozin daily.
- empagliflozin is administered to a patient at a starting dose of 10 mg daily, for example to a patient having an eGFR ⁇ 30 ml/min/1.73 m 2 or to a patient having an eGFR ⁇ 45 ml/min/1.73 m 2 .
- the dose is increased to 25 mg daily, for example if the patient requires additional glycemic control.
- the dose of empagliflozin is increased to 25 mg daily in a patient having an eGFR ⁇ 30 ml/min/1.73 m 2 , in a patient having an eGFR ⁇ 45 ml/min/1.73 m 2 or in a patient having an eGFR ⁇ 60 ml/min/1.73 m 2 .
- the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR ⁇ 30 ml/min/1.73 m 2 and b) increasing the dose of empagliflozin administered to the patient to 25 mg daily in a patient having an eGFR ⁇ 30 ml/min/1.73 m 2 .
- said patient in step a) requires additional glycemic control.
- the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR ⁇ 30 ml/min/1.73 m 2 , b) determining that the patient has an eGFR ⁇ 30 ml/min/1.73 m 2 and c) administering 25 mg of empagliflozin daily to the patient.
- step b) further comprises determining that the patient requires additional glycemic control.
- the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR ⁇ 30 ml/min/1.73 m 2 and b) increasing the dose of empagliflozin administered to the patient to 25 mg daily in a patient having an eGFR ⁇ 45 ml/min/1.73 m 2 .
- said patient in step a) requires additional glycemic control.
- the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR ⁇ 30 ml/min/1.73 m 2 , b) determining that the patient has an eGFR ⁇ 45 ml/min/1.73 m 2 and c) administering 25 mg of empagliflozin daily to the patient.
- step b) further comprises determining that the patient requires additional glycemic control.
- the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR ⁇ 30 ml/min/1.73 m 2 and b) increasing the dose of empagliflozin administered to the patient to 25 mg daily in a patient having an eGFR ⁇ 60 ml/min/1.73 m 2 .
- said patient in step a) requires additional glycemic control.
- the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR ⁇ 30 ml/min/1.73 m 2 , b) determining that the patient has an eGFR ⁇ 60 ml/min/1.73 m 2 and c) administering 25 mg of empagliflozin daily to the patient.
- step b) further comprises determining that the patient requires additional glycemic control.
- the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR ⁇ 45 ml/min/1.73 m 2 and b) increasing the dose of empagliflozin administered to the patient to 25 mg daily in a patient having an eGFR ⁇ 45 ml/min/1.73 m 2 .
- said patient in step a) requires additional glycemic control.
- the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR ⁇ 45 ml/min/1.73 m 2 , b) determining that the patient has an eGFR ⁇ 45 ml/min/1.73 m 2 and c) administering 25 mg of empagliflozin daily to the patient.
- step b) further comprises determining that the patient requires additional glycemic control.
- the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR ⁇ 45 ml/min/1.73 m 2 and b) increasing the dose of empagliflozin administered to the patient to 25 mg daily in a patient having an eGFR ⁇ 60 ml/min/1.73 m 2 .
- said patient in step a) requires additional glycemic control.
- the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR ⁇ 45 ml/min/1.73 m 2 , b) determining that the patient has an eGFR ⁇ 60 ml/min/1.73 m 2 and c) administering 25 mg of empagliflozin daily to the patient.
- step b) further comprises determining that the patient requires additional glycemic control.
- empagliflozin is administered to a patient at a dose of 10 mg daily to a patient having an eGFR ⁇ 60 ml/min/1.73 m 2 and the patient continues to be administered empagliflozin at a dose of 10 mg daily if the patient's eGFR is reduced to 30 to ⁇ 60 ml/min/1.73 m 2 or to ⁇ 45 to ⁇ 60 ml/min/1.73 m 2 .
- the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR ⁇ 60 ml/min/1.73 m 2 , b) determining that the patient has an eGFR ⁇ 30 to ⁇ 60 ml/min/1.73 m 2 and c) continuing to administer 10 mg of empagliflozin daily to the patient.
- the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR ⁇ 60 ml/min/1.73 m 2 , b) determining that the patient has an eGFR ⁇ 45 to ⁇ 60 ml/min/1.73 m 2 and c) continuing to administer 10 mg of empagliflozin daily to the patient.
- empagliflozin is administered to a patient at a starting dose of 10 mg daily to a patient having an eGFR ⁇ 60 ml/min/1.73 m 2 , the dose of empagliflozin is increased to 25 mg daily, for example if the patient requires additional glycemic control, and the dose of empagliflozin administered to the patient stays at a dose of 25 mg daily if the patient's eGFR is reduced to 30 to ⁇ 60 ml/min/1.73 m 2 or to 45 to ⁇ 60 ml/min/1.73 m 2 .
- the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR ⁇ 60 ml/min/1.73 m 2 , b) increasing the dose of empagliflozin administered to the patient to 25 mg daily, for example if the patient requires additional glycemic control, c) determining that the patient has an eGFR ⁇ 30 to ⁇ 60 ml/min/1.73 m 2 and d) administering 25 mg of empagliflozin daily to the patient.
- the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR ⁇ 60 ml/min/1.73 m 2 , b) increasing the dose of empagliflozin administered to the patient to 25 mg daily, for example if the patient requires additional glycemic control, c) determining that the patient has an eGFR ⁇ 45 to ⁇ 60 ml/min/1.73 m 2 and d) administering 25 mg empagliflozin daily to the patient.
- empagliflozin is administered to a patient at a starting dose of 10 mg daily to a patient having an eGFR ⁇ 60 ml/min/1.73 m 2 , the dose of empagliflozin is increased to 25 mg daily, for example if the patient requires additional glycemic control, and the dose of empagliflozin administered to the patient is reduced to a dose of 10 mg daily if the patient's eGFR is reduced to 30 to ⁇ 60 ml/min/1.73 m 2 or to ⁇ 45 to ⁇ 60 ml/min/1.73 m 2 .
- the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR ⁇ 60 ml/min/1.73 m 2 , b) increasing the dose of empagliflozin administered to the patient to 25 mg daily, for example if the patient requires additional glycemic control, c) determining that the patient has an eGFR ⁇ 30 to ⁇ 60 ml/min/1.73 m 2 and d) administering 10 mg of empagliflozin daily to the patient.
- the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR ⁇ 60 ml/min/1.73 m 2 , b) increasing the dose of empagliflozin administered to the patient to 25 mg daily, for example if the patient requires additional glycemic control, c) determining that the patient has an eGFR ⁇ 45 to ⁇ 60 ml/min/1.73 m 2 and d) administering 10 mg of empagliflozin daily to the patient.
- empagliflozin is administered once daily to a patient, i.e. for example 10 mg or 25 mg of empagliflozin is administered once daily to a patient.
- empagliflozin is administered with one or more other antidiabetic substances.
- the other antidiabetic substances are selected from metformin, sulphonylureas, nateglinide, repaglinide, thiazolidinediones, PPARalpha-glucosidase inhibitors, insulin and insulin analogues, GLP-1 and GLP-1 analogues and DPP-4 inhibitors.
- the present invention comprises administering empagliflozin in combination with metformin and/or a DPP-4 inhibitor, for example linagliptin.
- the present invention further provides for empagliflozin or a pharmaceutical composition comprising empagliflozin for use as a medicament in any one of the methods described herein.
- the present invention further provides for empagliflozin or a pharmaceutical composition comprising empagliflozin for use in the treatment of any one of the diseases or conditions described herein.
- the present invention further provides for empagliflozin or a pharmaceutical composition comprising empagliflozin for use in the manufacture of a medicament for use in any one of the methods described herein.
- active ingredient of a pharmaceutical composition according to the present invention means the SGLT2 inhibitor according to the present invention.
- An “active ingredient” is also sometimes referred to herein as an “active substance”.
- body mass index or “BMI” of a human patient is defined as the weight in kilograms divided by the square of the height in meters, such that BMI has units of kg/m 2 .
- weight is defined as the condition wherein the individual has a BMI greater than or 25 kg/m 2 and less than 30 kg/m 2 .
- overweight and “pre-obese” are used interchangeably.
- the terms “obesity” or “being obese” and the like are defined as the condition wherein the individual has a BMI equal to or greater than 30 kg/m 2 .
- the term obesity may be categorized as follows: the term “class I obesity” is the condition wherein the BMI is equal to or greater than 30 kg/m 2 but lower than 35 kg/m 2 ; the term “class II obesity” is the condition wherein the BMI is equal to or greater than 35 kg/m 2 but lower than 40 kg/m 2 ; the term “class III obesity” is the condition wherein the BMI is equal to or greater than 40 kg/m 2 .
- the indication obesity includes in particular exogenic obesity, hyperinsulinaemic obesity, hyperplasmic obesity, hyperphyseal adiposity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity, central obesity, visceral obesity, abdominal obesity.
- visceral obesity is defined as the condition wherein a waist-to-hip ratio of greater than or equal to 1.0 in men and 0.8 in women is measured. It defines the risk for insulin resistance and the development of pre-diabetes.
- abdominal obesity is usually defined as the condition wherein the waist circumference is >40 inches or 102 cm in men, and is >35 inches or 94 cm in women. With regard to a Japanese ethnicity or Japanese patients abdominal obesity may be defined as waist circumference 85 cm in men and ⁇ 90 cm in women (see e.g. investigating committee for the diagnosis of metabolic syndrome in Japan).
- euglycemia is defined as the condition in which a subject has a fasting blood glucose concentration within the normal range, greater than 70 mg/dL (3.89 mmol/L) and less than 100 mg/dL (5.6 mmol/L).
- fasting has the usual meaning as a medical term.
- hypoglycemia is defined as the condition in which a subject has a fasting blood glucose concentration above the normal range, greater than 100 mg/dL (5.6 mmol/L).
- fasting has the usual meaning as a medical term.
- hypoglycemia is defined as the condition in which a subject has a blood glucose concentration below the normal range, in particular below 70 mg/dL (3.89 mmol/L).
- postprandial hyperglycemia is defined as the condition in which a subject has a 2 hour postprandial blood glucose or serum glucose concentration greater than 200 mg/dL (11.11 mmol/L).
- IGF paired fasting blood glucose
- a subject with “normal fasting glucose” has a fasting glucose concentration smaller than 100 mg/dl, i.e. smaller than 5.6 mmol/l.
- ITT paired glucose tolerance
- the abnormal glucose tolerance i.e. the 2 hour postprandial blood glucose or serum glucose concentration can be measured as the blood sugar level in mg of glucose per dL of plasma 2 hours after taking 75 g of glucose after a fast.
- a subject with “normal glucose tolerance” has a 2 hour postprandial blood glucose or serum glucose concentration smaller than 140 mg/dl (7.78 mmol/L).
- hyperinsulinemia is defined as the condition in which a subject with insulin resistance, with or without euglycemia, has fasting or postprandial serum or plasma insulin concentration elevated above that of normal, lean individuals without insulin resistance, having a waist-to-hip ratio ⁇ 1.0 (for men) or ⁇ 0.8 (for women).
- Insulin-sensitizing As insulin-sensitizing, “insulin resistance-improving” or “insulin resistance-lowering” are synonymous and used interchangeably.
- insulin resistance is defined as a state in which circulating insulin levels in excess of the normal response to a glucose load are required to maintain the euglycemic state (Ford E S, et al. JAMA. (2002) 287:356-9).
- a method of determining insulin resistance is the euglycaemic-hyperinsulinaemic clamp test. The ratio of insulin to glucose is determined within the scope of a combined insulin-glucose infusion technique. There is found to be insulin resistance if the glucose absorption is below the 25th percentile of the background population investigated (WHO definition).
- insulin resistance the response of a patient with insulin resistance to therapy, insulin sensitivity and hyperinsulinemia may be quantified by assessing the “homeostasis model assessment to insulin resistance (HOMA-IR)” score, a reliable indicator of insulin resistance (Katsuki A, et al. Diabetes Care 2001; 24: 362-5). Further reference is made to methods for the determination of the HOMA-index for insulin sensitivity (Matthews et al., Diabetologia 1985, 28: 412-19), of the ratio of intact proinsulin to insulin (Forst et al., Diabetes 2003, 52(Suppl.1): A459) and to an euglycemic clamp study.
- HOMA-IR homeostasis model assessment to insulin resistance
- HOMA-IR score is calculated with the formula (Galvin P, et al. Diabet Med 1992; 9:921-8):
- HOMA-IR [fasting serum insulin ( ⁇ U/mL)] ⁇ [fasting plasma glucose(mmol/L)/22.5]
- Insulin resistance can be confirmed in these individuals by calculating the HOMA-IR score.
- insulin resistance is defined as the clinical condition in which an individual has a HOMA-IR score >4.0 or a HOMA-IR score above the upper limit of normal as defined for the laboratory performing the glucose and insulin assays.
- the patient's triglyceride concentration is used, for example, as increased triglyceride levels correlate significantly with the presence of insulin resistance.
- Individuals likely to have insulin resistance are those who have two or more of the following attributes: 1) overweight or obese, 2) high blood pressure, 3) hyperlipidemia, 4) one or more 1 st degree relative with a diagnosis of IGT or IFG or type 2 diabetes.
- Patients with a predisposition for the development of IGT or IFG or type 2 diabetes are those having euglycemia with hyperinsulinemia and are by definition, insulin resistant.
- a typical patient with insulin resistance is usually overweight or obese. If insulin resistance can be detected, this is a particularly strong indication of the presence of pre-diabetes. Thus, it may be that in order to maintain glucose homoeostasis a person needs 2-3 times as much insulin as a healthy person, without this resulting in any clinical symptoms.
- Pre-diabetes is a general term that refers to an intermediate stage between normal glucose tolerance (NGT) and overt type 2 diabetes mellitus (T2DM), also referred to as intermediate hyperglycaemia. As such, it represents 3 groups of individuals, those with impaired glucose tolerance (IGT) alone, those with impaired fasting glucose (IFG) alone or those with both IGT and IFG. IGT and IFG usually have distinct pathophysiologic etiologies, however also a mixed condition with features of both can exist in patients. Therefore in the context of the present invention a patient being diagnosed of having “pre-diabetes” is an individual with diagnosed IGT or diagnosed IFG or diagnosed with both IGT and IFG. Following the definition according to the American Diabetes Association (ADA) and in the context of the present invention a patient being diagnosed of having “pre-diabetes” is an individual with:
- a fasting plasma glucose (FPG) concentration ⁇ 100 mg/dL [1 mg/dL 0.05555 mmol/L] and a 2-hour plasma glucose (PG) concentration, measured by a 75-g oral glucose tolerance test (OGTT), ranging between ⁇ 140 mg/dL and ⁇ 200 mg/dL (i.e., IGT); or b) a fasting plasma glucose (FPG) concentration between ⁇ 100 mg/dL and ⁇ 126 mg/dL and a 2-hour plasma glucose (PG) concentration, measured by a 75-g oral glucose tolerance test (OGTT) of ⁇ 140 mg/dL (i.e., IFG); or c) a fasting plasma glucose (FPG) concentration between ⁇ 100 mg/dL and ⁇ 126 mg/dL and a 2-hour plasma glucose (PG) concentration, measured by a 75-g oral glucose tolerance test (OGTT), ranging between ⁇ 140 mg/dL and ⁇ 200 mg/dL (i.e., both IGT and IFG).
- Pre-diabetes are individuals being pre-disposed to the development of type 2 diabetes. Pre-diabetes extends the definition of IGT to include individuals with a fasting blood glucose within the high normal range ⁇ 100 mg/dL (J. B. Meigs, et al. Diabetes 2003; 52:1475-1484). The scientific and medical basis for identifying pre-diabetes as a serious health threat is laid out in a Position Statement entitled “The Prevention or Delay of Type 2 Diabetes” issued jointly by the American Diabetes Association and the National Institute of Diabetes and Digestive and Kidney Diseases (Diabetes Care 2002; 25:742-749).
- beta-cell function can be measured for example by determining a HOMA-index for beta-cell function (Matthews et al., Diabetologia 1985, 28: 412-19), the ratio of intact proinsulin to insulin (Forst et al., Diabetes 2003, 52(Suppl.1): A459), the insulin/C-peptide secretion after an oral glucose tolerance test or a meal tolerance test, or by employing a hyperglycemic clamp study and/or minimal modeling after a frequently sampled intravenous glucose tolerance test (Stumvoll et al., Eur J Clin Invest 2001, 31: 380-81).
- type 1 diabetes is defined as the condition in which a subject has, in the presence of autoimmunity towards the pancreatic beta-cell or insulin, a fasting blood glucose or serum glucose concentration greater than 125 mg/dL (6.94 mmol/L). If a glucose tolerance test is carried out, the blood sugar level of a diabetic will be in excess of 200 mg of glucose per dL (11.1 mmol/l) of plasma 2 hours after 75 g of glucose have been taken on an empty stomach, in the presence of autoimmunity towards the pancreatic beta cell or insulin. In a glucose tolerance test 75 g of glucose are administered orally to the patient being tested after 10-12 hours of fasting and the blood sugar level is recorded immediately before taking the glucose and 1 and 2 hours after taking it.
- the presence of autoimmunity towards the pancreatic beta-cell may be observed by detection of circulating islet cell autoantibodies [“type 1A diabetes mellitus”], i.e., at least one of: GAD65 [glutamic acid decarboxylase-65], ICA [islet-cell cytoplasm], IA-2 [intracytoplasmatic domain of the tyrosine phosphatase-like protein IA-2], ZnT8 [zinc-transporter-8] or anti-insulin; or other signs of autoimmunity without the presence of typical circulating autoantibodies [type 1B diabetes], i.e. as detected through pancreatic biopsy or imaging).
- a genetic predisposition is present (e.g. HLA, INS VNTR and PTPN22), but this is not always the case.
- type 2 diabetes mellitus or “T2DM” is defined as the condition in which a subject has a fasting blood glucose or serum glucose concentration greater than 125 mg/dL (6.94 mmol/L).
- the measurement of blood glucose values is a standard procedure in routine medical analysis. If a glucose tolerance test is carried out, the blood sugar level of a diabetic will be in excess of 200 mg of glucose per dL (11.1 mmol/l) of plasma 2 hours after 75 g of glucose have been taken on an empty stomach. In a glucose tolerance test 75 g of glucose are administered orally to the patient being tested after 10-12 hours of fasting and the blood sugar level is recorded immediately before taking the glucose and 1 and 2 hours after taking it.
- the blood sugar level before taking the glucose will be between 60 and 110 mg per dL of plasma, less than 200 mg per dL 1 hour after taking the glucose and less than 140 mg per dL after 2 hours. If after 2 hours the value is between 140 and 200 mg, this is regarded as abnormal glucose tolerance.
- late stage type 2 diabetes mellitus includes patients with a secondary drug failure, indication for insulin therapy and progression to micro- and macrovascular complications e.g. diabetic nephropathy, or coronary heart disease (CHD).
- CHD coronary heart disease
- HbA1c refers to the product of a non-enzymatic glycation of the haemoglobin B chain. Its determination is well known to one skilled in the art. In monitoring the treatment of diabetes mellitus the HbA1c value is of exceptional importance. As its production depends essentially on the blood sugar level and the life of the erythrocytes, the HbA1c in the sense of a “blood sugar memory” reflects the average blood sugar levels of the preceding 4-6 weeks. Diabetic patients whose HbA1c value is consistently well adjusted by intensive diabetes treatment (i.e. ⁇ 6.5% of the total haemoglobin in the sample), are significantly better protected against diabetic microangiopathy.
- metformin on its own achieves an average improvement in the HbA1c value in the diabetic of the order of 1.0-1.5%.
- This reduction of the HbA1C value is not sufficient in all diabetics to achieve the desired target range of ⁇ 6.5% and preferably ⁇ 6% HbA1c.
- insufficient glycemic control” or “inadequate glycemic control” in the scope of the present invention means a condition wherein patients show HbA1c values above 6.5%, in particular above 7.0%, even more preferably above 7.5%, especially above 8%.
- the “metabolic syndrome”, also called “syndrome X” (when used in the context of a metabolic disorder), also called the “dysmetabolic syndrome” is a syndrome complex with the cardinal feature being insulin resistance (Laaksonen D E, et al. Am J Epidemiol 2002; 156:1070-7).
- diagnosis of the metabolic syndrome is made when three or more of the following risk factors are present:
- Triglycerides and HDL cholesterol in the blood can also be determined by standard methods in medical analysis and are described for example in Thomas L (Editor): “Labor and Diagnose”, TH-Books Verlagsgesellschaft mbH, Frankfurt/Main, 2000.
- hypertension is diagnosed if the systolic blood pressure (SBP) exceeds a value of 140 mm Hg and diastolic blood pressure (DBP) exceeds a value of 90 mm Hg. If a patient is suffering from manifest diabetes it is currently recommended that the systolic blood pressure be reduced to a level below 130 mm Hg and the diastolic blood pressure be lowered to below 80 mm Hg.
- SBP systolic blood pressure
- DBP diastolic blood pressure
- GFR glomerular filtration rate
- the glomerular filtration rate (GFR) is defined as the volume of fluid filtered from the renal (kidney) glomerular capillaries into the Bowman's capsule per unit time. It is indicative of overall kidney function.
- the glomerular filtration rate (GFR) can be calculated by measuring any chemical that has a steady level in the blood, and is freely filtered but neither reabsorbed nor secreted by the kidneys. The rate therefore measured is the quantity of the substance in the urine that originated from a calculable volume of blood.
- the GFR is typically recorded in units of volume per time, e.g., milliliters per minute and the formula below can be used:
- GFR GFR
- the “estimated glomerular filtration rate (eGFR)” is defined as derived at screening from serum creatinine values based on e.g., the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, the Cockcroft-Gault formula or the Modification of Diet in Renal Disease (MDRD) formula, which are all known in the art.
- CKD-EPI Chronic Kidney Disease Epidemiology Collaboration
- MDRD Modification of Diet in Renal Disease
- SGLT2 inhibitor 1-chloro-4-( ⁇ -D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene of the formula
- empagliflozin also comprises its hydrates, solvates and polymorphic forms thereof, and prodrugs thereof.
- An advantageous crystalline form of empagliflozin is described in WO 2006/117359 and WO 2011/039107 which hereby are incorporated herein in their entirety.
- This crystalline form possesses good solubility properties which enables a good bioavailability of the SGLT2 inhibitor.
- the crystalline form is physico-chemically stable and thus provides a good shelf-life stability of the pharmaceutical composition.
- Preferred pharmaceutical compositions, such as solid formulations for oral administration, for example tablets, are described in WO 2010/092126, which hereby is incorporated herein in its entirety.
- treatment and “treating” comprise therapeutic treatment of patients having already developed said condition, in particular in manifest form.
- Therapeutic treatment may be symptomatic treatment in order to relieve the symptoms of the specific indication or causal treatment in order to reverse or partially reverse the conditions of the indication or to stop or slow down progression of the disease.
- compositions and methods of the present invention may be used for instance as therapeutic treatment over a period of time as well as for chronic therapy.
- prophylactically treating “preventivally treating” and “preventing” are used interchangeably and comprise a treatment of patients at risk to develop a condition mentioned hereinbefore, thus reducing said risk.
- tablette comprises tablets without a coating and tablets with one or more coatings. Furthermore the “term” tablet comprises tablets having one, two, three or even more layers and press-coated tablets, wherein each of the beforementioned types of tablets may be without or with one or more coatings.
- tablette also comprises mini, melt, chewable, effervescent and orally disintegrating tablets.
- pharmacopoe and “pharmacopoeias” refer to standard pharmacopoeias such as the “USP 31-NF 26 through Second Supplement” (United States Pharmacopeial Convention) or the “European Pharmacopoeia 6.3” (European Directorate for the Quality of Medicines and Health Care, 2000-2009).
- FIG. 1 A-C Change from baseline in HbA 1c fasting plasma glucose (FPG), weight and blood pressure (BP) at week 24 in patients with renal impairment treated with empagliflozin versus placebo.
- FPG fasting plasma glucose
- BP blood pressure
- FIG. 2 Pharmacokinetic and pharmacodynamic parameters for empagliflozin after administration of a single oral 50 mg dose in patients with renal impairment.
- FIG. 4 A-D Exposure to a single oral 50 mg dose of empagliflozin in subjects with normal and impaired renal function.
- A and
- C AUC 0- ⁇ and
- D C max ; midline of boxes are medians, and boundaries are 25th and 75th percentiles; whiskers are the standard span for the quartiles (1.5 ⁇ interquartile range).
- FIG. 7 A-D Change from baseline in HbA 1c fasting plasma glucose (FPG), weight and blood pressure (BP) at week 52 in patients with Type 2 Diabetes Mellitus (T2DM) and Stage 3A, 3B and 4 Chronic Kidney Disease (CKD) treated with empagliflozin versus placebo.
- FPG fasting plasma glucose
- BP blood pressure
- T2DM Type 2 Diabetes Mellitus
- CKD Chronic Kidney Disease
- the present invention relates to certain SGLT-2 inhibitors, in particular empagliflozin, for treating and/or preventing a metabolic disorder, in particular type 1 or type 2 diabetes or pre-diabetes and/or diseases related thereto (e.g. diabetic complications), in patients with renal impairment or chronic kidney disease (CKD).
- a metabolic disorder in particular type 1 or type 2 diabetes or pre-diabetes and/or diseases related thereto (e.g. diabetic complications)
- CKD renal impairment or chronic kidney disease
- the present invention relates to certain SGLT-2 inhibitors, in particular empagliflozin, for improving glycemic control in patient with type 1 or type 2 diabetes or pre-diabetes and with renal impairment or chronic kidney disease (CKD).
- type 2 diabetes typically begins with diet and exercise, followed by oral antidiabetic monotherapy, and although conventional monotherapy may initially control blood glucose in some patients, it is however associated with a high secondary failure rate.
- monotherapy may initially control blood glucose in some patients, it is however associated with a high secondary failure rate.
- the limitations of single-agent therapy for maintaining glycemic control may be overcome, at least in some patients, and for a limited period of time by combining multiple drugs to achieve reductions in blood glucose that cannot be sustained during long-term therapy with single agents.
- Available data support the conclusion that in most patients with type 2 diabetes current monotherapy will fail and treatment with multiple drugs will be required.
- type 2 diabetes is a progressive disease, even patients with good initial responses to conventional combination therapy will eventually require an increase of the dosage or further treatment with insulin because the blood glucose level is very difficult to maintain stable for a long period of time.
- This high incidence of therapeutic failure is a major contributor to the high rate of long-term hyperglycemia-associated complications or chronic damages (including micro- and makrovascular complications such as e.g. diabetic nephrophathy, retinopathy or neuropathy, or cardiovascular complications such as e.g. myocardial infarction, stroke or vascular mortality or morbidity) in patients with type 2 diabetes.
- micro- and makrovascular complications such as e.g. diabetic nephrophathy, retinopathy or neuropathy, or cardiovascular complications such as e.g. myocardial infarction, stroke or vascular mortality or morbidity
- Oral antidiabetic drugs conventionally used in therapy include, without being restricted thereto, metformin, sulphonylureas, thiazolidinediones, glinides and ⁇ -glucosidase inhibitors.
- Non-oral (typically injected) antidiabetic drugs conventionally used in therapy include, without being restricted thereto, GLP-1 or GLP-1 analogues, and insulin or insulin analogues.
- metformin can be associated with lactic acidosis or gastrointestinal side effects
- sulfonylureas, glinides and insulin or insulin analogues can be associated with hypoglycemia and weight gain
- thiazolidinediones can be associated with edema, bone fracture, weight gain and heart failure/cardiac effects
- alpha-glucosidase blockers and GLP-1 or GLP-1 analogues can be associated with gastrointestinal adverse effects (e.g. dyspepsia, flatulence or diarrhea, or nausea or vomiting) and, most seriously (but rare), pancreatitis.
- Type 1 diabetes mellitus also called insulin dependent diabetes mellitus or juvenile diabetes
- Type 1 diabetes is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood glucose concentrations and increased urinary glucose excretion. The classical symptoms are polyuria, polydipsia, polyphagia, and weight loss. Type 1 diabetes may be fatal unless treated with insulin. Complications from type I diabetes are the same or similar to complications from type 2 diabetes. Standard therapy of type 1 diabetes is insulin treatment. Therapies for type 1 diabetes are for example described in WO 2012/062698.
- SGLT2 inhibitors sodium-glucose co-transporter 2
- Glucopyranosyl-substituted benzene derivative are described as SGLT2 inhibitors, for example in WO 01/27128, WO 03/099836, WO 2005/092877, WO 2006/034489, WO 2006/064033, WO 2006/117359, WO 2006/117360, WO 2007/025943, WO 2007/028814, WO 2007/031548, WO 2007/093610, WO 2007/128749, WO 2008/049923, WO 2008/055870, WO 2008/055940.
- the glucopyranosyl-substituted benzene derivatives are proposed as inducers of urinary sugar excretion and as medicaments in the treatment of diabetes.
- Renal filtration and reuptake of glucose contributes, among other mechanisms, to the steady state plasma glucose concentration and can therefore serve as an antidiabetic target.
- Reuptake of filtered glucose across epithelial cells of the kidney proceeds via sodium-dependent glucose cotransporters (SGLTs) located in the brush-border membranes in the tubuli along the sodium gradient.
- SGLTs sodium-dependent glucose cotransporters
- SGLT2 is exclusively expressed in the kidney, whereas SGLT1 is expressed additionally in other tissues like intestine, colon, skeletal and cardiac muscle.
- SGLT3 has been found to be a glucose sensor in interstitial cells of the intestine without any transport function.
- Empagliflozin is a novel SGLT2 inhibitor that is described for the treatment or improvement in glycemic control in patients with type 2 diabetes mellitus, for example in WO 05/092877, WO 06/117359, WO 06/120208, WO 2010/092126, WO 2010/092123, WO 2011/039107, WO 2011/039108.
- a SGLT-2 inhibitor within the meaning of this invention is empagliflozin.
- the present invention relates to a therapeutic (treatment or prevention) method as described herein, said method comprising administering an effective amount of a SGLT-2 inhibitor as described herein and, optionally, one or more other active or therapeutic agents as described herein to a patient with renal impairment.
- Patients with renal disease, renal dysfunction or renal impairment may include patients with chronic renal insufficiency or impairment, which can be stratified (if not otherwise noted) according to glomerular filtration rate (GFR, ml/min/1.73 m 2 ) into 5 disease stages: stage 1 characterized by normal GFR 90 plus either persistent albuminuria (e.g.
- stage 2 characterized by mild reduction of GFR (GFR 60-89) describing mild renal impairment
- stage 3 characterized by moderate reduction of GFR (GFR 30-59) describing moderate renal impairment
- stage 4 characterized by severe reduction of GFR (GFR 15-29) describing severe renal impairment
- terminal stage 5 characterized by requiring dialysis or GFR ⁇ 15 describing established kidney failure (end-stage renal disease, ESRD).
- kidney disease and its stages can be usually characterized or classified accordingly, such as based on the presence of either kidney damage (albuminuria) or impaired estimated glomerular filtration rate (GFR ⁇ 60 [ml/min/1.73 m 2 ], with or without kidney damage).
- kidney damage albuminuria
- the degree of renal impairment in a patient is defined by the following estimated glomerular filtration rate (eGFR):
- a patient with normal renal function has an eGFR ⁇ 90 ml/min/1.73 m 2
- a patient with mild renal impairment has an eGFR ⁇ 60 to ⁇ 90 ml/min/1.73 m 2
- a patient with moderate renal impairment has an eGFR ⁇ 30 to ⁇ 60 ml/min/1.73 m 2
- a patient with severe renal impairment has an eGFR ⁇ 15 to ⁇ 30 ml/min/1.73 m 2
- a patient with kidney failure has an eGFR ⁇ 15 ml/min/1.73 m 2 .
- moderate renal impairment can be further divided into two sub-stages:
- Moderate A renal impairment CKD 3A
- Moderate B renal impairment CKD 3B
- CKD 3A eGFR ⁇ 45 to ⁇ 60 ml/min/1.73 m 2
- Moderate B renal impairment CKD 3B
- CKD 3A eGFR ⁇ 45 to ⁇ 60 ml/min/1.73 m 2
- a patient with moderate B renal impairment has an eGFR ⁇ 30 to ⁇ 45 ml/min/1.73 m 2 .
- the estimated glomerular filtration rate is derived from the serum creatinine (SCr) value based on the MDRD formula below:
- renal function can also be classified by the estimated creatinine clearance rate (eCCr) value, based on the Cockcroft-Gault formula below:
- eCCr (mL/min) (140 ⁇ age) ⁇ (weight in kg) ⁇ [0.85 if patient is female]/(72 ⁇ SCr (mg/dL))
- Renal function classification based on eCCr is similar to the eGFR classification: normal renal function ( ⁇ 90 mL/min), mild impairment (60 to ⁇ 90 mL/min), moderate impairment (30 to ⁇ 60 mL/min), and severe impairment ( ⁇ 15 to ⁇ 30 mL/min).
- mild renal impairment according to the present invention corresponds to stage 2 chronic kidney disease
- moderate renal impairment according to the present invention generally corresponds to stage 3 chronic kidney disease
- severe renal impairment according to the present invention generally corresponds to stage 4 chronic kidney disease
- moderate A renal impairment according to the present invention generally corresponds to stage 3A chronic kidney disease
- moderate B renal impairment according to the present invention generally corresponds to stage 3B chronic kidney disease. Therefore, the methods and uses of SGLT-2 inhibitors, particularly empagliflozin, in the context of the present invention and applied to patients having renal impairment as defined herein also apply to patients having the corresponding stage of chronic kidney disease.
- renal disease, renal dysfunction, or insufficiency or impairment of renal function may also be suggested (if not otherwise noted) by elevated serum creatinine levels (e.g. serum creatinine levels above the upper limit of normal for their age, e.g. ⁇ 130-150 ⁇ mol/l, or ⁇ 1.5 mg/dl ( ⁇ 136 ⁇ mol/l) in men and ⁇ 1.4 mg/dl ( ⁇ 124 ⁇ mol/l) in women) or abnormal creatinine clearance (e.g. glomerular filtration rate (GFR) ⁇ 30-60 ml/min).
- serum creatinine levels e.g. serum creatinine levels above the upper limit of normal for their age, e.g. ⁇ 130-150 ⁇ mol/l, or ⁇ 1.5 mg/dl ( ⁇ 136 ⁇ mol/l) in men and ⁇ 1.4 mg/dl ( ⁇ 124 ⁇ mol/l) in women
- abnormal creatinine clearance e.g. glomerular filtration rate (GFR) ⁇ 30-60 ml/min
- mild renal impairment may be also suggested (if not otherwise noted) by a creatinine clearance of 50-80 ml/min (approximately corresponding to serum creatine levels of 1.7 mg/dL in men and ⁇ 1.5 mg/dL in women); moderate renal impairment may be e.g. suggested (if not otherwise noted) by a creatinine clearance of 30-50 ml/min (approximately corresponding to serum creatinine levels of >1.7 to ⁇ 3.0 mg/dL in men and >1.5 to ⁇ 2.5 mg/dL in women); and severe renal impairment may be e.g.
- Albuminuria stages may be for example classified as disclosed herein and/or by urine albumin creatinine ratio (such as usually UACR 30 mg/g, in some instances 20 ⁇ g/min albumin excretion rate), such as e.g. microalbuminuria may be for example classified by UACR 30-300 mg/g (in some instances 20-200 ⁇ g/min) or, in another embodiment, by UACR 30-200 mg/g, and/or macroalbuminuria may be for example classified by UACR >300 mg/g (in some instances >200 ⁇ g/min), or, in another embodiment, by UACR >200 mg/g. Very high UACR ⁇ 2000 mg/g may be classified as nephrotic.
- urine albumin creatinine ratio such as usually UACR 30 mg/g, in some instances 20 ⁇ g/min albumin excretion rate
- microalbuminuria may be for example classified by UACR 30-300 mg/g (in some instances 20-200 ⁇ g/min) or, in another embodiment,
- the present invention provides a method of treating type 2 diabetes in patient comprising administering empagliflozin to the patient, wherein the patient has moderate renal impairment (or CKD stage 3).
- the patient has moderate A renal impairment (or CKD stage 3A).
- the patient has moderate B renal impairment (or CKD stage 3B).
- the present invention provides a method for improving glycemic control in a patient with type 2 diabetes comprising administering empagliflozin to the patient, wherein the patient has moderate renal impairment (or CKD stage 3).
- the patient has moderate A renal impairment (or CKD stage 3A).
- the patient has moderate B renal impairment (or CKD stage 3B).
- the renal function of a patient is monitored during the treatment with empagliflozin, for example by measuring the eGFR of the patient.
- the renal function of a patient is monitored during the treatment with empagliflozin if the eGFR of the patient is below 60 ml/min/1.73 m 2 or below 45 ml/min/1.73 m 2 .
- the treatment with empagliflozin is discontinued if the eGFR of the patient falls below a certain value, for example below 30 ml/min/1.73 m 2 or below 45 ml/min/1.73 m 2 .
- diabetes patients within the meaning of this invention may include patients who have not previously been treated with an antidiabetic drug (drug-na ⁇ ve patients).
- the therapies described herein may be used in na ⁇ ve patients.
- diabetes patients within the meaning of this invention may include patients with advanced or late stage type 2 diabetes mellitus (including patients with failure to conventional antidiabetic therapy), such as e.g. patients with inadequate glycemic control on one, two or more conventional oral and/or non-oral antidiabetic drugs as defined herein, such as e.g.
- the therapies described herein may be used in patients experienced with therapy, e.g. with conventional oral and/or non-oral antidiabetic mono- or dual or triple combination medication as mentioned herein.
- those diabetes patients especially type 2 diabetes
- the present invention further relates to a pharmaceutical composition comprising a certain SGLT-2 inhibitor as defined herein, empagliflozin, for use in the therapies described herein.
- this invention refers to patients requiring treatment or prevention, it relates primarily to treatment and prevention in humans.
- adult patients are preferably humans of the age of 18 years or older.
- patients are adolescent humans, i.e. humans of age 10 to 17 years, preferably of age 13 to 17 years. It is assumed that in a adolescent population the administration of the pharmaceutical composition according to the invention a very good HbA1c lowering and a very good lowering of the fasting plasma glucose can be seen.
- a pronounced weight loss can be observed.
- a treatment or prophylaxis according to this invention is advantageously suitable in those patients in need of such treatment or prophylaxis who are diagnosed of one or more of the conditions selected from the group consisting of overweight and obesity, in particular class I obesity, class II obesity, class III obesity, visceral obesity and abdominal obesity.
- a treatment or prophylaxis according to this invention is advantageously suitable in those patients in which a weight increase is contraindicated.
- the pharmaceutical composition as well as the methods according to the present invention allow a reduction of the HbA1c value to a desired target range, for example ⁇ 7% and preferably ⁇ 6.5%, for a higher number of patients and for a longer time of therapeutic treatment compared with a corresponding monotherapy or a therapy using only two of the combination partners.
- the pharmaceutical composition according to this invention and in particular the SGLT2 inhibitor therein exhibits a very good efficacy with regard to glycemic control, in particular in view of a reduction of fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin (HbA1c).
- HbA1c fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin
- the present invention also discloses the use of the pharmaceutical composition for improving glycemic control in patients having type 1 or type 2 diabetes or showing first signs of pre-diabetes.
- the invention also includes diabetes prevention. If therefore a pharmaceutical composition according to this invention is used to improve the glycemic control as soon as one of the above-mentioned signs of pre-diabetes is present, the onset of manifest type 2 diabetes mellitus can be delayed or prevented.
- the pharmaceutical composition according to this invention is particularly suitable in the treatment of patients with insulin dependency, i.e. in patients who are treated or otherwise would be treated or need treatment with an insulin or a derivative of insulin or a substitute of insulin or a formulation comprising an insulin or a derivative or substitute thereof.
- patients include patients with diabetes type 2 and patients with diabetes type 1.
- ITT impaired glucose tolerance
- IGF impaired fasting blood glucose
- a method for improving gycemic control in patients, in particular in adult patients, with type 2 diabetes mellitus as an adjunct to diet and exercise is provided.
- a pharmaceutical composition according to this invention an improvement of the glycemic control can be achieved even in those patients who have insufficient glycemic control in particular despite treatment with an antidiabetic drug, for example despite maximal recommended or tolerated dose of oral monotherapy with metformin.
- a maximal recommended dose with regard to metformin is for example 2000 mg per day or 850 mg three times a day or any equivalent thereof.
- a pharmaceutical composition according to this invention is particularly suitable in the treatment of patients who are diagnosed having one or more of the following conditions
- composition according to this invention is particularly suitable in the treatment of patients who are diagnosed having one or more of the following conditions
- ITT impaired glucose tolerance
- IGF impaired fasting blood glucose
- metabolic syndrome suffer from an increased risk of developing a cardiovascular disease, such as for example myocardial infarction, coronary heart disease, heart insufficiency, thromboembolic events.
- a pharmaceutical composition according to this invention is particularly suitable in the treatment of patients after organ transplantation, in particular those patients who are diagnosed having one or more of the following conditions
- composition according to this invention is particularly suitable in the treatment of patients who are diagnosed having one or more of the following conditions:
- the patient may be a diabetic or non-diabetic mammal, in particular human.
- composition according to this invention is particularly suitable in the treatment of patients who are diagnosed having one or more of the following conditions:
- the patients which may be amenable to to the therapies of this invention may have or are at-risk of one or more of the following diseases, disorders or conditions: type 1 diabetes, type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, postabsorptive hyperglycemia, latent autoimmune diabetes in adults (LADA), overweight, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperNEFA-emia, postprandial lipemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, non alcoholic fatty liver disease (NAFLD), polycystic ovarian syndrome, metabolic syndrome, nephropathy, micro- or macroalbuminuria, proteinuria, retinopathy, cataracts, neuropathy, learning or memory impairment, neurodegenerative or cognitive disorders, cardiovascular diseases, tissue ischaemia, diabetic foot or ulcus, atherosclerosis
- ITT
- uremic cardiomyopathy heart failure, cardiac hypertrophy, heart rhythm disorders, vascular restenosis, stroke, (renal, cardiac, cerebral or hepatic) ischemia/reperfusion injuries, (renal, cardiac, cerebral or hepatic) fibrosis, (renal, cardiac, cerebral or hepatic) vascular remodeling; a diabetic disease, especially type 2 diabetes, mellitus may be preferred (e.g. as underlying disease).
- the patients which may be amenable to to the therapies of this invention have a diabetic disease, especially type 2 diabetes mellitus, and may have or are at-risk of one or more other diseases, disorders or conditions, such as e.g. selected from those mentioned immediately above.
- certain SGLT-2 inhibitors as defined herein optionally in combination with one or more other therapeutic substances (e.g. selected from those described herein), as well as pharmaceutical combinations, compositions or combined uses according to this invention of such SGLT-2 inhibitors as defined herein have properties, which make them suitable for the purpose of this invention and/or for fulfilling one or more of above needs.
- the present invention thus relates to a certain SGLT-2 inhibitor as defined herein, preferably empagliflozin, for use in the therapies described herein.
- a pharmaceutical composition according to this invention results in no risk or in a low risk of hypoglycemia. Therefore, a treatment or prophylaxis according to this invention is also advantageously possible in those patients showing or having an increased risk for hypoglycemia.
- a pharmaceutical composition according to this invention is particularly suitable in the long term treatment or prophylaxis of the diseases and/or conditions as described hereinbefore and hereinafter, in particular in the long term glycemic control in patients with type 2 diabetes mellitus.
- long term indicates a treatment of or administration in a patient within a period of time longer than 12 weeks, preferably longer than 25 weeks, even more preferably longer than 1 year.
- a particularly preferred embodiment of the present invention provides a method for therapy, preferably oral therapy, for improvement, especially long term improvement, of glycemic control in patients with type 2 diabetes mellitus, especially in patients with late stage type 2 diabetes mellitus, in particular in patients additionally diagnosed of overweight, obesity (including class I, class II and/or class III obesity), visceral obesity and/or abdominal obesity.
- a method for therapy preferably oral therapy, for improvement, especially long term improvement, of glycemic control in patients with type 2 diabetes mellitus, especially in patients with late stage type 2 diabetes mellitus, in particular in patients additionally diagnosed of overweight, obesity (including class I, class II and/or class III obesity), visceral obesity and/or abdominal obesity.
- the amount of the pharmaceutical composition according to this invention to be administered to the patient and required for use in treatment or prophylaxis according to the present invention will vary with the route of administration, the nature and severity of the condition for which treatment or prophylaxis is required, the age, weight and condition of the patient, concomitant medication and will be ultimately at the discretion of the attendant physician.
- the SGLT2 inhibitor according to this invention is included in the pharmaceutical composition or dosage form in an amount sufficient that by its administration the glycemic control in the patient to be treated is improved.
- the SGLT2 inhibitor according to this invention is included in the pharmaceutical composition or dosage form in an amount sufficient that is sufficient to treat hyperuricemia without disturbing the patient's plasma glucose homeostasis, in particular without inducing hypoglycemia.
- the SGLT2 inhibitor according to this invention is included in the pharmaceutical composition or dosage form in an amount sufficient that is sufficient to treat or prevent kidney stones without disturbing the patient's plasma glucose homeostasis, in particular without inducing hypoglycemia.
- the SGLT2 inhibitor according to this invention is included in the pharmaceutical composition or dosage form in an amount sufficient that is sufficient to treat hyponatremia or the associated conditions without disturbing the patient's plasma glucose homeostasis, in particular without inducing hypoglycemia.
- the amount of the SGLT2 inhibitor to be employed in the pharmaceutical composition and the methods and uses according to this invention are described. These ranges refer to the amounts to be administered per day with respect to an adult patient, in particular to a human being, for example of approximately 70 kg body weight, and can be adapted accordingly with regard to an administration 2, 3, 4 or more times daily and with regard to other routes of administration and with regard to the age of the patient.
- the pharmaceutical composition is preferably administered orally. Other forms of administration are possible and described hereinafter.
- the one or more dosage forms comprising the SGLT2 inhibitor is oral or usually well known.
- the amount of the SGLT2 inhibitor in the pharmaceutical composition and methods according to this invention is preferably the amount usually recommended for a monotherapy using said SGLT2 inhibitor.
- the preferred dosage range of the SGLT2 inhibitor is in the range from 0.5 mg to 200 mg, even more preferably from 1 to 100 mg, most preferably from 1 to 50 mg per day.
- a preferred dosage of the SGLT2 inhibitor empagliflozin is 10 mg or 25 mg per day.
- the oral administration is preferred. Therefore, a pharmaceutical composition may comprise the hereinbefore mentioned amounts, in particular from 1 to 50 mg or 1 to 25 mg.
- Particular dosage strengths e.g. per tablet or capsule
- a pharmaceutical composition comprises 10 mg or 25 mg of empagliflozin.
- the application of the active ingredient may occur up to three times a day, preferably one or two times a day, most preferably once a day.
- a preferred kit of parts comprises a containment containing a dosage form comprising the SGLT2 inhibitor and at least one pharmaceutically acceptable carrier.
- a further aspect of the present invention is a manufacture comprising the pharmaceutical composition being present as separate dosage forms according to the present invention and a label or package insert comprising instructions that the separate dosage forms are to be administered in combination or alternation.
- a manufacture comprises (a) a pharmaceutical composition comprising a SGLT2 inhibitor according to the present invention and (b) a label or package insert which comprises instructions that the medicament is to be administered.
- the desired dose of the pharmaceutical composition according to this invention may conveniently be presented in a once daily or as divided dose administered at appropriate intervals, for example as two, three or more doses per day.
- the pharmaceutical composition may be formulated for oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration in liquid or solid form or in a form suitable for administration by inhalation or insufflation. Oral administration is preferred.
- the formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active ingredient with one or more pharmaceutically acceptable carriers, like liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.
- the pharmaceutical composition may be formulated in the form of tablets, granules, fine granules, powders, capsules, caplets, soft capsules, pills, oral solutions, syrups, dry syrups, chewable tablets, troches, effervescent tablets, drops, suspension, fast dissolving tablets, oral fast-dispersing tablets, etc.
- the pharmaceutical composition and the dosage forms preferably comprises one or more pharmaceutical acceptable carriers which must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- pharmaceutically acceptable carriers are known to the one skilled in the art.
- compositions suitable for oral administration may conveniently be presented as discrete units such as capsules, including soft gelatin capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution, a suspension or as an emulsion, for example as syrups, elixirs or self-emulsifying delivery systems (SEDDS).
- the active ingredients may also be presented as a bolus, electuary or paste.
- Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents.
- the tablets may be coated according to methods well known in the art.
- Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
- Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives.
- compositions according to the invention may also be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
- the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
- the active ingredients may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
- compositions suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories.
- suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by admixture of the active compound(s) with the softened or melted carrier(s) followed by chilling and shaping in moulds.
- compositions and methods according to this invention show advantageous effects in the treatment and prevention of those diseases and conditions as described hereinbefore.
- Advantageous effects may be seen for example with respect to efficacy, dosage strength, dosage frequency, pharmacodynamic properties, pharmacokinetic properties, fewer adverse effects, convenience, compliance, etc.
- the active ingredients may be present in the form of a pharmaceutically acceptable salt.
- Pharmaceutically acceptable salts include, without being restricted thereto, such as salts of inorganic acid like hydrochloric acid, sulfuric acid and phosphoric acid; salts of organic carboxylic acid like oxalic acid, acetic acid, citric acid, malic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid and glutamic acid and salts of organic sulfonic acid like methanesulfonic acid and p-toluenesulfonic acid.
- the salts can be formed by combining the compound and an acid in the appropriate amount and ratio in a solvent and decomposer. They can be also obtained by the cation or anion exchange from the form of other salts.
- the active ingredients or a pharmaceutically acceptable salt thereof may be present in the form of a solvate such as a hydrate or alcohol adduct.
- compositions or combinations for use in these therapies comprising the SGLT-2 inhibitor as defined herein optionally together with one or more other active substances are also contemplated.
- the present invention relates to the SGLT-2 inhibitors, optionally in combination with one, two or more further active agents, each as defined herein, for use in the therapies as described herein.
- the present invention relates to the use of the SGLT-2 inhibitors, optionally in combination with one, two or more further active agents, each as defined herein, for preparing pharmaceutical compositions which are suitable for the treatment and/or prevention purposes of this invention.
- the present invention further relates to a pharmaceutical composition
- a pharmaceutical composition comprising a certain SGLT-2 inhibitor as defined herein, preferably empagliflozin, and metformin and/or a DPP-4 inhibitor, for example linagliptin, for use in the therapies described herein.
- the present invention further relates to a combination comprising a certain SGLT-2 inhibitor (particularly empagliflozin) and one or more other antidiabetics selected from the group consisting of metformin, a sulphonylurea, nateglinide, repaglinide, a thiazolidinedione, an alpha-glucosidase inhibitor, insulin or an insulin analogue, GLP-1 or a GLP-1 analogue and a DPP-4 inhibitor, particularly for simultaneous, separate or sequential use in the therapies described herein.
- a certain SGLT-2 inhibitor particularly empagliflozin
- one or more other antidiabetics selected from the group consisting of metformin, a sulphonylurea, nateglinide, repaglinide, a thiazolidinedione, an alpha-glucosidase inhibitor, insulin or an insulin analogue, GLP-1 or a GLP-1 analogue and a DPP-4
- the present invention further relates to a method for treating and/or preventing metabolic diseases, especially type 2 diabetes mellitus and/or conditions related thereto (e.g. diabetic complications) comprising the combined (e.g. simultaneous, separate or sequential) administration of an effective amount of one or more other antidiabetics selected from the group consisting of metformin, a sulphonylurea, nateglinide, repaglinide, a thiazolidinedione, a PPAR-gamma-agonist, an alpha-glucosidase inhibitor, insulin or an insulin analogue, GLP-1 or a GLP-1 analogue and a DPP-4 inhibitor, to the patient (particularly human patient) in need thereof, such as e.g. a patient as described herein.
- metabolic diseases especially type 2 diabetes mellitus and/or conditions related thereto (e.g. diabetic complications)
- an effective amount of one or more other antidiabetics selected from the group consisting of metformin,
- the present invention further relates to therapies or therapeutic methods described herein, such as e.g. a method for treating and/or preventing metabolic diseases, especially type 2 diabetes mellitus and/or conditions related thereto (e.g. diabetic complications), comprising administering a therapeutically effective amount of empagliflozin and, optionally, one or more other therapeutic agents, such as e.g.
- antidiabetics selected from the group consisting of metformin, a sulphonylurea, nateglinide, repaglinide, a thiazolidinedione, a PPAR-gamma-agonist, an alpha-glucosidase inhibitor, insulin or an insulin analogue, GLP-1 or a GLP-1 analogue and a DPP-4 inhibitor, to the patient (particularly human patient) in need thereof, such as e.g. a patient as described herein.
- “combination” or “combined” within the meaning of this invention may include, without being limited, fixed and non-fixed (e.g. free) forms (including kits) and uses, such as e.g. the simultaneous, sequential or separate use of the components or ingredients.
- the combined administration of this invention may take place by administering the active components or ingredients together, such as e.g. by administering them simultaneously in one single or in two separate formulations or dosage forms.
- the administration may take place by administering the active components or ingredients sequentially, such as e.g. successively in two separate formulations or dosage forms.
- the active components or ingredients may be administered separately (which implies that they are formulated separately) or formulated altogether (which implies that they are formulated in the same preparation or in the same dosage form).
- the administration of one element of the combination of the present invention may be prior to, concurrent to, or subsequent to the administration of the other element of the combination.
- combination therapy may refer to first line, second line or third line therapy, or initial or add-on combination therapy or replacement therapy.
- the present invention further relates to a certain SGLT-2 inhibitor as defined herein, preferably empagliflozin, in combination with metformin, for use in the therapies described herein.
- Metformin is usually given in doses varying from about 500 mg to 2000 mg up to 2500 mg per day using various dosing regimens from about 100 mg to 500 mg or 200 mg to 850 mg (1-3 times a day), or about 300 mg to 1000 mg once or twice a day, or delayed-release metformin in doses of about 100 mg to 1000 mg or preferably 500 mg to 1000 mg once or twice a day or about 500 mg to 2000 mg once a day.
- Particular dosage strengths may be 250, 500, 625, 750, 850 and 1000 mg of metformin hydrochloride.
- metformin For children 10 to 16 years of age, the recommended starting dose of metformin is 500 mg given once daily. If this dose fails to produce adequate results, the dose may be increased to 500 mg twice daily. Further increases may be made in increments of 500 mg weekly to a maximum daily dose of 2000 mg, given in divided doses (e.g. 2 or 3 divided doses). Metformin may be administered with food to decrease nausea.
- a DPP-4 inhibitor is linagliptin, which is usually given in a dosage of 5 mg per day. Therefore, a pharmaceutical composition may comprise 5 mg linagliptin in addition to the SGLT2 inhibitor, in particular empagliflozin in an amount of 10 mg or 25 mg.
- a dosage of pioglitazone is usually of about 1-10 mg, 15 mg, 30 mg, or 45 mg once a day.
- Rosiglitazone is usually given in doses from 4 to 8 mg once (or divided twice) a day (typical dosage strengths are 2, 4 and 8 mg).
- Glibenclamide is usually given in doses from 2.5-5 to 20 mg once (or divided twice) a day (typical dosage strengths are 1.25, 2.5 and 5 mg), or micronized glibenclamide in doses from 0.75-3 to 12 mg once (or divided twice) a day (typical dosage strengths are 1.5, 3, 4.5 and 6 mg).
- Glipizide is usually given in doses from 2.5 to 10-20 mg once (or up to 40 mg divided twice) a day (typical dosage strengths are 5 and 10 mg), or extended-release glibenclamide in doses from 5 to 10 mg (up to 20 mg) once a day (typical dosage strengths are 2.5, 5 and 10 mg).
- Glimepiride is usually given in doses from 1-2 to 4 mg (up to 8 mg) once a day (typical dosage strengths are 1, 2 and 4 mg).
- the non-sulphonylurea insulin secretagogue nateglinide is usually given in doses from 60 to 120 mg with meals (up to 360 mg/day, typical dosage strengths are 60 and 120 mg); repaglinide is usually given in doses from 0.5 to 4 mg with meals (up to 16 mg/day, typical dosage strengths are 0.5, 1 and 2 mg).
- a dual combination of repaglinide/metformin is available in dosage strengths of 1/500 and 2/850 mg.
- T2DM Type 2 Diabetes Mellitus
- RI Renal Impairment
- a Phase III trial investigated the efficacy and safety of empagliflozin (EMPA) as add-on to existing therapy for 52 weeks in patients with T2DM and RI.
- the primary endpoint was change from baseline in HbA 1c at week 24. Exploratory endpoints included changes from baseline in fasting plasma glucose (FPG), weight and blood pressure (BP) at week 24 ( FIG. 1 ).
- FPG fasting plasma glucose
- BP blood pressure
- EMPA significantly reduced HbA 1c vs PBO at week 24. Further analyses showed significant reductions in FPG, weight and BP.
- Hypoglycemia plasma glucose ⁇ 70 mg/dL and/or requiring assistance was reported in 23.5% of patients on EMPA 10 mg, 22.1% on EMPA 25 mg and 22.9% on PBO.
- AEs consistent with urinary tract infection were reported in 10.2% of patients on EMPA 10 mg, 9.0% on EMPA 25 mg and 8.2% on PBO. AEs consistent with genital infection were reported in 6.1% of patients on EMPA 10 mg, 2.5% on EMPA 25 mg and 1.3% on PBO.
- the primary endpoint was also analysed for patients with moderate A and moderate B renal impairment.
- the difference to placebo for the adjusted mean change in HbA 1c from baseline at Week 24 was ⁇ 0.46% (95% CI: ⁇ 0.66, ⁇ 0.27).
- the difference to placebo for the adjusted mean change in HbA 1c from baseline at Week 24 was ⁇ 0.39% (95% CI: ⁇ 0.58, ⁇ 0.19).
- Empagliflozin a selective and potent SGLT2 inhibitor, reduces renal glucose reabsorption by lowering the renal threshold for glucose (RT G ) leading to increased urinary glucose excretion (UGE) and decreased plasma glucose (PG) in patients with type 2 diabetes mellitus (T2DM).
- RT G renal threshold for glucose
- UGE urinary glucose excretion
- PG plasma glucose
- T2DM type 2 diabetes mellitus
- the model assumed that when PG>RT G , UGE increased with increasing PG and eGFR; and when PGRT G slight glucose leakage into urine occurred (estimated as fraction reabsorbed [FRAC]).
- Reabsorption was estimated by a nonlinear function parameterized in terms of maximum reabsorbed glucose concentration (G max ) and PG concentration to reach half maximum transport (K m ).
- the parameter estimates (95% CI) were G max : 374 (347, 391) mg/dL; K m : 144 (113, 163) mg/dL; I max : 0.559 (0.545, 0.607); IC 50 : 5.28 (3.53, 8.91) nmol/L; FRAC: 0.999 (0.998, 0.999).
- the calculated RT G for placebo was 230 mg/dL.
- RT G decreased with increasing empagliflozin concentration; doses of 1, 5, 10, and 25 mg yielded RT G values of 100.5, 43.8, 33.1, and 26.0 mg/dL, respectively.
- External predictive check demonstrated unbiased prediction of UGE across a range of eGFR values (end-stage renal disease to normal renal function). Simulation indicated that for 10 and 25 mg QD, >50% and 90% of subjects, respectively, maintained steady-state empagliflozin concentrations >IC 80 for RT G lowering over the dosing interval.
- Subjects Male and female subjects aged 18 to 75 years weighing at least 45 kg (females only) and with a body mass index (BMI) of 18 to 34 kg/m 2 were eligible for inclusion in this study. Participants with normal renal function (eGFR >90 mL/min/1.73 m 2 ; control) were required to have T2DM. Patients with mild renal impairment (eGFR 60-89 mL/min/1.73 m 2 ), moderate renal impairment (eGFR 30-59 mL/min/1.73 m 2 ), severe renal impairment (eGFR ⁇ 30 mL/min/1.73 m 2 ) or renal failure/ESRD (requiring dialysis) did not need to have T2DM. eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) formula: 186 ⁇ serum creatinine ⁇ 1.154 ⁇ age ⁇ 0.203 ⁇ [0.742 if female].
- MDRD Modification of Diet in Renal Disease
- Subjects were excluded from the study if they had recently participated in a study (multiple-dose: within 2 months; single-dose: within 1 month), were abusing alcohol (males >60 g/day; females >40 g/day) or drugs, had donated >100 mL blood in the previous 4 weeks, were taking concomitant medications known to inhibit or induce p-glycoprotein or cytochrome P450 3A, or had any medical or laboratory results deviating from normal and of clinical relevance.
- Subjects with renal impairment were excluded if they had significant diseases other than renal impairment or T2DM, including moderate and severe concurrent hepatic impairment, hemoglobin ⁇ 8 g/dL indicating severe renal anemia (erythropoietin could be used to maintain hemoglobin levels), and intake of drugs with a long half-life (>24 h) within the previous month (or within 10 half-lives of that drug, if longer), except for those being taken for the treatment of renal disease.
- diseases other than renal impairment or T2DM including moderate and severe concurrent hepatic impairment, hemoglobin ⁇ 8 g/dL indicating severe renal anemia (erythropoietin could be used to maintain hemoglobin levels), and intake of drugs with a long half-life (>24 h) within the previous month (or within 10 half-lives of that drug, if longer), except for those being taken for the treatment of renal disease.
- the investigators in cooperation with nephrology centers, aimed to recruit 8 subjects for every group.
- Subjects with normal renal function were matched to those in the renal impairment groups by age ( ⁇ 5 years) and weight ( ⁇ 15%), where possible.
- One objective of the study was to determine the effect of renal impairment on the relative bioavailability of empagliflozin, based on the primary endpoints of AUC 0- ⁇ and C max .
- Secondary pharmacokinetic endpoints included: t max , t 1/2 , fe 0-96 , CL R,0-96 , and plasma protein binding of empagliflozin.
- the pharmacodynamic endpoint of the study was the cumulative amount of UGE over a 24 h period following drug administration (UGE 0-24 ), relative to baseline, with a baseline measurement obtained over 24 h preceding administration of study drug.
- the lower limit of quantification for empagliflozin in human plasma was 1.11 nmol/L, with linearity to 1110 nmol/L using a sample volume of 0.15 mL, and in human urine was 4.44 nmol/L, with linearity to 4440 nmol/L using a sample volume of 0.05 mL.
- results were calculated using peak area ratios and calibration curves were created using weighted (1/x 2 ) quadratic regression.
- Pharmacokinetic parameters were calculated using WinNonlinTM software (v5.01, Pharsight Corporation, Mountain View, Calif., USA). C max and t max values were directly determined from the plasma concentration time profiles of each subject.
- the apparent terminal rate constant ( ⁇ z ) was estimated from a regression of ln(C) versus time over the terminal log-linear drug disposition portion of the concentration-time profiles.
- the t 1/2 was calculated as the quotient of ln(2) and ⁇ z .
- Area under the plasma concentration-time curve to the last time point (AUC 0-tz ) was calculated using the linear trapezoidal method for ascending concentrations and the log trapezoidal method for descending concentrations.
- the AUC 0- ⁇ value was estimated as the sum of AUC to the last measured concentration, with the extrapolated area given by the quotient of the last measured concentration and ⁇ z .
- the amount of drug (A e ) excreted unchanged in urine in each collection interval was determined by the product of the urine concentration and the urine volume.
- the fraction of the dose (f e ) that was excreted unchanged in urine was determined by the quotient of the sum of drug excreted over all dosing intervals and the dose administered. Renal clearance (CL R ) was determined as the quotient of A e over AUC.
- Cumulative UGE was calculated using the glucose concentration measured in every urine sample collected from ⁇ 24-0 h and 0-96 h after dosing. UGE (mg) was calculated as follows: glucose concentration [mg/dL] ⁇ urine volume [dL]). Results are shown in FIGS. 2 to 6 .
- AUC 0- ⁇ and C max were analyzed using an analysis of variance (ANOVA) model on the logarithmic scale including a fixed effect corresponding to the renal function (normal, mild impairment, moderate impairment, severe impairment, or renal failure/ESRD).
- T2DM Type 2 Diabetes Mellitus
- CKD Chronic Kidney Disease
- a Phase III trial investigated the efficacy and safety of empagliflozin (EMPA) as add-on to existing therapy for 52 weeks in patients with T2DM and CKD stage 3A, 3B and 4.
- AEs adverse events
- AEs consistent with urinary tract infection were reported by 16.5% and 18.0% of patients with CKD stage 3A on EMPA 25 mg and PBO, respectively, by 16.7% and 13.3% of patients with CKD stage 3B on EMPA 25 mg and PBO, respectively, and by 18.9% and 8.1% of patients with CKD stage 4 on EMPA 25 mg and PBO, respectively.
- EMPA 25 mg for 52 weeks was associated with significant and clinically meaningful reductions in HbA 1c compared with placebo in patients with T2DM and CKD stage 3A or 3B.
- compositions and dosage forms for oral administration serves to illustrate the present invention more fully without restricting it to the contents of the example. Further examples of compositions and dosage forms for oral administration, are described in WO 2010/092126.
- active substance denotes empagliflozin according to this invention, especially its crystalline form as described in WO 2006/117359 and WO 2011/039107.
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Publication number | Priority date | Publication date | Assignee | Title |
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US9024010B2 (en) | 2009-09-30 | 2015-05-05 | Boehringer Ingelheim International Gmbh | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives |
US9127034B2 (en) | 2005-05-10 | 2015-09-08 | Boehringer Ingelheim International Gmbh | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivates and intermediates therein |
US9192617B2 (en) | 2012-03-20 | 2015-11-24 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
US9902751B2 (en) | 2013-12-30 | 2018-02-27 | Mylan Laboratories Limited | Process for the preparation of empagliflozin |
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Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7713938B2 (en) * | 2005-05-03 | 2010-05-11 | Boehringer Ingelheim International Gmbh | Crystalline form of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments |
Family Cites Families (201)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3174901A (en) | 1963-01-31 | 1965-03-23 | Jan Marcel Didier Aron Samuel | Process for the oral treatment of diabetes |
NL167151C (nl) | 1971-04-09 | 1981-11-16 | Acf Chemiefarma Nv | Werkwijze ter bereiding van geneesmiddelen met anti-parasitaire werking op basis van halogeen bevatten- de 2,2'-methyleendifenolderivaten, alsmede werkwijze ter bereiding van deze geneeskrachtige verbindingen. |
NO154918C (no) | 1977-08-27 | 1987-01-14 | Bayer Ag | Analogifremgangsmaate til fremstilling av terapeutisk aktive derivater av 3,4,5-trihydroksypiperidin. |
DE2758025A1 (de) | 1977-12-24 | 1979-07-12 | Bayer Ag | Neue derivate von 3,4,5-trihydroxypiperidin, verfahren zu ihrer herstellung und ihre verwendung |
DE2951135A1 (de) | 1979-12-19 | 1981-06-25 | Hoechst Ag, 6230 Frankfurt | Sulfonylharnstoffe, verfahren zu ihrer herstellung, pharmazeutische praeparate auf basis dieser verbindungen und ihre verwendung |
JPS5639056A (en) | 1980-07-16 | 1981-04-14 | Kanebo Ltd | Preparation of n,n,n',n'-tetraacylated nucleus halogenated aromatic diamine |
JPS58164502A (ja) | 1982-03-26 | 1983-09-29 | Chugai Pharmaceut Co Ltd | 除草用組成物 |
US4786755A (en) | 1985-06-03 | 1988-11-22 | Warner-Lambert Company | Diphenic acid monoamides |
US4602023A (en) | 1985-06-03 | 1986-07-22 | Warner-Lambert Company | Diphenic acid monoamides |
US4786023A (en) | 1987-08-19 | 1988-11-22 | Harris Leverett D | Drafting implement holder |
US5145684A (en) | 1991-01-25 | 1992-09-08 | Sterling Drug Inc. | Surface modified drug nanoparticles |
ATE138563T1 (de) | 1991-12-20 | 1996-06-15 | Pfizer | Poröse geformte abgabevorrichtung und verfahren zur herstellung derselbe |
GB9401460D0 (en) | 1994-01-26 | 1994-03-23 | Rhone Poulenc Rorer Ltd | Compositions of matter |
WO1997025992A1 (en) | 1996-01-16 | 1997-07-24 | Merck & Co., Inc. | Tocolytic oxytocin receptor antagonists |
US6297273B1 (en) | 1996-04-02 | 2001-10-02 | Mars, Inc. | Use of cocoa solids having high cocoa polyphenol content in tabletting compositions and capsule filling compositions |
JPH1085502A (ja) | 1996-09-19 | 1998-04-07 | Konica Corp | 晶析方法 |
US5807580A (en) | 1996-10-30 | 1998-09-15 | Mcneil-Ppc, Inc. | Film coated tablet compositions having enhanced disintegration characteristics |
AU6024998A (en) | 1997-01-15 | 1998-08-07 | Glycomed Incorporated | Aryl c-glycoside compounds and sulfated esters thereof |
US6159978A (en) | 1997-05-28 | 2000-12-12 | Aventis Pharmaceuticals Product, Inc. | Quinoline and quinoxaline compounds which inhibit platelet-derived growth factor and/or p56lck tyrosine kinases |
JPH1185502A (ja) | 1997-09-02 | 1999-03-30 | Fujitsu Ltd | ソフトウェア利用管理システム |
JPH11124392A (ja) | 1997-10-21 | 1999-05-11 | Sankyo Co Ltd | C−グリコシル化されたアリールスズ化合物 |
US6291471B1 (en) | 1998-12-17 | 2001-09-18 | Abb Holdings, Inc. | Use of apomorphine for the treatment of organic erectile dysfunction in males |
JP2000219632A (ja) | 1999-01-28 | 2000-08-08 | Toyotama Koryo Kk | カロリー軽減剤 |
US6613806B1 (en) | 1999-01-29 | 2003-09-02 | Basf Corporation | Enhancement of the efficacy of benzoylbenzenes |
CA2382480C (en) | 1999-08-31 | 2008-09-30 | Kissei Pharmaceutical Co., Ltd. | Glucopyranosyloxypyrazole derivatives, medicinal compositions containing the same and intermediates in the production thereof |
US6515117B2 (en) | 1999-10-12 | 2003-02-04 | Bristol-Myers Squibb Company | C-aryl glucoside SGLT2 inhibitors and method |
PH12000002657B1 (en) | 1999-10-12 | 2006-02-21 | Bristol Myers Squibb Co | C-aryl glucoside SGLT2 inhibitors |
US6498193B2 (en) | 1999-12-22 | 2002-12-24 | Trustees Of Dartmouth College | Treatment for complications of type 2 diabetes |
US6627611B2 (en) | 2000-02-02 | 2003-09-30 | Kotobuki Pharmaceutical Co Ltd | C-glycosides and preparation of thereof as antidiabetic agents |
JP4456768B2 (ja) | 2000-02-02 | 2010-04-28 | 壽製薬株式会社 | C−配糖体を含有する薬剤 |
AU4114601A (en) | 2000-03-17 | 2001-09-24 | Kissei Pharmaceutical | Glucopyranosyloxy benzylbenzene derivatives, medicinal compositions containing the same and intermediates for the preparation of the derivatives |
US6683056B2 (en) | 2000-03-30 | 2004-01-27 | Bristol-Myers Squibb Company | O-aryl glucoside SGLT2 inhibitors and method |
US6627634B2 (en) | 2000-04-08 | 2003-09-30 | Boehringer Ingelheim Pharma Kg | Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them |
DE60122193T2 (de) | 2000-09-29 | 2007-07-05 | Kissei Pharmaceutical Co., Ltd., Matsumoto | Glucopyranosyloxybenzylbenzol derivate und medizinische zusammensetzungen, die diese verbindungen enthalten |
AU2002223127A1 (en) | 2000-11-30 | 2002-06-11 | Kissei Pharmaceutical Co., Ltd. Intellectual Property | Glucopyranosyloxybenzyl benzene derivatives, medicinal compositions containing the same and intermediates in the production thereof |
US7019012B2 (en) | 2000-12-20 | 2006-03-28 | Boehringer Ingelheim International Pharma Gmbh & Co. Kg | Quinazoline derivatives and pharmaceutical compositions containing them |
DE10063435A1 (de) | 2000-12-20 | 2002-07-04 | Boehringer Ingelheim Pharma | Chinazolinderviate,diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
US6878714B2 (en) | 2001-01-12 | 2005-04-12 | Amgen Inc. | Substituted alkylamine derivatives and methods of use |
TWI255817B (en) | 2001-02-14 | 2006-06-01 | Kissei Pharmaceutical | Glucopyranosyloxybenzylbenzene derivatives and medicinal use thereof |
JP2004529097A (ja) | 2001-02-15 | 2004-09-24 | ファイザー・プロダクツ・インク | Pparアゴニスト |
CZ305402B6 (cs) | 2001-02-24 | 2015-09-02 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Xanthinové deriváty, jejich výroba a použití v kombinační terapii |
ES2319263T3 (es) | 2001-02-26 | 2009-05-06 | Kissei Pharmaceutical Co., Ltd. | Derivados de glucopiranosilooxipirazol y su utilizacion como medicamentos. |
CA2438595C (en) | 2001-02-27 | 2011-08-09 | Kissei Pharmaceutical Co., Ltd. | Glucopyranosyloxypyrazole derivatives and medicinal use thereof |
US6936590B2 (en) | 2001-03-13 | 2005-08-30 | Bristol Myers Squibb Company | C-aryl glucoside SGLT2 inhibitors and method |
JP3698067B2 (ja) | 2001-03-30 | 2005-09-21 | Jsr株式会社 | 電子吸引性基および電子供与性基を有するモノマー、それを用いた共重合体、ならびにプロトン伝導膜 |
WO2002083066A2 (en) | 2001-04-11 | 2002-10-24 | Bristol-Myers Squibb Company | Amino acid complexes of c-aryl glucosides for treatment of diabetes and method |
JP2002338471A (ja) | 2001-05-23 | 2002-11-27 | Asahi Kasei Corp | 勃起機能不全のための治療薬 |
DE10139416A1 (de) | 2001-08-17 | 2003-03-06 | Aventis Pharma Gmbh | Aminoalkyl substituierte aromatische Bicyclen, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
EP1432720A1 (en) | 2001-09-05 | 2004-06-30 | Bristol-Myers Squibb Company | O-pyrazole glucoside sglt2 inhibitors and method of use |
WO2003031458A1 (en) | 2001-10-12 | 2003-04-17 | Dana-Farber Cancer Institute | Methods for synthesis of diarylmethanes |
ITRM20010708A1 (it) | 2001-12-04 | 2003-06-04 | Sigma Tau Ind Farmaceuti | Uso di una alcanoil l-carnitina per il trattamento della disfunzione erettile. |
PL371435A1 (en) | 2002-02-01 | 2005-06-13 | Novo Nordisk A/S | Amides of aminoalkyl-substituted azetidines, pyrrolidines, piperidines and azepanes |
GB0206215D0 (en) | 2002-03-15 | 2002-05-01 | Novartis Ag | Organic compounds |
JP2005538958A (ja) | 2002-06-05 | 2005-12-22 | ファルマシア・コーポレーション | p38キナーゼ阻害薬としてのピラゾール誘導体 |
SE0201837D0 (sv) | 2002-06-14 | 2002-06-14 | Astrazeneca Ab | Chemical compounds |
DE10231370B4 (de) | 2002-07-11 | 2006-04-06 | Sanofi-Aventis Deutschland Gmbh | Thiophenglycosidderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zur Herstellung dieser Arzneimittel |
EP1521747B1 (en) | 2002-07-15 | 2018-09-05 | Symphony Evolution, Inc. | Receptor-type kinase modulators and methods of use |
TWI254635B (en) | 2002-08-05 | 2006-05-11 | Yamanouchi Pharma Co Ltd | Azulene derivative and salt thereof |
US7375087B2 (en) | 2002-08-08 | 2008-05-20 | Kissei Pharmaceutical Co., Ltd. | Pyrazole derivative, medicinal composition containing the same, medicinal use thereof, and intermediate for production thereof |
PL372865A1 (en) | 2002-08-09 | 2005-08-08 | Taisho Pharmaceutical Co, Ltd. | Aryl 5-thio-beta-d-glucopyranoside derivatives and remedies for diabetes containing the same |
JP4233524B2 (ja) | 2002-08-21 | 2009-03-04 | ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト | 8−[3−アミノ−ピペリジン−1−イル]−キサンチン、その製造およびその薬理組成物としての使用 |
US7407955B2 (en) | 2002-08-21 | 2008-08-05 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
JP3567162B1 (ja) | 2002-11-20 | 2004-09-22 | 日本たばこ産業株式会社 | 4−オキソキノリン化合物及びそのhivインテグラーゼ阻害剤としての利用 |
DE60329318D1 (de) | 2002-11-20 | 2009-10-29 | Japan Tobacco Inc | 4-oxochinolinverbindungen und deren verwendung als hiv-integrase-inhibitoren |
JP4651934B2 (ja) | 2002-12-04 | 2011-03-16 | キッセイ薬品工業株式会社 | ベンジルフェノール誘導体、それを含有する医薬組成物およびその医薬用途 |
DE10258008B4 (de) | 2002-12-12 | 2006-02-02 | Sanofi-Aventis Deutschland Gmbh | Heterocyclische Fluorglycosidderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zur Herstellung dieser Arzneimittel |
DE10258007B4 (de) | 2002-12-12 | 2006-02-09 | Sanofi-Aventis Deutschland Gmbh | Aromatische Fluorglycosidderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zur Herstellung dieser Arzneimittel |
US7375213B2 (en) | 2003-01-03 | 2008-05-20 | Bristol-Myers Squibb Company | Methods of producing C-aryl glucoside SGLT2 inhibitors |
EP1597266A4 (en) | 2003-02-27 | 2008-02-20 | Bristol Myers Squibb Co | NON-CRYOGENIC PROCESS FOR THE PRODUCTION OF GLYCOSIDES |
KR101001848B1 (ko) | 2003-03-14 | 2010-12-17 | 고토부키 세이야쿠 가부시키가이샤 | C-글리코시드 유도체 또는 이의 염, 및 이를 포함하는 의약 조성물 |
US7674486B2 (en) | 2003-05-14 | 2010-03-09 | Indus Biotech Pvt. Ltd. | Synergistic composition for the treatment of diabetes mellitus |
EP1664073A2 (en) | 2003-06-03 | 2006-06-07 | The Regents of the University of California | Compositions and methods for treatment of disease with acetylated disaccharides |
JP2004359630A (ja) | 2003-06-06 | 2004-12-24 | Yamanouchi Pharmaceut Co Ltd | ジフルオロジフェニルメタン誘導体及びその塩 |
FR2855756B1 (fr) | 2003-06-06 | 2005-08-26 | Ethypharm Sa | Comprime orodispersible multicouche |
US20050027236A1 (en) | 2003-07-30 | 2005-02-03 | Medtronic Ave, Inc. | Aspiration catheter having a variable over-the-wire length and methods of use |
US6995183B2 (en) | 2003-08-01 | 2006-02-07 | Bristol Myers Squibb Company | Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods |
WO2005011592A2 (en) | 2003-08-01 | 2005-02-10 | Janssen Pharmaceutica N.V. | Substituted indazole-o-glucosides |
ME00411B (me) | 2003-08-01 | 2011-10-10 | Tanabe Seiyaku Co | Nova jedinjenja koja imaju inhibitorno dejstvo na transporter glukoze zavistan od natrijuma |
US7094763B2 (en) | 2003-08-01 | 2006-08-22 | Janssen Pharaceutica, N.V. | Substituted fused heterocyclic C-glycosides |
JP4131216B2 (ja) | 2003-08-20 | 2008-08-13 | Jsr株式会社 | ポリアリーレンおよびその製造方法、ならびに高分子固体電解質およびプロトン伝導膜 |
ATE422204T1 (de) | 2003-08-26 | 2009-02-15 | Boehringer Ingelheim Int | Glucopyranosyloxy-pyrazole, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
US7375090B2 (en) | 2003-08-26 | 2008-05-20 | Boehringer Ingelheim International Gmbh | Glucopyranosyloxy-pyrazoles, pharmaceutical compositions containing these compounds, the use thereof and processed for the preparation thereof |
US20050085680A1 (en) | 2003-10-21 | 2005-04-21 | Joseph Auerbach | Method for industrial decontamination |
CN1905876B (zh) | 2003-11-17 | 2010-06-09 | 诺瓦提斯公司 | 二肽基肽酶iv抑制剂的用途 |
DE10361133A1 (de) | 2003-12-22 | 2005-07-21 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Glucopyranosyloxy-substituierte Aromaten, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
US7371732B2 (en) | 2003-12-22 | 2008-05-13 | Boehringer Ingelheim International Gmbh | Glucopyranosyloxy-substituted aromatic compounds, medicaments containing such compounds, their use and process for their manufacture |
EP2165703A3 (en) | 2004-01-20 | 2012-03-28 | Novartis Pharma AG | Direct compression formulation and process |
PT1758905E (pt) | 2004-02-18 | 2009-07-16 | Boehringer Ingelheim Int | 8-[3-amino-piperidin-1-il]-xantinas, sua preparação e sua utilização como inibidores de dpp-iv |
US7501426B2 (en) | 2004-02-18 | 2009-03-10 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions |
RU2387663C2 (ru) | 2004-03-04 | 2010-04-27 | Киссеи Фармасьютикал Ко., Лтд. | Конденсированные гетероциклические производные, содержащие их медицинские композиции и их медицинское применение |
JP4950657B2 (ja) | 2004-03-04 | 2012-06-13 | キッセイ薬品工業株式会社 | 縮合複素環誘導体、それを含有する医薬組成物およびその医薬用途 |
CN103030617A (zh) | 2004-03-16 | 2013-04-10 | 贝林格尔.英格海姆国际有限公司 | 吡喃葡萄糖基取代的苯基衍生物、含该化合物的药物、其用途及其制造方法 |
DE102004012676A1 (de) | 2004-03-16 | 2005-10-06 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Glucopyranosyl-substituierte Phenyle, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
WO2005117861A1 (en) | 2004-06-04 | 2005-12-15 | Novartis Ag | Use of organic compounds |
TW200611704A (en) | 2004-07-02 | 2006-04-16 | Bristol Myers Squibb Co | Human glucagon-like-peptide-1 modulators and their use in the treatment of diabetes and related conditions |
US7393836B2 (en) | 2004-07-06 | 2008-07-01 | Boehringer Ingelheim International Gmbh | D-xylopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture |
CN1984898A (zh) | 2004-07-08 | 2007-06-20 | 安斯泰来制药有限公司 | 生产薁衍生物的方法和合成该薁衍生物的中间体 |
DE102004034690A1 (de) | 2004-07-17 | 2006-02-02 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Methyliden-D-xylopyranosyl-und Oxo-D-xylopyranosyl-substituierte Phenyle, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
TW200606129A (en) | 2004-07-26 | 2006-02-16 | Chugai Pharmaceutical Co Ltd | Novel cyclohexane derivative, its prodrug, its salt and diabetic therapeutic agent containing the same |
JP2008508213A (ja) | 2004-07-27 | 2008-03-21 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | D−グルコピラノシル−フェニル置換環状体、そのような化合物を含有する医薬品、それらの使用及びその製造方法 |
WO2006018150A1 (de) | 2004-08-11 | 2006-02-23 | Boehringer Ingelheim International Gmbh | D-xylopyranosyl-phenyl-substituierte cyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
DE102004044221A1 (de) | 2004-09-14 | 2006-03-16 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue 3-Methyl-7-butinyl-xanthine, deren Herstellung und deren Verwendung als Arzneimittel |
AR051446A1 (es) | 2004-09-23 | 2007-01-17 | Bristol Myers Squibb Co | Glucosidos de c-arilo como inhibidores selectivos de transportadores de glucosa (sglt2) |
JP5046370B2 (ja) | 2004-09-29 | 2012-10-10 | キッセイ薬品工業株式会社 | 1−(β−D−グリコピラノシル)−3−置換含窒素ヘテロ環化合物、それを含有する医薬組成物及びその医薬用途 |
DE102004048388A1 (de) | 2004-10-01 | 2006-04-06 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | D-Pyranosyl-substituierte Phenyle, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
DE102004054054A1 (de) | 2004-11-05 | 2006-05-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verfahren zur Herstellung chiraler 8-(3-Amino-piperidin-1-yl)-xanthine |
EP1828216B1 (en) | 2004-12-16 | 2008-09-10 | Boehringer Ingelheim International GmbH | Glucopyranosyl-substituted benzene derivatives, medicaments containing such compounds, their use and process for their manufacture |
JP2006176443A (ja) | 2004-12-22 | 2006-07-06 | Shionogi & Co Ltd | メラニン凝集ホルモン受容体アンタゴニスト |
GB0428180D0 (en) | 2004-12-23 | 2005-01-26 | Biopartners Ltd | Combination therapy |
GT200600008A (es) | 2005-01-18 | 2006-08-09 | Formulacion de compresion directa y proceso | |
ES2334940T3 (es) | 2005-02-23 | 2010-03-17 | Boehringer Ingelheim International Gmbh | Derivados de ((hetero)ariletinilbencil)benceno sustituidos con glucopiranosilo y uso de los mismos como inhibidores del cotransportador 2 de glucosa dependiente de sodio (sglt2). |
WO2006108842A1 (en) | 2005-04-15 | 2006-10-19 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted (heteroaryloxy-benzyl)-benzene derivatives as sglt inhibitors |
US7723309B2 (en) | 2005-05-03 | 2010-05-25 | Boehringer Ingelheim International Gmbh | Crystalline forms of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments |
US7772191B2 (en) | 2005-05-10 | 2010-08-10 | Boehringer Ingelheim International Gmbh | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein |
WO2007000445A1 (en) | 2005-06-29 | 2007-01-04 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted benzyl-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture |
ATE468347T1 (de) | 2005-07-27 | 2010-06-15 | Boehringer Ingelheim Int | Glucopyranosyl-substituierte ((hetero)cycloalyklethynyl-benzyl)- benzenderivative und deren verwendung als inhibitoren des natriumabhängigen glucose- cotransporters (sglt) |
KR100780553B1 (ko) | 2005-08-18 | 2007-11-29 | 한올제약주식회사 | 메트포르민 서방정 및 그의 제조방법 |
US7452872B2 (en) | 2005-08-24 | 2008-11-18 | Salix Pharmaceuticals, Inc. | Formulations and uses of 2-hydroxy-5-phenylazobenzoic acid derivatives |
DE602006017566D1 (de) | 2005-08-30 | 2010-11-25 | Boehringer Ingelheim Pharma | Glucopyranosyl-substituierte benzyl-derivate, medikamente mit solchen verbindungen, ihre verwendung und herstellungsverfahren dafür |
CA2621314A1 (en) | 2005-09-08 | 2007-03-15 | Boehringer Ingelheim International Gmbh | Crystalline forms of 1-chloro-4-(.beta.-d-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene, methods for its preparation and the use thereof for preparing medicaments |
NZ566799A (en) | 2005-09-14 | 2011-04-29 | Takeda Pharmaceutical | Dipeptidyl peptidase inhibitors for treating diabetes |
AR056195A1 (es) | 2005-09-15 | 2007-09-26 | Boehringer Ingelheim Int | Procedimientos para preparar derivados de (etinil-bencil)-benceno sustituidos de glucopiranosilo y compuestos intermedios de los mismos |
JOP20180109A1 (ar) | 2005-09-29 | 2019-01-30 | Novartis Ag | تركيبة جديدة |
EP1942902A1 (en) | 2005-09-30 | 2008-07-16 | Boehringer Ingelheim Vetmedica Gmbh | Pharmaceutical preparation containing meloxicam |
JP2009531291A (ja) | 2006-02-15 | 2009-09-03 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | グルコピラノシル置換ベンゾニトリル誘導体、それらの化合物を含有する医薬組成物、それらの使用及び製造方法 |
PE20080697A1 (es) | 2006-05-03 | 2008-08-05 | Boehringer Ingelheim Int | Derivados de benzonitrilo sustituidos con glucopiranosilo, composiciones farmaceuticas que contienen compuestos de este tipo, su uso y procedimiento para su fabricacion |
PE20110235A1 (es) | 2006-05-04 | 2011-04-14 | Boehringer Ingelheim Int | Combinaciones farmaceuticas que comprenden linagliptina y metmorfina |
EP1852108A1 (en) | 2006-05-04 | 2007-11-07 | Boehringer Ingelheim Pharma GmbH & Co.KG | DPP IV inhibitor formulations |
TW200812995A (en) | 2006-05-19 | 2008-03-16 | Taisho Pharmaceutical Co Ltd | C-phenyl glycitol compound |
DE602007012692D1 (de) | 2006-06-16 | 2011-04-07 | Lek Pharmaceuticals | Pharmazeutische zusammensetzung mit hydrochlorothiazid und telmisartan |
AR061627A1 (es) | 2006-06-27 | 2008-09-10 | Novartis Ag | Formas de dosificacion solidas de valsartan, amlodipina, e hidroclorotiazida, y metodo para elaborarlas |
TW200817424A (en) | 2006-08-04 | 2008-04-16 | Daiichi Sankyo Co Ltd | Benzylphenyl glucopyranoside derivatives |
US8039441B2 (en) | 2006-08-15 | 2011-10-18 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted cyclopropylbenzene derivatives, pharmaceutical compositions containing such compounds, their use as SGLT inhibitors and process for their manufacture |
AU2007285827A1 (en) | 2006-08-17 | 2008-02-21 | Wellstat Therapeutics Corporation | Combination treatment for metabolic disorders |
EP2074130A1 (en) | 2006-09-21 | 2009-07-01 | Boehringer Ingelheim International GmbH | Glucopyranosyl-substituted difluorobenzyl-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture |
CA2667550A1 (en) | 2006-10-27 | 2008-05-02 | Boehringer Ingelheim International Gmbh | Crystalline form of 4-(.beta.-d-glucopyranos-1-yl)-1-methyl-2-[4-((s)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments |
CL2007003187A1 (es) | 2006-11-06 | 2008-03-07 | Boehringer Ingelheim Int | Compuestos derivados de bencil-benzonitrilo sustituido con glucopiranosilo y sus sales; procedimiento de preparacion; compuestos intermediarios; proceso para preparar los compuestos intermediarios; composicion farmaceutica; y uso en el tratamiento de |
JP5337040B2 (ja) | 2006-11-09 | 2013-11-06 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Sglt−2インヒビターとの組み合わせ治療及びそれらの医薬組成物 |
WO2008062273A2 (en) | 2006-11-20 | 2008-05-29 | Cadila Pharmaceuticals Limited | Solid oral dosage form having antidiabetic drug combination |
JP2010516721A (ja) | 2007-01-26 | 2010-05-20 | サノフィ−アベンティス | フェノチアジン誘導体、その製造方法及び医薬としてその使用 |
CL2008000224A1 (es) | 2007-01-26 | 2008-05-23 | Boehringer Ingelheim Int | Composicion farmaceutica que comprende un compuesto derivado glucopiranosilo; y uso para el tratamiento de uno o mas trastornos neurodegenerativos. |
ITFI20070042A1 (it) | 2007-02-21 | 2008-08-22 | Laboratori Guidotti Spa | Formulazione farmaceutica e compressa comprendente detta formulazione. |
WO2008101938A1 (en) | 2007-02-21 | 2008-08-28 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted benzyl-benzonitrile derivatives, medicaments containing such compounds, their use and process for their manufacture |
EP2125768A1 (en) | 2007-02-21 | 2009-12-02 | Boehringer Ingelheim International GmbH | Tetrasubstituted glucopyranosylated benzene derivatives, medicaments containing such compounds, their use and process for their manufacture |
TW200904405A (en) | 2007-03-22 | 2009-02-01 | Bristol Myers Squibb Co | Pharmaceutical formulations containing an SGLT2 inhibitor |
TW200904454A (en) | 2007-03-22 | 2009-02-01 | Bristol Myers Squibb Co | Methods for treating obesity employing an SGLT2 inhibitor and compositions thereof |
CA2684618A1 (en) | 2007-04-20 | 2008-10-30 | Schering Corporation | Tetrahydropyrido[4,3-d]pyrimidinone derivatives and methods of use thereof |
PE20090696A1 (es) | 2007-04-20 | 2009-06-20 | Bristol Myers Squibb Co | Formas cristalinas de saxagliptina y procesos para preparar las mismas |
JP2010528023A (ja) | 2007-05-18 | 2010-08-19 | ブリストル−マイヤーズ スクイブ カンパニー | Sglt2阻害剤の結晶構造およびその製造方法 |
PE20090938A1 (es) | 2007-08-16 | 2009-08-08 | Boehringer Ingelheim Int | Composicion farmaceutica que comprende un derivado de benceno sustituido con glucopiranosilo |
PE20090603A1 (es) | 2007-08-16 | 2009-06-11 | Boehringer Ingelheim Int | Composicion farmaceutica que comprende un inhibidor de sglt2 y un inhibidor de dpp iv |
CN101801371B (zh) | 2007-09-10 | 2012-11-28 | 詹森药业有限公司 | 可用作sglt抑制剂的化合物的制备方法 |
CL2008003653A1 (es) | 2008-01-17 | 2010-03-05 | Mitsubishi Tanabe Pharma Corp | Uso de un inhibidor de sglt derivado de glucopiranosilo y un inhibidor de dppiv seleccionado para tratar la diabetes; y composicion farmaceutica. |
CN101503399B (zh) | 2008-02-04 | 2012-06-27 | 白鹭医药技术(上海)有限公司 | C-芳基葡萄糖苷sglt2抑制剂 |
EP2249643A4 (en) | 2008-02-05 | 2013-10-09 | Merck Sharp & Dohme | PHARMACEUTICAL COMPOSITIONS OF A METFORMIN AND DIPEPTIDYL PEPTIDASE-IV INHIBITOR ASSOCIATION |
US8551524B2 (en) | 2008-03-14 | 2013-10-08 | Iycus, Llc | Anti-diabetic combinations |
WO2009123194A1 (ja) | 2008-04-01 | 2009-10-08 | 武田薬品工業株式会社 | 複素環化合物 |
PE20091730A1 (es) | 2008-04-03 | 2009-12-10 | Boehringer Ingelheim Int | Formulaciones que comprenden un inhibidor de dpp4 |
CN101638423B (zh) | 2008-07-29 | 2012-09-05 | 常州高新技术产业开发区三维工业技术研究所有限公司 | 根皮苷衍生物及其制备方法和用途 |
WO2010045656A2 (en) | 2008-10-17 | 2010-04-22 | Nectid, Inc. | Novel sglt2 inhibitor dosage forms |
WO2010049678A2 (en) | 2008-10-31 | 2010-05-06 | Summit Corporation Plc | Treatment of energy utilization diseases |
AU2009331471B2 (en) | 2008-12-23 | 2015-09-03 | Boehringer Ingelheim International Gmbh | Salt forms of organic compound |
JP2012517977A (ja) | 2009-02-13 | 2012-08-09 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Dpp−4阻害剤(リナグリプチン)を任意で他の抗糖尿病薬と組み合わせて含む抗糖尿病薬 |
MA33044B1 (fr) | 2009-02-13 | 2012-02-01 | Boehringer Ingelheim Int | Composition pharmaceutique contenant des derives de glucopyranosyl diphenylmethane, sa forme posologique galenique, son procede de preparation et ses utilisations pour une regulation glycemique amelioree chez un patient |
SG173587A1 (en) | 2009-02-13 | 2011-09-29 | Boehringer Ingelheim Int | Sglt-2 inhibitor for treating type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance or hyperglycemia |
UY32427A (es) | 2009-02-13 | 2010-09-30 | Boheringer Ingelheim Internat Gmbh | Composicion farmaceutica, forma farmaceutica, procedimiento para su preparacion, metodos de tratamiento y usos de la misma |
PL2395983T3 (pl) | 2009-02-13 | 2020-09-07 | Boehringer Ingelheim International Gmbh | Kompozycja farmaceutyczna zawierająca inhibitor sglt2, inhibitor dpp-iv i ewentualnie dalszy środek przeciwcukrzycowy oraz jej zastosowania |
NZ606888A (en) | 2009-04-16 | 2014-07-25 | Taisho Pharmaceutical Co Ltd | Pharmaceutical compositions for the treatment of diabetes mellitus |
US8685934B2 (en) | 2009-05-27 | 2014-04-01 | Bristol-Myers Squibb Company | Methods for treating extreme insulin resistance in patients resistant to previous treatment with other anti-diabetic drugs employing an SGLT2 inhibitor and compositions thereof |
US20110077212A1 (en) | 2009-09-25 | 2011-03-31 | Theracos, Inc. | Therapeutic uses of sglt2 inhibitors |
CN102574829B (zh) | 2009-09-30 | 2015-07-01 | 贝林格尔.英格海姆国际有限公司 | 吡喃葡萄糖基取代的苄基-苯衍生物的制备方法 |
WO2011039107A1 (en) | 2009-09-30 | 2011-04-07 | Boehringer Ingelheim International Gmbh | Method for the preparation of a crystalline form of 1-chloro-4- (beta-d-glucopyranos-1-yl)-2-(4-((s)-tetrahydrofuran-3-yloxy)benzyl)benzene |
UY32919A (es) | 2009-10-02 | 2011-04-29 | Boehringer Ingelheim Int | Composición farmacéutica, forma de dosificación farmacéutica, procedimiento para su preparación, mé todos para su tratamiento y sus usos |
BR112012011733A2 (pt) | 2009-11-13 | 2019-09-24 | Bristol-Myers Squibb Company | formulações de comprimido de liberação imediata |
US20140088027A1 (en) | 2010-03-30 | 2014-03-27 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition comprising an sglt2 inhibitor and a ppar- gamma agonist and uses thereof |
WO2012031124A2 (en) | 2010-09-03 | 2012-03-08 | Bristol-Myers Squibb Company | Drug formulations using water soluble antioxidants |
US20120283169A1 (en) | 2010-11-08 | 2012-11-08 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
AR083878A1 (es) | 2010-11-15 | 2013-03-27 | Boehringer Ingelheim Int | Terapia antidiabetica vasoprotectora y cardioprotectora, linagliptina, metodo de tratamiento |
RU2607480C2 (ru) | 2011-02-01 | 2017-01-10 | Бристол-Майерс Сквибб Компани | Фармацевтические композиции, содержащие аминосоединение |
US20130035281A1 (en) | 2011-02-09 | 2013-02-07 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
UY33937A (es) | 2011-03-07 | 2012-09-28 | Boehringer Ingelheim Int | Composiciones farmacéuticas que contienen inhibidores de dpp-4 y/o sglt-2 y metformina |
WO2012163990A1 (en) | 2011-06-03 | 2012-12-06 | Boehringer Ingelheim International Gmbh | Sglt-2 inhibitors for treating metabolic disorders in patients treated with neuroleptic agents |
US20130035298A1 (en) | 2011-07-08 | 2013-02-07 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
US20150119399A1 (en) | 2012-01-10 | 2015-04-30 | President And Fellows Of Harvard College | Beta-cell replication promoting compounds and methods of their use |
US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
US9192617B2 (en) | 2012-03-20 | 2015-11-24 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
CN104780915A (zh) | 2012-07-11 | 2015-07-15 | 埃尔舍利克斯治疗公司 | 包含他汀、双胍和用于减小心脏代谢风险的其它药剂的组合物 |
CA2812016A1 (en) | 2013-04-05 | 2014-10-05 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
US20160000816A1 (en) | 2013-04-05 | 2016-01-07 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
CA2812519A1 (en) | 2013-04-05 | 2014-10-05 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
US20140303098A1 (en) | 2013-04-05 | 2014-10-09 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
US20140303097A1 (en) | 2013-04-05 | 2014-10-09 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
CN105377266A (zh) | 2013-04-18 | 2016-03-02 | 勃林格殷格翰国际有限公司 | 药物组合物、治疗方法及其用途 |
ES2811261T3 (es) | 2014-04-01 | 2021-03-11 | Boehringer Ingelheim Vetmedica Gmbh | Tratamiento de trastornos metabólicos en animales equinos |
KR102539788B1 (ko) | 2014-09-25 | 2023-06-07 | 베링거잉겔하임베트메디카게엠베하 | 말과 동물의 대사 장애를 예방하기 위한 sglt2 억제제와 도파민 작용제의 병용 치료 |
JP6561136B2 (ja) | 2015-04-30 | 2019-08-14 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 勃起機能不全を治療又は改善するための方法及びsglt2阻害薬を含む医薬組成物 |
EP3362055B1 (en) | 2015-10-15 | 2023-01-18 | Boehringer Ingelheim International GmbH | Sglt-2 inhibitor for use in the treatment of a metabolic myopathy |
WO2017093419A1 (en) | 2015-12-04 | 2017-06-08 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
US20170266152A1 (en) | 2016-03-16 | 2017-09-21 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
US20190309004A1 (en) | 2016-10-13 | 2019-10-10 | Boehringer Ingelheim International Gmbh | Process for preparing glucopyranosyl-substituted benzyl-benzene derivatives |
EP3538107A1 (en) | 2016-11-10 | 2019-09-18 | Boehringer Ingelheim International GmbH | Pharmaceutical composition, methods for treating and uses thereof |
-
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- 2014-04-03 US US14/244,208 patent/US20140303098A1/en not_active Abandoned
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- 2015-09-03 IL IL241102A patent/IL241102B/en active IP Right Grant
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- 2017-07-12 JP JP2017135958A patent/JP6431959B2/ja active Active
-
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- 2018-03-12 US US15/918,401 patent/US10258637B2/en active Active
-
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- 2019-01-16 HR HRP20190101TT patent/HRP20190101T1/hr unknown
- 2019-01-24 CY CY20191100108T patent/CY1121203T1/el unknown
- 2019-02-28 US US16/288,192 patent/US11090323B2/en active Active
-
2021
- 2021-06-10 US US17/344,003 patent/US11833166B2/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7713938B2 (en) * | 2005-05-03 | 2010-05-11 | Boehringer Ingelheim International Gmbh | Crystalline form of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments |
Non-Patent Citations (2)
Title |
---|
Malatiali et al., Experimental Diabetes Research, 2008, volume 2008, 7 pages. * |
Vervoort et al., European Journal of Clinical Investigation, 2005, vol. 35, pp.330-336. * |
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HUE041709T2 (hu) | 2019-05-28 |
HRP20190101T1 (hr) | 2019-03-08 |
HK1215398A1 (zh) | 2016-08-26 |
PH12015502275B1 (en) | 2016-02-01 |
US9949998B2 (en) | 2018-04-24 |
TR201901110T4 (tr) | 2019-02-21 |
US20190350957A1 (en) | 2019-11-21 |
US11090323B2 (en) | 2021-08-17 |
JP2017186371A (ja) | 2017-10-12 |
PT2981271T (pt) | 2019-02-19 |
ES2702174T3 (es) | 2019-02-27 |
CY1121203T1 (el) | 2020-05-29 |
US10258637B2 (en) | 2019-04-16 |
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