U.S. patent application number 12/703988 was filed with the patent office on 2011-02-24 for pharmaceutical composition, methods for treating and uses thereof.
This patent application is currently assigned to BOEHRINGER INGELHEIM INTERNATIONAL GMBH. Invention is credited to Uli Broedl, Peter Eickelmann, Rolf Grempler, Michael Mark, Leo John Seman, Leo Thomas.
Application Number | 20110046076 12/703988 |
Document ID | / |
Family ID | 42109921 |
Filed Date | 2011-02-24 |
United States Patent
Application |
20110046076 |
Kind Code |
A1 |
Eickelmann; Peter ; et
al. |
February 24, 2011 |
PHARMACEUTICAL COMPOSITION, METHODS FOR TREATING AND USES
THEREOF
Abstract
The invention relates to a pharmaceutical composition according
to the claim 1 comprising an SGLT2 inhibitor, a DPPIV inhibitor and
a third antidiabetic agent which is suitable in the treatment or
prevention of one or more conditions selected from type 1 diabetes
mellitus, type 2 diabetes mellitus, impaired glucose tolerance and
hyperglycemia. In addition the present invention relates to methods
for preventing or treating of metabolic disorders and related
conditions.
Inventors: |
Eickelmann; Peter;
(Mittelbiberach, DE) ; Mark; Michael; (Biberach,
DE) ; Seman; Leo John; (Cheshire, CT) ;
Thomas; Leo; (Biberach, DE) ; Broedl; Uli;
(Biberach, DE) ; Grempler; Rolf; (Warthausen
Birkenhard, DE) |
Correspondence
Address: |
MICHAEL P. MORRIS;BOEHRINGER INGELHEIM USA CORPORATION
900 RIDGEBURY ROAD, P. O. BOX 368
RIDGEFIELD
CT
06877-0368
US
|
Assignee: |
BOEHRINGER INGELHEIM INTERNATIONAL
GMBH
Ingelheim
DE
|
Family ID: |
42109921 |
Appl. No.: |
12/703988 |
Filed: |
February 11, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61152302 |
Feb 13, 2009 |
|
|
|
Current U.S.
Class: |
514/23 |
Current CPC
Class: |
A61K 31/351 20130101;
A61K 31/39 20130101; A61K 31/522 20130101; A61P 3/12 20180101; A61P
3/04 20180101; A61K 45/06 20130101; A61K 31/403 20130101; A61P 3/00
20180101; A61K 31/341 20130101; A61P 3/08 20180101; A61K 31/7004
20130101; A61K 31/4439 20130101; A61K 31/00 20130101; A61P 13/12
20180101; A61P 13/04 20180101; A61K 31/7048 20130101; A61K 31/155
20130101; A61P 3/10 20180101; A61K 31/7008 20130101; A61P 43/00
20180101; A61K 31/198 20130101; A61P 19/06 20180101; A61K 31/70
20130101; A61P 3/06 20180101; A61P 9/00 20180101; A61P 9/10
20180101; A61K 31/00 20130101; A61K 2300/00 20130101; A61K 31/155
20130101; A61K 2300/00 20130101; A61K 31/198 20130101; A61K 2300/00
20130101; A61K 31/341 20130101; A61K 2300/00 20130101; A61K 31/351
20130101; A61K 2300/00 20130101; A61K 31/39 20130101; A61K 2300/00
20130101; A61K 31/403 20130101; A61K 2300/00 20130101; A61K 31/4439
20130101; A61K 2300/00 20130101; A61K 31/70 20130101; A61K 2300/00
20130101; A61K 31/7004 20130101; A61K 2300/00 20130101; A61K
31/7008 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/23 |
International
Class: |
A61K 31/7034 20060101
A61K031/7034; A61P 3/10 20060101 A61P003/10; A61P 3/04 20060101
A61P003/04; A61P 9/10 20060101 A61P009/10; A61P 9/00 20060101
A61P009/00 |
Claims
1. A pharmaceutical composition comprising (a) an SGLT2 inhibitor,
and (b) a DPPIV inhibitor, and (c) a third antidiabetic agent
selected from the group G3 consisting of biguanides,
thiazolidindiones, sulfonylureas, glinides, inhibitors of
alpha-glucosidase, GLP-1 analogues or a pharmaceutically acceptable
salt thereof.
2. The pharmaceutical composition according to the claim 1 wherein
the SGLT2 inhibitor is selected from the group G1 consisting of
dapagliflozin, canagliflozin, atigliflozin, remogliflozin,
sergliflozin and glucopyranosyl-substituted benzene derivatives of
the formula (I) ##STR00015## wherein R.sup.1 denotes CI, methyl or
cyano; R.sup.2 denotes H, methyl, methoxy or hydroxy and R.sup.3
denotes ethyl, cyclopropyl, ethynyl, ethoxy,
(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; or a
prodrug thereof.
3. The pharmaceutical composition according to the claim 1 wherein
the DPP IV inhibitor is selected from the group G2 consisting of
linagliptin, sitagliptin, vildagliptin, alogliptin, saxagliptin,
denagliptin, carmegliptin, melogliptin and dutogliptin, or a
pharmaceutically acceptable salt of one of the beforementioned
DPPIV inhibitors, or a prodrug thereof.
4. The pharmaceutical composition according to claim 1 wherein the
third antidiabetic agent is selected from the group consisting of
metformin, pioglitazone, rosiglitazone, troglitazone, ciglitazone,
glibenclamide, tolbutamide, glimepiride, glipizide, gliquidone,
glibornurid, glyburide, glisoepide, gliclazide, nateglinide,
repaglinide, mitiglinide, acarbose, voglibose, miglitol, exenatide
and liraglutide or a pharmaceutically acceptable salt of one of the
beforementioned therapeutic agents.
5. The pharmaceutical composition according to claim 1 wherein the
composition is suitable for combined or simultaneous or sequential
use of the SGLT2 inhibitor, the DPP IV inhibitor and the third
antidiabetic agent.
6. Method for preventing, slowing the progression of, delaying or
treating a metabolic disorder selected from the group consisting of
type 1 diabetes mellitus, type 2 diabetes mellitus, impaired
glucose tolerance, impaired fasting blood glucose, hyperglycemia,
postprandial hyperglycemia, overweight, obesity, metabolic
syndrome, gestational diabetes, new onset diabetes after
transplantation (NODAT) and complications associated therewith, and
post-transplant metabolic syndrome (PTMS) and complications
associated therewith in a patient in need thereof characterized in
that an SGLT2 inhibitor, a DPP IV inhibitor and optionally a third
antidiabetic agent according to claim 1 are administered in
combination or alternation to the patient.
7. Method according to claim 6 wherein the patient: (1) is an
individual diagnosed of one or more of the conditions selected from
the group consisting of overweight, obesity, visceral obesity and
abdominal obesity; or (2) is an individual who shows one, two or
more of the following conditions: (a) a fasting blood glucose or
serum glucose concentration greater than 110 mg/dL, in particular
greater than 125 mg/dL; (b) a postprandial plasma glucose equal to
or greater than 140 mg/dL; (c) an HbA1c value equal to or greater
than 6.5%, in particular equal to or greater than 7.0%; or (3) is
an individual wherein one, two, three or more of the following
conditions are present: (a) obesity, visceral obesity and/or
abdominal obesity, (b) triglyceride blood level.gtoreq.150 mg/dL,
(c) HDL-cholesterol blood level<40 mg/dL in female patients and
<50 mg/dL in male patients, (d) a systolic blood
pressure.gtoreq.130 mm Hg and a diastolic blood pressure.gtoreq.85
mm Hg, (e) a fasting blood glucose level.gtoreq.100 mg/dL; or (4)
has insufficient glycemic control despite diet and exercise or
despite monotherapy with either the SGLT2 inhibitor, the DPPIV
inhibitor or the third antidiabetic agent, or despite combination
therapy with two agents selected from the group of the SGLT2
inhibitor, the DPPIV inhibitor and the third antidiabetic
agent.
8. Method for improving glycemic control and/or for reducing of
fasting plasma glucose, of postprandial plasma glucose and/or of
glycosylated hemoglobin HbA1c in a patient in need thereof
characterized in that an SGLT2 inhibitor, a DPP IV inhibitor and
optionally a third antidiabetic agent according to claim 1 are
administered in combination or alternation to the patient.
9. Method according to claim 8 wherein the patient: (1) is an
individual diagnosed of one or more of the conditions selected from
the group consisting of overweight, obesity, visceral obesity and
abdominal obesity; or (2) is an individual who shows one, two or
more of the following conditions: (a) a fasting blood glucose or
serum glucose concentration greater than 110 mg/dL, in particular
greater than 125 mg/dL; (b) a postprandial plasma glucose equal to
or greater than 140 mg/dL; (c) an HbA1c value equal to or greater
than 6.5%, in particular equal to or greater than 7.0%; or (3) is
an individual wherein one, two, three or more of the following
conditions are present: (a) obesity, visceral obesity and/or
abdominal obesity, (b) triglyceride blood level.gtoreq.150 mg/dL,
(c) HDL-cholesterol blood level<40 mg/dL in female patients and
<50 mg/dL in male patients, (d) a systolic blood
pressure.gtoreq.130 mm Hg and a diastolic blood pressure.gtoreq.85
mm Hg, (e) a fasting blood glucose level.gtoreq.100 mg/dL; or (4)
has insufficient glycemic control despite diet and exercise or
despite monotherapy with either the SGLT2 inhibitor, the DPPIV
inhibitor or the third antidiabetic agent, or despite combination
therapy with two agents selected from the group of the SGLT2
inhibitor, the DPPIV inhibitor and the third antidiabetic
agent.
10. Method for preventing, slowing, delaying or reversing
progression from impaired glucose tolerance, impaired fasting blood
glucose, insulin resistance and/or from metabolic syndrome to type
2 diabetes mellitus in a patient in need thereof characterized in
that an SGLT2 inhibitor, a DPP IV inhibitor and optionally a third
antidiabetic agent according to claim 1 are administered in
combination or alternation to the patient.
11. Method according to claim 10 wherein the patient: (1) is an
individual diagnosed of one or more of the conditions selected from
the group consisting of overweight, obesity, visceral obesity and
abdominal obesity; or (2) is an individual who shows one, two or
more of the following conditions: (a) a fasting blood glucose or
serum glucose concentration greater than 110 mg/dL, in particular
greater than 125 mg/dL; (b) a postprandial plasma glucose equal to
or greater than 140 mg/dL; (c) an HbA1c value equal to or greater
than 6.5%, in particular equal to or greater than 7.0%; or (3) is
an individual wherein one, two, three or more of the following
conditions are present: (a) obesity, visceral obesity and/or
abdominal obesity, (b) triglyceride blood level.gtoreq.150 mg/dL,
(c) HDL-cholesterol blood level<40 mg/dL in female patients and
<50 mg/dL in male patients, (d) a systolic blood
pressure.gtoreq.130 mm Hg and a diastolic blood pressure.gtoreq.85
mm Hg, (e) a fasting blood glucose level.gtoreq.100 mg/dL; or (4)
has insufficient glycemic control despite diet and exercise or
despite monotherapy with either the SGLT2 inhibitor, the DPPIV
inhibitor or the third antidiabetic agent, or despite combination
therapy with two agents selected from the group of the SGLT2
inhibitor, the DPPIV inhibitor and the third antidiabetic
agent.
12. Method for preventing, slowing the progression of, delaying or
treating of a condition or disorder selected from the group
consisting of complications of diabetes mellitus such as cataracts
and micro- and macrovascular diseases, such as nephropathy,
retinopathy, neuropathy, tissue ischaemia, diabetic foot,
arteriosclerosis, myocardial infarction, acute coronary syndrome,
unstable angina pectoris, stable angina pectoris, stroke,
peripheral arterial occlusive disease, cardiomyopathy, heart
failure, heart rhythm disorders and vascular restenosis, in a
patient in need thereof characterized in that an SGLT2 inhibitor, a
DPP IV inhibitor and optionally a third antidiabetic agent
according to claim 1 are administered in combination or alternation
to the patient.
13. Method according to claim 12 wherein the patient: (1) is an
individual diagnosed of one or more of the conditions selected from
the group consisting of overweight, obesity, visceral obesity and
abdominal obesity; or (2) is an individual who shows one, two or
more of the following conditions: (a) a fasting blood glucose or
serum glucose concentration greater than 110 mg/dL, in particular
greater than 125 mg/dL; (b) a postprandial plasma glucose equal to
or greater than 140 mg/dL; (c) an HbA1c value equal to or greater
than 6.5%, in particular equal to or greater than 7.0%; or (3) is
an individual wherein one, two, three or more of the following
conditions are present: (a) obesity, visceral obesity and/or
abdominal obesity, (b) triglyceride blood level.gtoreq.150 mg/dL,
(c) HDL-cholesterol blood level<40 mg/dL in female patients and
<50 mg/dL in male patients, (d) a systolic blood
pressure.gtoreq.130 mm Hg and a diastolic blood pressure.gtoreq.85
mm Hg, (e) a fasting blood glucose level.gtoreq.100 mg/dL; or (4)
has insufficient glycemic control despite diet and exercise or
despite monotherapy with either the SGLT2 inhibitor, the DPPIV
inhibitor or the third antidiabetic agent, or despite combination
therapy with two agents selected from the group of the SGLT2
inhibitor, the DPPIV inhibitor and the third antidiabetic
agent.
14. Method for reducing body weight and/or body fat or preventing
an increase in body weight and/or body fat or facilitating a
reduction in body weight and/or body fat in a patient in need
thereof characterized in that an SGLT2 inhibitor, a DPP IV
inhibitor and optionally a third antidiabetic agent according to
claim 1 are administered in combination or alternation to the
patient.
15. Method according to claim 14 wherein the patient: (1) is an
individual diagnosed of one or more of the conditions selected from
the group consisting of overweight, obesity, visceral obesity and
abdominal obesity; or (2) is an individual who shows one, two or
more of the following conditions: (a) a fasting blood glucose or
serum glucose concentration greater than 110 mg/dL, in particular
greater than 125 mg/dL; (b) a postprandial plasma glucose equal to
or greater than 140 mg/dL; (c) an HbA1c value equal to or greater
than 6.5%, in particular equal to or greater than 7.0%; or (3) is
an individual wherein one, two, three or more of the following
conditions are present: (a) obesity, visceral obesity and/or
abdominal obesity, (b) triglyceride blood level.gtoreq.150 mg/dL,
(c) HDL-cholesterol blood level<40 mg/dL in female patients and
<50 mg/dL in male patients, (d) a systolic blood
pressure.gtoreq.130 mm Hg and a diastolic blood pressure.gtoreq.85
mm Hg, (e) a fasting blood glucose level.gtoreq.100 mg/dL; or (4)
has insufficient glycemic control despite diet and exercise or
despite monotherapy with either the SGLT2 inhibitor, the DPPIV
inhibitor or the third antidiabetic agent, or despite combination
therapy with two agents selected from the group of the SGLT2
inhibitor, the DPPIV inhibitor and the third antidiabetic
agent.
16. Method for preventing, slowing, delaying or treating the
degeneration of pancreatic beta cells and/or the decline of the
functionality of pancreatic beta cells and/or for improving and/or
restoring the functionality of pancreatic beta cells and/or
restoring the functionality of pancreatic insulin secretion in a
patient in need thereof characterized in that an SGLT2 inhibitor, a
DPP IV inhibitor and optionally a third antidiabetic agent
according to claim 1 are administered in combination or alternation
to the patient.
17. Method according to claim 16 wherein the patient: (1) is an
individual diagnosed of one or more of the conditions selected from
the group consisting of overweight, obesity, visceral obesity and
abdominal obesity; or (2) is an individual who shows one, two or
more of the following conditions: (a) a fasting blood glucose or
serum glucose concentration greater than 110 mg/dL, in particular
greater than 125 mg/dL; (b) a postprandial plasma glucose equal to
or greater than 140 mg/dL; (c) an HbA1c value equal to or greater
than 6.5%, in particular equal to or greater than 7.0%; or (3) is
an individual wherein one, two, three or more of the following
conditions are present: (a) obesity, visceral obesity and/or
abdominal obesity, (b) triglyceride blood level.gtoreq.150 mg/dL,
(c) HDL-cholesterol blood level<40 mg/dL in female patients and
<50 mg/dL in male patients, (d) a systolic blood
pressure.gtoreq.130 mm Hg and a diastolic blood pressure.gtoreq.85
mm Hg, (e) a fasting blood glucose level.gtoreq.100 mg/dL; or (4)
has insufficient glycemic control despite diet and exercise or
despite monotherapy with either the SGLT2 inhibitor, the DPPIV
inhibitor or the third antidiabetic agent, or despite combination
therapy with two agents selected from the group of the SGLT2
inhibitor, the DPPIV inhibitor and the third antidiabetic
agent.
18. Method for preventing, slowing, delaying or treating diseases
or conditions attributed to an abnormal accumulation of ectopic fat
in a patient in need thereof characterized in that an SGLT2
inhibitor, a DPP IV inhibitor and optionally a third antidiabetic
agent according to claim 1 are administered in combination or
alternation to the patient.
19. Method according to claim 18 wherein the patient: (1) is an
individual diagnosed of one or more of the conditions selected from
the group consisting of overweight, obesity, visceral obesity and
abdominal obesity; or (2) is an individual who shows one, two or
more of the following conditions: (a) a fasting blood glucose or
serum glucose concentration greater than 110 mg/dL, in particular
greater than 125 mg/dL; (b) a postprandial plasma glucose equal to
or greater than 140 mg/dL; (c) an HbA1c value equal to or greater
than 6.5%, in particular equal to or greater than 7.0%; or (3) is
an individual wherein one, two, three or more of the following
conditions are present: (a) obesity, visceral obesity and/or
abdominal obesity, (b) triglyceride blood level.gtoreq.150 mg/dL,
(c) HDL-cholesterol blood level<40 mg/dL in female patients and
<50 mg/dL in male patients, (d) a systolic blood
pressure.gtoreq.130 mm Hg and a diastolic blood pressure.gtoreq.85
mm Hg, (e) a fasting blood glucose level.gtoreq.100 mg/dL; or (4)
has insufficient glycemic control despite diet and exercise or
despite monotherapy with either the SGLT2 inhibitor, the DPPIV
inhibitor or the third antidiabetic agent, or despite combination
therapy with two agents selected from the group of the SGLT2
inhibitor, the DPPIV inhibitor and the third antidiabetic
agent.
20. Method for maintaining and/or improving the insulin sensitivity
and/or for treating or preventing hyperinsulinemia and/or insulin
resistance in a patient in need thereof characterized in that an
SGLT2 inhibitor, a DPP IV inhibitor and optionally a third
antidiabetic agent according to claim 1 are administered in
combination or alternation to the patient.
21. Method according to claim 20 wherein the patient: (1) is an
individual diagnosed of one or more of the conditions selected from
the group consisting of overweight, obesity, visceral obesity and
abdominal obesity; or (2) is an individual who shows one, two or
more of the following conditions: (a) a fasting blood glucose or
serum glucose concentration greater than 110 mg/dL, in particular
greater than 125 mg/dL; (b) a postprandial plasma glucose equal to
or greater than 140 mg/dL; (c) an HbA1c value equal to or greater
than 6.5%, in particular equal to or greater than 7.0%; or (3) is
an individual wherein one, two, three or more of the following
conditions are present: (a) obesity, visceral obesity and/or
abdominal obesity, (b) triglyceride blood level.gtoreq.150 mg/dL,
(c) HDL-cholesterol blood level<40 mg/dL in female patients and
<50 mg/dL in male patients, (d) a systolic blood
pressure.gtoreq.130 mm Hg and a diastolic blood pressure.gtoreq.85
mm Hg, (e) a fasting blood glucose level.gtoreq.100 mg/dL; or (4)
has insufficient glycemic control despite diet and exercise or
despite monotherapy with either the SGLT2 inhibitor, the DPPIV
inhibitor or the third antidiabetic agent, or despite combination
therapy with two agents selected from the group of the SGLT2
inhibitor, the DPPIV inhibitor and the third antidiabetic
agent.
22. Method for treating and preventing hyperuricemia and
hyperuricemia associated conditions, kidney stones and hyponatremia
in a patient in need thereof characterized in that an SGLT2
inhibitor, a DPP IV inhibitor and optionally a third antidiabetic
agent according to claim 1 are administered in combination or
alternation to the patient.
23. Method according to claim 22 wherein the patient: (1) is an
individual diagnosed of one or more of the conditions selected from
the group consisting of overweight, obesity, visceral obesity and
abdominal obesity; or (2) is an individual who shows one, two or
more of the following conditions: (a) a fasting blood glucose or
serum glucose concentration greater than 110 mg/dL, in particular
greater than 125 mg/dL; (b) a postprandial plasma glucose equal to
or greater than 140 mg/dL; (c) an HbA1c value equal to or greater
than 6.5%, in particular equal to or greater than 7.0%; or (3) is
an individual wherein one, two, three or more of the following
conditions are present: (a) obesity, visceral obesity and/or
abdominal obesity, (b) triglyceride blood level.gtoreq.150 mg/dL,
(c) HDL-cholesterol blood level<40 mg/dL in female patients and
<50 mg/dL in male patients, (d) a systolic blood
pressure.gtoreq.130 mm Hg and a diastolic blood pressure.gtoreq.85
mm Hg, (e) a fasting blood glucose level.gtoreq.100 mg/dL; or (4)
has insufficient glycemic control despite diet and exercise or
despite monotherapy with either the SGLT2 inhibitor, the DPPIV
inhibitor or the third antidiabetic agent, or despite combination
therapy with two agents selected from the group of the SGLT2
inhibitor, the DPPIV inhibitor and the third antidiabetic agent.
Description
[0001] This application claims benefit from U.S. Provisional
Application No. 61/152,302, filed on Feb. 13, 2009, the content of
which is incorporated herein in its entirety.
TECHNICAL FIELD OF THE INVENTION
[0002] The invention relates to a pharmaceutical composition
comprising an SGLT2-inhibitor, a DPPIV inhibitor and a third
antidiabetic agent selected from the group G3 as described
hereinafter which is suitable in the treatment or prevention of one
or more conditions selected from type 1 diabetes mellitus, type 2
diabetes mellitus, impaired glucose tolerance, impaired fasting
blood glucose and hyperglycemia inter alia.
[0003] Furthermore the invention relates to methods [0004] for
preventing, slowing progression of, delaying, or treating a
metabolic disorder; [0005] for improving glycemic control and/or
for reducing of fasting plasma glucose, of postprandial plasma
glucose and/or of glycosylated hemoglobin HbA1c; [0006] for
preventing, slowing, delaying or reversing progression from
impaired glucose tolerance, impaired fasting blood glucose, insulin
resistance and/or from metabolic syndrome to type 2 diabetes
mellitus; [0007] for preventing, slowing progression of, delaying
or treating of a condition or disorder selected from the group
consisting of complications of diabetes mellitus; [0008] for
reducing body weight and/or body fat or preventing an increase in
body weight and/or body fat or facilitating a reduction in body
weight and/or body fat; [0009] for preventing or treating the
degeneration of pancreatic beta cells and/or for improving and/or
restoring the functionality of pancreatic beta cells and/or
restoring the functionality of pancreatic insulin secretion; [0010]
for preventing, slowing, delaying or treating diseases or
conditions attributed to an abnormal accumulation of ectopic fat;
[0011] maintaining and/or improving the insulin sensitivity and/or
for treating or preventing hyperinsulinemia and/or insulin
resistance, [0012] for preventing, slowing progression of,
delaying, or treating new onset diabetes after transplantation
(NODAT) and/or post-transplant metabolic syndrome (PTMS); [0013]
for preventing, delaying, or reducing NODAT and/or PTMS associated
complications including micro- and macrovascular diseases and
events, graft rejection, infection, and death; [0014] for treating
hyperuricemia and hyperuricemia associated conditions; [0015] for
treating or preventing kidney stones; [0016] for treating
hyponatremia; in patients in need thereof characterized in that an
SGLT2 inhibitor, a DPPIV inhibitor and optionally a third
antidiabetic agent as defined hereinafter is administered in
combination or alternation.
[0017] In addition the present invention relates to the use of an
SGLT2 inhibitor for the manufacture of a medicament for use in a
method as described hereinbefore and hereinafter.
[0018] In addition, the present invention relates to the use of a
DPP IV inhibitor for the manufacture of a medicament for use in a
method as described hereinbefore and hereinafter.
[0019] In addition, the present invention relates to the use of a
third antidiabetic agent as defined hereinafter for the manufacture
of a medicament for use in a method as described hereinbefore and
hereinafter.
[0020] The invention also relates to a use of a pharmaceutical
composition according to this invention for the manufacture of a
medicament for use in a method as described hereinbefore and
hereinafter.
BACKGROUND OF THE INVENTION
[0021] Type 2 diabetes is an increasingly prevalent disease that
due to a high frequency of complications leads to a significant
reduction of life expectancy. Because of diabetes-associated
microvascular complications, type 2 diabetes is currently the most
frequent cause of adult-onset loss of vision, renal failure, and
amputations in the industrialized world. In addition, the presence
of type 2 diabetes is associated with a two to five fold increase
in cardiovascular disease risk.
[0022] After long duration of disease, most patients with type 2
diabetes will eventually fail on oral therapy and become insulin
dependent with the necessity for daily injections and multiple
daily glucose measurements.
[0023] The UKPDS (United Kingdom Prospective Diabetes Study)
demonstrated that intensive treatment with metformin, sulfonylureas
or insulin resulted in only a limited improvement of glycemic
control (difference in HbA1c .about.0.9%). In addition, even in
patients within the intensive treatment arm glycemic control
deteriorated significantly over time and this was attributed to
deterioration of .beta.-cell function. Importantly, intensive
treatment was not associated with a significant reduction in
macrovascular complications, i.e. cardiovascular events. Therefore
many patients with type 2 diabetes remain inadequately treated,
partly because of limitations in long term efficacy, tolerability
and dosing inconvenience of existing antihyperglycemic
therapies.
[0024] Oral antidiabetic drugs conventionally used in therapy (such
as e.g. first- or second-line, and/or mono- or (initial or add-on)
combination therapy) include, without being restricted thereto,
metformin, sulphonylureas, thiazolidinediones, glinides and
.alpha.-glucosidase inhibitors.
[0025] The 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
macrovascular complications such as e.g. diabetic nephrophathy,
retinopathy or neuropathy, or cardiovascular complications) in
patients with type 2 diabetes.
[0026] Therefore, there is an unmet medical need for methods,
medicaments and pharmaceutical compositions with a good efficacy
with regard to glycemic control, with regard to disease-modifying
properties and with regard to reduction of cardiovascular morbidity
and mortality while at the same time showing an improved safety
profile.
[0027] SGLT2 inhibitors inhibitors represent a novel class of
agents that are being developed for the treatment or improvement in
glycemic control in patients with type 2 diabetes.
Glucopyranosyl-substituted benzene derivative are described in the
prior art 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.
[0028] 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.
There are at least 3 SGLT isoforms that differ in their expression
pattern as well as in their physico-chemical properties. 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.
Potentially, other related, but not yet characterized genes, may
contribute further to renal glucose reuptake. Under normoglycemia,
glucose is completely reabsorbed by SGLTs in the kidney, whereas
the reuptake capacity of the kidney is saturated at glucose
concentrations higher than 10 mM, resulting in glucosuria
("diabetes mellitus"). This threshold concentration can be
decreased by SGLT2-inhibition. It has been shown in experiments
with the SGLT inhibitor phlorizin that SGLT-inhibition will
partially inhibit the reuptake of glucose from the glomerular
filtrate into the blood leading to a decrease in blood glucose
concentrations and to glucosuria.
[0029] DPP IV inhibitors represent another novel class of agents
that are being developed for the treatment or improvement in
glycemic control in patients with type 2 diabetes.
[0030] For example, DPP IV inhibitors and their uses are disclosed
in WO 2002/068420, WO 2004/018467, WO 2004/018468, WO 2004/018469,
WO 2004/041820, WO 2004/046148, WO 2005/051950, WO 2005/082906, WO
2005/063750, WO 2005/085246, WO 2006/027204, WO 2006/029769,
WO2007/014886; WO 2004/050658, WO 2004/111051, WO 2005/058901, WO
2005/097798; WO 2006/068163, WO 2007/071738, WO 2008/017670; WO
2007/054201, WO 2007/128721 or WO 2007/128761.
AIM OF THE PRESENT INVENTION
[0031] The aim of the present invention is to provide a
pharmaceutical composition and method for preventing, slowing
progression of, delaying or treating a metabolic disorder, in
particular of type 2 diabetes mellitus.
[0032] A further aim of the present invention is to provide a
pharmaceutical composition and method for improving glycemic
control in a patient in need thereof, in particular in patients
with type 2 diabetes mellitus.
[0033] Another aim of the present invention is to provide a
pharmaceutical composition and method for improving glycemic
control in a patient with insufficient glycemic control despite
monotherapy with an antidiabetic drug, for example metformin, or
despite combination therapy with two antidiabetic drugs.
[0034] Another aim of the present invention is to provide a
pharmaceutical composition and method for preventing, slowing or
delaying progression from impaired glucose tolerance (IGT),
impaired fasting blood glucose (IFG), insulin resistance and/or
metabolic syndrome to type 2 diabetes mellitus.
[0035] Yet another aim of the present invention is to provide a
pharmaceutical composition and method for preventing, slowing
progression of, delaying or treating of a condition or disorder
from the group consisting of complications of diabetes
mellitus.
[0036] A further aim of the present invention is to provide a
pharmaceutical composition and method for reducing the weight or
preventing an increase of the weight in a patient in need
thereof.
[0037] Another aim of the present invention is to provide a new
pharmaceutical composition with a high efficacy for the treatment
of metabolic disorders, in particular of diabetes mellitus,
impaired glucose tolerance (IGT), impaired fasting blood glucose
(IFG), and/or hyperglycemia, which has good to very good
pharmacological and/or pharmacokinetic and/or physicochemical
properties.
[0038] Further aims of the present invention become apparent to the
one skilled in the art by description hereinbefore and in the
following and by the examples.
SUMMARY OF THE INVENTION
[0039] Within the scope of the present invention it has now
surprisingly been found that a pharmaceutical composition
comprising a SGLT2 inhibitor and a DPP IV inhibitor and a third
antidiabetic agent selected from the group G3 as defined
hereinafter can advantageously be used for preventing, slowing
progression of, delaying or treating a metabolic disorder, in
particular for improving glycemic control in patients. This opens
up new therapeutic possibilities in the treatment and prevention of
type 2 diabetes mellitus, overweight, obesity, complications of
diabetes mellitus and of neighboring disease states.
[0040] Therefore, in a first aspect the present invention provides
a pharmaceutical composition comprising [0041] (a) an SGLT2
inhibitor, and [0042] (b) a DPPIV inhibitor, and [0043] (c) a third
antidiabetic agent selected from the group G3 consisting of
biguanides, thiazolidindiones, sulfonylureas, glinides, inhibitors
of alpha-glucosidase, GLP-1 analogues or a pharmaceutically
acceptable salt thereof.
[0044] According to another aspect of the invention, there is
provided a method for preventing, slowing the progression of,
delaying or treating a metabolic disorder selected from the group
consisting of type 1 diabetes mellitus, type 2 diabetes mellitus,
impaired glucose tolerance (IGT), impaired fasting blood glucose
(IFG), hyperglycemia, postprandial hyperglycemia, overweight,
obesity, metabolic syndrome and gestational diabetes in a patient
in need thereof characterized in that an SGLT2 inhibitor, a DPPIV
inhibitor and optionally a third antidiabetic agent as defined
hereinbefore and hereinafter are administered, for example in
combination or alternation, to the patient.
[0045] According to another aspect of the invention, there is
provided a method for improving glycemic control and/or for
reducing of fasting plasma glucose, of postprandial plasma glucose
and/or of glycosylated hemoglobin HbA1c in a patient in need
thereof characterized in that an SGLT2 inhibitor, a DPPIV inhibitor
and optionally a third antidiabetic agent as defined hereinbefore
and hereinafter are administered, for example in combination or
alternation, to the patient.
[0046] The pharmaceutical composition according to this invention
may also have valuable disease-modifying properties with respect to
diseases or conditions related to impaired glucose tolerance (IGT),
impaired fasting blood glucose (IFG), insulin resistance and/or
metabolic syndrome.
[0047] According to another aspect of the invention, there is
provided a method for preventing, slowing, delaying or reversing
progression from impaired glucose tolerance (IGT), impaired fasting
blood glucose (IFG), insulin resistance and/or from metabolic
syndrome to type 2 diabetes mellitus in a patient in need thereof
characterized in that an SGLT2 inhibitor, a DPPIV inhibitor and
optionally a third antidiabetic agent as defined hereinbefore and
hereinafter are administered, for example in combination or
alternation, to the patient.
[0048] As by the use of a pharmaceutical composition according to
this invention, an improvement of the glycemic control in patients
in need thereof is obtainable, also those conditions and/or
diseases related to or caused by an increased blood glucose level
may be treated.
[0049] According to another aspect of the invention, there is
provided a method for preventing, slowing the progression of,
delaying or treating of a condition or disorder selected from the
group consisting of complications of diabetes mellitus such as
cataracts and micro- and macrovascular diseases, such as
nephropathy, retinopathy, neuropathy, tissue ischaemia, diabetic
foot, arteriosclerosis, myocardial infarction, accute coronary
syndrome, unstable angina pectoris, stable angina pectoris, stroke,
peripheral arterial occlusive disease, cardiomyopathy, heart
failure, heart rhythm disorders and vascular restenosis, in a
patient in need thereof characterized in that an SGLT2 inhibitor, a
DPPIV inhibitor and optionally a third antidiabetic agent as
defined hereinbefore and hereinafter are administered, for example
in combination or alternation, to the patient. In particular one or
more aspects of diabetic nephropathy such as hyperperfusion,
proteinuria and albuminuria may be treated, their progression
slowed or their onset delayed or prevented. The term "tissue
ischaemia" particularly comprises diabetic macroangiopathy,
diabetic microangiopathy, impaired wound healing and diabetic
ulcer. The terms "micro- and macrovascular diseases" and "micro-
and macrovascular complications" are used interchangeably in this
application.
[0050] By the administration of a pharmaceutical composition
according to this invention and due to the activity of the SGLT2
inhibitor excessive blood glucose levels are not converted to
insoluble storage forms, like fat, but excreted through the urine
of the patient. In animal models using a SGLT2 inhibitor it can be
seen that loss of fat accounts for the majority of the observed
weight loss whereas no significant changes in body water or protein
content are observed. Therefore, no gain in weight or even a
reduction in body weight is the result.
[0051] According to another aspect of the invention, there is
provided a method for reducing body weight and/or body fat or
preventing an increase in body weight and/or body fat or
facilitating a reduction in body weight and/or body fat in a
patient in need thereof characterized in that an SGLT2 inhibitor, a
DPPIV inhibitor and optionally a third antidiabetic agent as
defined hereinbefore and hereinafter are administered, for example
in combination or alternation, to the patient.
[0052] The pharmacological effect of the SGLT2 inhibitor in the
pharmaceutical composition according to this invention is
independent of insulin. Therefore, an improvement of the glycemic
control is possible without an additional strain on the pancreatic
beta cells. By an administration of a pharmaceutical composition
according to this invention a beta-cell degeneration and a decline
of beta-cell functionality such as for example apoptosis or
necrosis of pancreatic beta cells can be delayed or prevented.
Furthermore, the functionality of pancreatic cells can be improved
or restored, and the number and size of pancreatic beta cells
increased. It may be shown that the differentiation status and
hyperplasia of pancreatic beta-cells disturbed by hyperglycemia can
be normalized by treatment with a pharmaceutical composition
according to this invention.
[0053] According to another aspect of the invention, there is
provided a method for preventing, slowing, delaying or treating the
degeneration of pancreatic beta cells and/or the decline of the
functionality of pancreatic beta cells and/or for improving and/or
restoring the functionality of pancreatic beta cells and/or
restoring the functionality of pancreatic insulin secretion in a
patient in need thereof characterized in that an SGLT2 inhibitor, a
DPPIV inhibitor and optionally a third antidiabetic agent as
defined hereinbefore and hereinafter are administered, for example
in combination or alternation, to the patient.
[0054] By the administration of a combination or pharmaceutical
composition according to the present invention, an abnormal
accumulation of ectopic fat, in particular of the liver, may be
reduced or inhibited. Therefore, according to another aspect of the
present invention, there is provided a method for preventing,
slowing, delaying or treating diseases or conditions attributed to
an abnormal accumulation of ectopic fat, in particular of the
liver, in a patient in need thereof characterized in that an SGLT2
inhibitor, a DPPIV inhibitor and optionally a third antidiabetic
agent as defined hereinbefore and hereinafter are administered, for
example in combination or alternation, to the patient. Diseases or
conditions which are attributed to an abnormal accumulation of
liver fat are particularly selected from the group consisting of
general fatty liver, non-alcoholic fatty liver (NAFL),
non-alcoholic steatohepatitis (NASH), hyperalimentation-induced
fatty liver, diabetic fatty liver, alcoholic-induced fatty liver or
toxic fatty liver.
[0055] As a result thereof, another aspect of the invention
provides a method for maintaining and/or improving the insulin
sensitivity and/or for treating or preventing hyperinsulinemia
and/or insulin resistance in a patient in need thereof
characterized in that an SGLT2 inhibitor, a DPPIV inhibitor and
optionally a third antidiabetic agent as defined hereinbefore and
hereinafter are administered, for example in combination or
alternation, to the patient.
[0056] According to another aspect of the invention, there is
provided a method for preventing, slowing progression of, delaying,
or treating new onset diabetes after transplantation (NODAT) and/or
post-transplant metabolic syndrome (PTMS) in a patient in need
thereof characterized in that an SGLT2 inhibitor, a DPPIV inhibitor
and optionally a third antidiabetic agent as defined hereinbefore
and hereinafter are administered, for example in combination or
alternation, to the patient.
[0057] According to a further aspect of the invention, there is
provided a method for preventing, delaying, or reducing NODAT
and/or PTMS associated complications including micro- and
macrovascular diseases and events, graft rejection, infection, and
death in a patient in need thereof characterized in that an SGLT2
inhibitor, a DPPIV inhibitor and optionally a third antidiabetic
agent as defined hereinbefore and hereinafter are administered, for
example in combination or alternation, to the patient.
[0058] The pharmaceutical composition according to the invention is
capable of facilitating the lowering of serum total urate levels in
the patient. Therefore according to another aspect of the
invention, there is provided a method for treating hyperuricemia
and hyperuricemia-associated conditions, such as for example gout,
hypertension and renal failure, in a patient in need thereof
characterized in that an SGLT2 inhibitor, a DPPIV inhibitor and
optionally a third antidiabetic agent as defined hereinbefore and
hereinafter are administered, for example in combination or
alternation, to the patient. The patient may be a diabetic or
non-diabetic patient.
[0059] The administration of a pharmaceutical composition increases
the urine excretion of glucose. This increase in osmotic excretion
and water release and the lowering of urate levels are beneficial
as a treatment or prevention for kidney stones. Therefore in a
further aspect of the invention, there is provided a method for
treating or preventing kidney stones in a patient in need thereof
characterized in that an SGLT2 inhibitor, a DPPIV inhibitor and
optionally a third antidiabetic agent as defined hereinbefore and
hereinafter are administered, for example in combination or
alternation, to the patient.
[0060] According to a further aspect of the invention, there is
provided a method for treating hyponatremia, water retention and
water intoxication in a patient in need thereof characterized in
that an SGLT2 inhibitor, a DPPIV inhibitor and optionally a third
antidiabetic agent as defined hereinbefore and hereinafter are
administered, for example in combination or alternation, to the
patient. By the administration of the pharmaceutical composition
according to this invention it may be possible to reverse the
effects of hyponatremia, water retention and water intoxication by
acting on the kidney to reverse water retention and electrolyte
imbalances associated with these diseases and disorders.
[0061] According to another aspect of the invention there is
provided the use of an SGLT2 inhibitor for the manufacture of a
medicament for [0062] preventing, slowing the progression of,
delaying or treating a metabolic disorder selected from the group
consisting of type 1 diabetes mellitus, type 2 diabetes mellitus,
impaired glucose tolerance (IGT), impaired fasting blood glucose
(IFG), hyperglycemia, postprandial hyperglycemia, overweight,
obesity, metabolic syndrome and gestational diabetes; or [0063]
improving glycemic control and/or for reducing of fasting plasma
glucose, of postprandial plasma glucose and/or of glycosylated
hemoglobin HbA1c; or [0064] preventing, slowing, delaying or
reversing progression from impaired glucose tolerance (IGT),
impaired fasting blood glucose (IFG), insulin resistance and/or
from metabolic syndrome to type 2 diabetes mellitus; or [0065]
preventing, slowing the progression of, delaying or treating of a
condition or disorder selected from the group consisting of
complications of diabetes mellitus such as cataracts and micro- and
macrovascular diseases, such as nephropathy, retinopathy,
neuropathy, tissue ischaemia, arteriosclerosis, myocardial
infarction, stroke and peripheral arterial occlusive disease; or
[0066] reducing body weight and/or body fat or preventing an
increase in body weight and/or body fat or facilitating a reduction
in body weight and/or body fat; or [0067] preventing, slowing,
delaying or treating the degeneration of pancreatic beta cells
and/or the decline of the functionality of pancreatic beta cells
and/or for improving and/or restoring the functionality of
pancreatic beta cells and/or restoring the functionality of
pancreatic insulin secretion; or [0068] preventing, slowing,
delaying or treating diseases or conditions attributed to an
abnormal accumulation of ectopic fat; or [0069] maintaining and/or
improving the insulin sensitivity and/or for treating or preventing
hyperinsulinemia and/or insulin resistance; [0070] preventing,
slowing progression of, delaying, or treating new onset diabetes
after transplantation (NODAT) and/or post-transplant metabolic
syndrome (PTMS); [0071] preventing, delaying, or reducing NODAT
and/or PTMS associated complications including micro- and
macrovascular diseases and events, graft rejection, infection, and
death; [0072] treating hyperuricemia and hyperuricemia associated
conditions; [0073] treating or prevention kidney stones; [0074]
treating hyponatremia; in a patient in need thereof characterized
in that the SGLT2 inhibitor is administered, for example in
combination or alternation, with a DPP IV inhibitor and optionally
a third antidiabetic agent as defined hereinbefore and
hereinafter.
[0075] According to another aspect of the invention, there is
provided the use of a DPP IV inhibitor as defined hereinbefore and
hereinafter for the manufacture of a medicament for [0076]
preventing, slowing the progression of, delaying or treating a
metabolic disorder selected from the group consisting of type 1
diabetes mellitus, type 2 diabetes mellitus, impaired glucose
tolerance (IGT), impaired fasting blood glucose (IFG),
hyperglycemia, postprandial hyperglycemia, overweight, obesity and
metabolic syndrome; or [0077] improving glycemic control and/or for
reducing of fasting plasma glucose, of postprandial plasma glucose
and/or of glycosylated hemoglobin HbA1c; or [0078] preventing,
slowing, delaying or reversing progression from impaired glucose
tolerance (IGT), impaired fasting blood glucose (IFG), insulin
resistance and/or from metabolic syndrome to type 2 diabetes
mellitus; or [0079] preventing, slowing the progression of,
delaying or treating of a condition or disorder selected from the
group consisting of complications of diabetes mellitus such as
cataracts and micro- and macrovascular diseases, such as
nephropathy, retinopathy, neuropathy, tissue ischaemia,
arteriosclerosis, myocardial infarction, stroke and peripheral
arterial occlusive disease; or [0080] reducing body weight and/or
body fat or preventing an increase in body weight and/or body fat
or facilitating a reduction in body weight and/or body fat; or
[0081] preventing, slowing, delaying or treating the degeneration
of pancreatic beta cells and/or the decline of the functionality of
pancreatic beta cells and/or for improving and/or restoring the
functionality of pancreatic beta cells and/or restoring the
functionality of pancreatic insulin secretion; or [0082]
preventing, slowing, delaying or treating diseases or conditions
attributed to an abnormal accumulation of liver fat; or [0083]
maintaining and/or improving the insulin sensitivity and/or for
treating or preventing hyperinsulinemia and/or insulin resistance;
in a patient in need thereof characterized in that the DPP IV
inhibitor is administered, for example in combination or
alternation, with an SGLT2 inhibitor and optionally a third
antidiabetic agent as defined hereinbefore and hereinafter.
[0084] According to another aspect of the invention, there is
provided the use of a third antidiabetic agent as defined
hereinbefore and hereinafter for the manufacture of a medicament
for [0085] preventing, slowing the progression of, delaying or
treating a metabolic disorder selected from the group consisting of
type 1 diabetes mellitus, type 2 diabetes mellitus, impaired
glucose tolerance (IGT), impaired fasting blood glucose (IFG),
hyperglycemia, postprandial hyperglycemia, overweight, obesity and
metabolic syndrome; or [0086] improving glycemic control and/or for
reducing of fasting plasma glucose, of postprandial plasma glucose
and/or of glycosylated hemoglobin HbA1c; or [0087] preventing,
slowing, delaying or reversing progression from impaired glucose
tolerance (IGT), impaired fasting blood glucose (IFG), insulin
resistance and/or from metabolic syndrome to type 2 diabetes
mellitus; or [0088] preventing, slowing the progression of,
delaying or treating of a condition or disorder selected from the
group consisting of complications of diabetes mellitus such as
cataracts and micro- and macrovascular diseases, such as
nephropathy, retinopathy, neuropathy, tissue ischaemia,
arteriosclerosis, myocardial infarction, stroke and peripheral
arterial occlusive disease; or [0089] reducing body weight and/or
body fat or preventing an increase in body weight and/or body fat
or facilitating a reduction in body weight and/or body fat; or
[0090] preventing, slowing, delaying or treating the degeneration
of pancreatic beta cells and/or the decline of the functionality of
pancreatic beta cells and/or for improving and/or restoring the
functionality of pancreatic beta cells and/or restoring the
functionality of pancreatic insulin secretion; or [0091]
preventing, slowing, delaying or treating diseases or conditions
attributed to an abnormal accumulation of liver fat; or [0092]
maintaining and/or improving the insulin sensitivity and/or for
treating or preventing hyperinsulinemia and/or insulin resistance;
in a patient in need thereof characterized in that the third
antidiabetic agent is administered, for example in combination or
alternation, with an SGLT2 inhibitor and a DPPIV inhibitor as
defined hereinbefore and hereinafter.
[0093] According to another aspect of the invention, there is
provided the use of a pharmaceutical composition according to the
present invention for the manufacture of a medicament for a
therapeutic and preventive method as described hereinbefore and
hereinafter.
DEFINITIONS
[0094] The term "active ingredient" of a pharmaceutical composition
according to the present invention means the SGLT2 inhibitor and/or
the DPP IV inhibitor according to the present invention.
[0095] The term "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.sup.2.
[0096] The term "overweight" is defined as the condition wherein
the individual has a BMI greater than or 25 kg/m.sup.2 and less
than 30 kg/m.sup.2. The terms "overweight" and "pre-obese" are used
interchangeably.
[0097] The term "obesity" is defined as the condition wherein the
individual has a BMI equal to or greater than 30 kg/m.sup.2.
According to a WHO definition 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.sup.2 but lower than 35
kg/m.sup.2; the term "class II obesity" is the condition wherein
the BMI is equal to or greater than 35 kg/m.sup.2 but lower than 40
kg/m.sup.2; the term "class III obesity" is the condition wherein
the BMI is equal to or greater than 40 kg/m.sup.2.
[0098] The term "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.
[0099] The term "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.gtoreq.85 cm in men and .gtoreq.90
cm in women (see e.g. investigating committee for the diagnosis of
metabolic syndrome in Japan).
[0100] The term "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). The word "fasting" has the usual meaning as a medical
term.
[0101] The term "hyperglycemia" 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). The word
"fasting" has the usual meaning as a medical term.
[0102] The 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).
[0103] The term "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).
[0104] The term "impaired fasting blood glucose" or "IFG" is
defined as the condition in which a subject has a fasting blood
glucose concentration or fasting serum glucose concentration in a
range from 100 to 125 mg/dl (i.e. from 5.6 to 6.9 mmol/l), in
particular greater than 110 mg/dL and less than 126 mg/dl (7.00
mmol/L). A subject with "normal fasting glucose" has a fasting
glucose concentration smaller than 100 mg/dl, i.e. smaller than 5.6
mmol/l.
[0105] The term "impaired glucose tolerance" or "IGT" is defined as
the condition in which a subject has a 2 hour postprandial blood
glucose or serum glucose concentration greater than 140 mg/dl (7.78
mmol/L) and less than 200 mg/dL (11.11 mmol/L). 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).
[0106] The term "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).
[0107] The terms "insulin-sensitizing", "insulin
resistance-improving" or "insulin resistance-lowering" are
synonymous and used interchangeably.
[0108] The term "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
ES, 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). Rather less laborious than the clamp test are so
called minimal models in which, during an intravenous glucose
tolerance test, the insulin and glucose concentrations in the blood
are measured at fixed time intervals and from these the insulin
resistance is calculated. With this method, it is not possible to
distinguish between hepatic and peripheral insulin resistance.
[0109] Furthermore, 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. In addition, plasma
adiponectin levels can be monitored as a potential surrogate of
insulin sensitivity. The estimate of insulin resistance by the
homeostasis assessment model (HOMA)-IR score is calculated with the
formula (Galvin P, et al. Diabet Med 1992; 9:921-8):
HOMA-IR=[fasting serum insulin(.mu.U/mL)].times.[fasting plasma
glucose(mmol/L)/22.5]
[0110] As a rule, other parameters are used in everyday clinical
practice to assess insulin resistance. Preferably, the patient's
triglyceride concentration is used, for example, as increased
triglyceride levels correlate significantly with the presence of
insulin resistance.
[0111] 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.
[0112] The methods to investigate the function of pancreatic
beta-cells are similar to the above methods with regard to insulin
sensitivity, hyperinsulinemia or insulin resistance: An improvement
of 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).
[0113] The term "pre-diabetes" is the condition wherein an
individual is pre-disposed to the development of type 2 diabetes.
Pre-diabetes extends the definition of impaired glucose tolerance
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) and fasting hyperinsulinemia (elevated plasma insulin
concentration). 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).
[0114] 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.sup.st degree relative with a diagnosis of IGT or IFG or type 2
diabetes. Insulin resistance can be confirmed in these individuals
by calculating the HOMA-IR score. For the purpose of this
invention, 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.
[0115] The term "type 2 diabetes" 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. In a healthy subject, 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.
[0116] The term "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).
[0117] The term "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. For example, 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.
[0118] The term "insufficient glycemic control" or "inadequate
glycemic control" in the scope of the present invention means a
condition wherein patients show HbA1c values above 6.5%, in
particular above 7.0%, even more preferably above 7.5%, especially
above 8%.
[0119] 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). According to the ATP III/NCEP
guidelines (Executive Summary of the Third Report of the National
Cholesterol Education Program (NCEP) Expert Panel on Detection,
Evaluation, and Treatment of High Blood Cholesterol in Adults
(Adult Treatment Panel III) JAMA: Journal of the American Medical
Association (2001) 285:2486-2497), diagnosis of the metabolic
syndrome is made when three or more of the following risk factors
are present: [0120] 1. Abdominal obesity, defined as waist
circumference>40 inches or 102 cm in men, and >35 inches or
94 cm in women; or with regard to a Japanese ethnicity or Japanese
patients defined as waist circumference.gtoreq.85 cm in men and
.gtoreq.90 cm in women; [0121] 2. Triglycerides: .gtoreq.150 mg/dL
[0122] 3. HDL-cholesterol<40 mg/dL in men [0123] 4. Blood
pressure.gtoreq.130/85 mm Hg (SBP.gtoreq.130 or DBP.gtoreq.85)
[0124] 5. Fasting blood glucose.gtoreq.100 mg/dL
[0125] The NCEP definitions have been validated (Laaksonen D E, et
al. Am J Epidemiol. (2002) 156:1070-7). 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.
[0126] According to a commonly used definition, 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.
[0127] The definitions of NODAT (new onset diabetes after
transplantation) and PTMS (post-transplant metabolic syndrome)
follow closely that of the American Diabetes Association diagnostic
criteria for type 2 diabetes, and that of the International
Diabetes Federation (IDF) and the American Heart
Association/National Heart, Lung, and Blood Institute, for the
metabolic syndrome. NODAT and/or PTMS are associated with an
increased risk of micro- and macrovascular disease and events,
graft rejection, infection, and death. A number of predictors have
been identified as potential risk factors related to NODAT and/or
PTMS including a higher age at transplant, male gender, the
pre-transplant body mass index, pre-transplant diabetes, and
immunosuppression.
[0128] The term "gestational diabetes" (diabetes of pregnancy)
denotes a form of the diabetes which develops during pregnancy and
usually ceases again immediately after the birth. Gestational
diabetes is diagnosed by a screening test which is carried out
between the 24th and 28th weeks of pregnancy. It is usually a
simple test in which the blood sugar level is measured one hour
after the administration of 50 g of glucose solution. If this 1 h
level is above 140 mg/dl, gestational diabetes is suspected. Final
confirmation may be obtained by a standard glucose tolerance test,
for example with 75 g of glucose.
[0129] The term "hyperuricemia" denotes a condition of high serum
total urate levels. In human blood, uric acid concentrations
between 3.6 mg/dL (ca. 214 .mu.mol/L) and 8.3 mg/dL (ca. 494
.mu.mol/L) are considered normal by the American Medical
Association. High serum total urate levels, or hyperuricemia, are
often associated with several maladies. For example, high serum
total urate levels can lead to a type of arthritis in the joints
known as gout. Gout is a condition created by a build up of
monosodium urate or uric acid crystals on the articular cartilage
of joints, tendons and surrounding tissues due to elevated
concentrations of total urate levels in the blood stream. The build
up of urate or uric acid on these tissues provokes an inflammatory
reaction of these tissues. Saturation levels of uric acid in urine
may result in kidney stone formation when the uric acid or urate
crystallizes in the kidney. Additionally, high serum total urate
levels are often associated with the so-called metabolic syndrome,
including cardiovascular disease and hypertension.
[0130] The term "hyponatremia" denotes a condition of a positive
balance of water with or without a deficit of sodium, which is
recognized when the plasma sodium falls below the level of 135
mml/L. Hyponatremia is a condition which can occur in isolation in
individuals that over-consume water; however, more often
hyponatremia is a complication of medication or other underlying
medical condition that leas to a diminished excretion of water.
Hyponatremia may lead to water intoxication, which occurs when the
normal tonicity of extracellular fluid falls below the safe limit,
due to retention of excess water. Water intoxication is a
potentially fatal disturbance in brain function. Typical symptoms
of water intoxication include nausea, vomiting, headache and
malaise.
[0131] The term "SGLT2 inhibitor" in the scope of the present
invention relates to a compound, in particular to a
glucopyranosyl-derivative, i.e. compound having a
glucopyranosyl-moiety, which shows an inhibitory effect on the
sodium-glucose transporter 2 (SGLT2), in particular the human
SGLT2. The inhibitory effect on hSGLT2 measured as IC50 is prerably
below 1000 nM, even more preferably below 100 nM, most preferably
below 50 nM. IC50 values of SGLT2 inhibitors are usually above 0.01
nM, or even equal to or above 0.1 nM. The inhibitory effect on
hSGLT2 can be determined by methods known in the literature, in
particular as described in the application WO 2005/092877 or WO
2007/093610 (pages 23/24), which are incorporated herein by
reference in its entirety. The term "SGLT2 inhibitor" also
comprises any pharmaceutically acceptable salts thereof, hydrates
and solvates thereof, including the respective crystalline
forms.
[0132] The term "DPPIV inhibitor" in the scope of the present
invention relates to a compound that exhibits inhibitory activity
on the enzyme dipeptidyl peptidase IV. Such inhibitory activity can
be characterised by the IC50 value. A DPPIV inhibitor preferably
exhibits an IC50 value below 10000 nM, preferably below 1000 nM.
Certain DPPIV inhibitors exhibit an IC50 value below 100 nM, or
even .ltoreq.50 nM. IC50 values of DPPIV inhibitors are usually
above 0.01 nM, or even above 0.1 nM. DPPIV inhibitors may include
biologic and non-biologic, in particular non-peptidic compounds.
The inhibitory effect on DPPIV can be determined by methods known
in the literature, in particular as described in the application WO
02/068420 or WO 2004/018468 (page 34), which are incorporated
herein by reference in its entirety. The term "DPPIV inhibitor"
also comprises any pharmaceutically acceptable salts thereof,
hydrates and solvates thereof, including the respective crystalline
forms.
[0133] The terms "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. Thus the 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.
[0134] The terms "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.
BRIEF DESCRIPTION OF THE FIGURES
[0135] The FIG. 1 shows the glucose excursion as glucose AUC in
Zucker rats to which an SGLT2 inhibitor (A), a DPPIV inhibitor (B),
metformin (Met) and combinations thereof (A+Met, B+Met, A+B,
A+B+Met) were administered.
DETAILED DESCRIPTION
[0136] The aspects according to the present invention, in
particular the pharmaceutical compositions, methods and uses, refer
to SGLT2 inhibitors, DPPIV inhibitors and third antidiabetic agents
as defined hereinbefore and hereinafter. In the methods and uses
according to this invention a third antidiabetic agent is
optionally administered, i.e. the SGLT2 inhibitor and the DPPIV
inhibitor are administered in combination with a third antidiabetic
agent or without a third antidiabetic agent. Preferably in the
methods and uses according to this invention the SGLT2 inhibitor
and the DPPIV inhibitor are administered in combination with a
third antidiabetic agent.
[0137] Preferably the SGLT2 inhibitor is selected from the group G1
consisting of dapagliflozin, canagliflozin, atigliflozin,
remogliflozin, sergliflozin and glucopyranosyl-substituted benzene
derivatives of the formula (I)
##STR00001##
wherein R.sup.1 denotes CI, methyl or cyano; R.sup.2 denotes H,
methyl, methoxy or hydroxy and R.sup.3 denotes ethyl, cyclopropyl,
ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or
(S)-tetrahydrofuran-3-yloxy; or a prodrug of one of the
beforementioned SGLT2 inhibitors.
[0138] Compounds of the formula (I) and methods of their synthesis
are described for example in the following patent applications: WO
2005/092877, WO 2006/117360, WO 2006/117359, WO 2006/120208, WO
2006/064033, WO 2007/031548, WO 2007/093610, WO 2008/020011, WO
2008/055870.
[0139] In the above glucopyranosyl-substituted benzene derivatives
of the formula (I) the following definitions of the substituents
are preferred.
[0140] Preferably R.sup.1 denotes chloro or cyano; in particular
chloro.
[0141] Preferably R.sup.2 denotes H.
[0142] Preferably R.sup.3 denotes ethyl, cyclopropyl, ethynyl,
(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. Even
more preferably R.sup.3 denotes cyclopropyl, ethynyl,
(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. Most
preferably R.sup.3 denotes ethynyl, (R)-tetrahydrofuran-3-yloxy or
(S)-tetrahydrofuran-3-yloxy.
[0143] Preferred glucopyranosyl-substituted benzene derivatives of
the formula (I) are selected from the group of compounds (I.1) to
(I.11):
TABLE-US-00001 (I.1) ##STR00002## (I.2) ##STR00003## (I.3)
##STR00004## (I.4) ##STR00005## (I.5) ##STR00006## (I.6)
##STR00007## (I.7) ##STR00008## (I.8) ##STR00009## (I.9)
##STR00010## (I.10) ##STR00011## (I.11) ##STR00012##
[0144] Even more preferred glucopyranosyl-substituted benzene
derivatives of the formula (I) are selected from the compounds
(I.6), (I.7), (I.8), (I.9) and (I.11).
[0145] Therefore the group G1 preferably consists of dapagliflozin,
remogliflozin, the compound (I.6), the compound (I.7), the compound
(I.8), the compound (I.9) and the compound (I.11).
[0146] Even more preferably the group G1 consists of dapagliflozin
and the compound (I.9).
[0147] According to this invention, it is to be understood that the
definitions of the above listed glucopyranosyl-substituted benzene
derivatives of the formula (I) also comprise their hydrates,
solvates and polymorphic forms thereof, and prodrugs thereof. With
regard to the preferred compound (I.7) an advantageous crystalline
form is described in the international patent application WO
2007/028814 which hereby is incorporated herein in its entirety.
With regard to the preferred compound (I.8), an advantageous
crystalline form is described in the international patent
application WO 2006/117360 which hereby is incorporated herein in
its entirety. With regard to the preferred compound (I.9) an
advantageous crystalline form is described in the international
patent application WO 2006/117359 which hereby is incorporated
herein in its entirety. With regard to the preferred compound
(I.11) an advantageous crystalline form is described in the
international patent application WO 2008/049923 which hereby is
incorporated herein in its entirety. These crystalline forms
possess good solubility properties which enable a good
bioavailability of the SGLT2 inhibitor. Furthermore, the
crystalline forms are physico-chemically stable and thus provide a
good shelf-life stability of the pharmaceutical composition.
[0148] The term "dapagliflozin" as employed herein refers to
dapagliflozin, including hydrates and solvates thereof, and
crystalline forms thereof. The compound and methods of its
synthesis are described in WO 03/099836 for example. Preferred
hydrates, solvates and crystalline forms are described in the
patent applications WO 2008/116179 and WO 2008/002824 for
example.
[0149] The term "canagliflozin" as employed herein refers to
canagliflozin, including hydrates and solvates thereof, and
crystalline forms thereof and has the following structure:
##STR00013##
[0150] The compound and methods of its synthesis are described in
WO 2005/012326 and WO 2009/035969 for example. Preferred hydrates,
solvates and crystalline forms are described in the patent
applications WO 2008/069327 for example.
[0151] The term "atigliflozin" as employed herein refers to
atigliflozin, including hydrates and solvates thereof, and
crystalline forms thereof. The compound and methods of its
synthesis are described in WO 2004/007517 for example.
[0152] The term "remogliflozin" as employed herein refers to
remogliflozin and prodrugs of remogliflozin, in particular
remogliflozin etabonate, including hydrates and solvates thereof,
and crystalline forms thereof. Methods of its synthesis are
described in the patent applications EP 1213296 and EP 1354888 for
example.
[0153] The term "sergliflozin" as employed herein refers to
sergliflozin and prodrugs of sergliflozin, in particular
sergliflozin etabonate, including hydrates and solvates thereof,
and crystalline forms thereof. Methods for its manufacture are
described in the patent applications EP 1344780 and EP 1489089 for
example.
[0154] For avoidance of any doubt, the disclosure of each of the
foregoing documents cited above in connection with the specified
SGLT2 inhibitors is specifically incorporated herein by reference
in its entirety.
[0155] The aspects according to the present invention, in
particular the pharmaceutical compositions, methods and uses, refer
to a DPP IV inhibitor as defined hereinbefore and hereinafter, or
prodrugs thereof, or pharmaceutically acceptable salts thereof.
[0156] Preferably the DPPIV inhibitor is selected from the group G2
consisting of linagliptin, sitagliptin, vildagliptin, alogliptin,
saxagliptin, denagliptin, carmegliptin, melogliptin and
dutogliptin, or a pharmaceutically acceptable salt of one of the
beforementioned DPPIV inhibitors, or a prodrug thereof.
[0157] The term "linagliptin" as employed herein refers to
linagliptin and pharmaceutically acceptable salts thereof,
including hydrates and solvates thereof, and crystalline forms
thereof. Crystalline forms are described in WO 2007/128721. Methods
for the manufacture of linagliptin are described in the patent
applications WO 2004/018468 and WO 2006/048427 for example.
Linagliptin is distinguished from structurally comparable DPP IV
inhibitors, as it combines exceptional potency and a long-lasting
effect with favourable pharmacological properties, receptor
selectivity and a favourable side-effect profile or bring about
unexpected therapeutic advantages or improvements when used in
combination with an SGLT2 inhibitor and a third antidiabetic agent
according to this invention.
[0158] The term "sitagliptin" as employed herein refers to
sitagliptin (or MK-0431) and pharmaceutically acceptable salts
thereof, including hydrates and solvates thereof, and crystalline
forms thereof. In one embodiment, sitagliptin is in the form of its
dihydrogenphosphate salt, i.e. sitagliptin phosphate. In a further
embodiment, sitagliptin phosphate is in the form of a crystalline
anhydrate or monohydrate. A class of this embodiment refers to
sitagliptin phosphate monohydrate. Sitagliptin free base and
pharmaceutically acceptable salts thereof are disclosed in U.S.
Pat. No. 6,699,871 and in Example 7 of WO 03/004498. Crystalline
sitagliptin phosphate monohydrate is disclosed in WO 2005/003135
and in WO 2007/050485. For details, e.g. on a process to
manufacture or to formulate this compound or a salt thereof,
reference is thus made to these documents. A tablet formulation for
sitagliptin is commercially available under the trade name
Januvia.RTM..
[0159] The term "vildagliptin" as employed herein refers to
vildagliptin (or LAF-237) and pharmaceutically acceptable salts
thereof, including hydrates and solvates thereof, and crystalline
forms thereof. Specific salts of vildagliptin are disclosed in WO
2007/019255. A crystalline form of vildagliptin as well as a
vildagliptin tablet formulation are disclosed in WO 2006/078593.
Vildagliptin can be formulated as described in WO 00/34241 or in WO
2005/067976. A modified release vildagliptin formulation is
described in WO 2006/135723. For details, e.g. on a process to
manufacture or to formulate this compound or a salt thereof,
reference is thus made to these documents and U.S. Pat. No.
6,166,063. A tablet formulation for vildagliptin is expected to be
commercially available under the trade name Galvus.RTM..
[0160] The term "saxagliptin" as employed herein refers to
saxagliptin (or BMS-477118) and pharmaceutically acceptable salts
thereof, including hydrates and solvates thereof, and crystalline
forms thereof. In one embodiment, saxagliptin is in the form of the
free base or a HCl salt (for example as mono- or dihydrochloride,
including hydrates thereof), or a mono-benzoate salt as disclosed
in WO 2004/052850 and WO 2008/131149. In a further embodiment,
saxagliptin is in the form of the free base. In a yet further
embodiment, saxagliptin is in the form of the monohydrate of the
free base as disclosed in WO 2004/052850. A process for preparing
saxagliptin is also disclosed in WO 2005/106011 and WO 2005/115982.
Saxagliptin can be formulated in a tablet as described in WO
2005/117841. For details, e.g. on a process to manufacture, to
formulate or to use this compound or a salt thereof, reference is
thus made to these documents and U.S. Pat. No. 6,395,767 and WO
01/68603.
[0161] The term "denagliptin" as employed herein refers to
denagliptin (or GSK-823093) and pharmaceutically acceptable salts
thereof, including hydrates and solvates thereof, and crystalline
forms thereof. In one embodiment, denagliptin is in the form of its
hydrochloride salt as disclosed in Example 2 of WO 03/002531 or its
tosylate salt as disclosed in WO 2005/009956. A class of this
embodiment refers to denagliptin tosylate. Crystalline anhydrous
denagliptin tosylate is disclosed in WO 2005/009956. For details on
a process to manufacture this compound or a salt thereof, reference
is thus made to these documents and to the U.S. Pat. No.
7,132,443.
[0162] The term "alogliptin" as employed herein refers to
alogliptin (or SYR-322) and pharmaceutically acceptable salts
thereof, including hydrates and solvates thereof, and crystalline
forms thereof. In one embodiment, alogliptin is in the form of its
benzoate salt, its hydrochloride salt or its tosylate salt each as
disclosed in WO 2007/035629. A class of this embodiment refers to
alogliptin benzoate. Polymorphs of alogliptin benzoate are
disclosed in WO 2007/035372. A process for preparing alogliptin is
disclosed in WO 2007/112368 and, specifically, in WO 2007/035629.
Alogliptin (namely its benzoate salt) can be formulated in a tablet
and administered as described in WO 2007/033266. For details, e.g.
on a process to manufacture, to formulate or to use this compound
or a salt thereof, reference is thus made to these documents and to
US 2005/261271, EP 1586571 and WO 2005/095381.
[0163] The term "carmegliptin" as employed herein refers to
carmegliptin and pharmaceutically acceptable salts thereof,
including hydrates and solvates thereof, and crystalline forms
thereof. A process for preparing this compound (specifically its
dihydrochloride salt) is also disclosed in WO 2008/031749, WO
2008/031750 and WO 2008/055814. This compound can be formulated in
a pharmaceutical composition as described in WO 2007/017423. For
details, e.g. on a process to manufacture, to formulate or to use
this compound or a salt thereof, reference is thus made to these
documents and to WO 2005/000848.
[0164] The term "melogliptin" as employed herein refers to
melogliptin and pharmaceutically acceptable salts thereof,
including hydrates and solvates thereof, and crystalline forms
thereof. Methods for its preparation are inter alia disclosed in WO
2006/040625 and WO 2008/001195. Specifically claimed salts include
the methanesulfonate and p-toluenesulfonate. For details, e.g. on a
process to manufacture, to formulate or to use this compound or a
salt thereof, reference is thus made to these documents.
[0165] The term "dutogliptin" as employed herein refers to
dutogliptin (or PHX-1149, PHX-1149T) and pharmaceutically
acceptable salts thereof, including hydrates and solvates thereof,
and crystalline forms thereof. Methods for its preparation are
inter alia disclosed in WO 2005/047297. Pharmaceutically acceptable
salts include the tartrate. For details, e.g. on a process to
manufacture, to formulate or to use this compound or a salt
thereof, reference is thus made to these documents.
[0166] For avoidance of any doubt, the disclosure of each of the
foregoing documents cited above in connection with the specified
DPP IV inhibitors is specifically incorporated herein by reference
in its entirety.
[0167] The third antidiabetic agent is selected from the group G3
consisting of biguanides, thiazolidindiones, sulfonylureas,
glinides, inhibitors of alpha-glucosidase, GLP-1 analogues or a
pharmaceutically acceptable salt thereof. In the following
preferred embodiments regarding the third antidiabetic agent are
described.
[0168] The group G3 comprises biguanides. Examples of biguanides
are metformin, phenformin and buformin. A preferred biguanide is
metformin. An SGLT2 inhibitor and a DPPIV inhibitor in combination
with a biguanide, in particular metformin, can provide more
efficacious glycemic control and may act synergistically with the
biguanide, for example to reduce weight that has overall beneficial
effects on the metabolic syndrome which is commonly associated with
type 2 diabetes mellitus.
[0169] The term "metformin" as employed herein refers to metformin
or a pharmaceutically acceptable salt thereof such as the
hydrochloride salt, the metformin (2:1) fumarate salt, and the
metformin (2:1) succinate salt, the hydrobromide salt, the
p-chlorophenoxy acetate or the embonate, and other known metformin
salts of mono and dibasic carboxylic acids. It is preferred that
the metformin employed herein is the metformin hydrochloride
salt.
[0170] The group G3 comprises thiazolidindiones. Examples of
thiazolidindiones (TZD) are pioglitazone and rosiglitazone. TZD
therapy is associated with massive weight gain and fat
redistribution. In addition, TZD cause fluid retention and are not
indicated in patients with congestive heart failure. Long term
treatment with TZD are further associated with an increased risk of
bone fractures. The advantageous properties, like the weight
reducing capability, of a SGLT2 inhibitor and a DPPIV inhibitor can
minimize side effects of the treatment with TZD.
[0171] The term "pioglitazone" as employed herein refers to
pioglitazone, including its enantiomers, mixtures thereof and its
racemate, or a pharmaceutically acceptable salt thereof such as the
hydrochloride salt.
[0172] The term "rosiglitazone" as employed herein refers to
rosiglitazone, including its enantiomers, mixtures thereof and its
racemate, or a pharmaceutically acceptable salt thereof such as the
maleate salt.
[0173] The group G3 comprises sulfonylureas. Examples of
sulfonylureas are glibenclamide, tolbutamide, glimepiride,
glipizide, gliquidone, glibornuride, glyburide, glisoxepide and
gliclazide. Preferred sulfonylureas are tolbutamide, gliquidone,
glibenclamide and glimepiride, in particular glibenclamide and
glimepiride. As the efficacy of sulfonylureas wears off over the
course of treatment, a combination of an SGLT2 inhibitor and a
DPPIV inhibitor with a sulfonylurea may offer additional benefit to
the patient in terms of better glycemic control. Also, treatment
with sulfonylureas is normally associated with gradual weight gain
over the course of treatment and weight reducing capability of a
SGLT2 inhibitor and a DPPIV inhibitor can minimize this side effect
of the treatment with an sulfonylurea and improve the metabolic
syndrome. This combination may also allow a reduction in the dose
of sulfonylureas which may translate into less hypoglycemia which
is an undesirable side effect of sulfonylureas.
[0174] Each term of the group "glibenclamide", "glimepiride",
"gliquidone", "glibornuride", "gliclazide", "glisoxepide",
"tolbutamide" and "glipizide" as employed herein refers to the
respective active drug or a pharmaceutically acceptable salt
thereof.
[0175] The group G3 comprises glinides. Examples of glinides are
nateglinide, repaglinide and mitiglinide. As their efficacy wears
off over the course of treatment, a combination of a SGLT2
inhibitor with a meglitinide may offer additional benefit to the
patient in terms of better glycemic control. Also, treatment with
meglitinides is normally associated with gradual weight gain over
the course of treatment and weight reducing capability of a SGLT2
inhibitor can minimize this side effect of the treatment with an
meglitinide and improve the metabolic syndrome. This combination
may also allow a reduction in the dose of meglitinides which may
translate into less hypoglycemia which is an undesirable side
effect of meglitinides.
[0176] The term "nateglinide" as employed herein refers to
nateglinide, including its enantiomers, mixtures thereof and its
racemate, or a pharmaceutically acceptable salts and esters
thereof.
[0177] The term "repaglinide" as employed herein refers to
repaglinide, including its enantiomers, mixtures thereof and its
racemate, or a pharmaceutically acceptable salts and esters
thereof.
[0178] The group G3 comprises inhibitors of alpha-glucosidase.
Examples of inhibitors of alpha-glucosidase are acarbose, voglibose
and miglitol. Additional benefits from the combination of an SGLT2
inhibitor, a DPPIV inhibitor and an alpha-glucosidase inhibitor may
relate to more efficacious glycemic control at lower doses of the
individual drugs, which in particular would reduce undesirable
gastrointestinal side effects of alpha-glucosidase inhibitors. An
additional benefit would be that the combination may result in
higher systemic levels of systemic GLP-1 than the respective
monotherapies with expected long-term benefits on pancreatic alpha-
and beta-cells. Furthermore, combining both inhibition of glucose
uptake in the intestine and increasing urinary excretion of blood
glucose may lower blood glucose, in particular a post-prandial
glucose peak, much more efficiently than the respective
monotherapies. Inhibitors of alpha-glucosidase are not absorbed or
have exceedingly low systemic absorption and thus are expected not
to interfere with the clearance of the DPPIV and the SGLT2
inhibitor.
[0179] Each term of the group "acarbose", "voglibose" and
"miglitol" as employed herein refers to the respective active drug
or a pharmaceutically acceptable salt thereof.
[0180] The group G3 comprises inhibitors of GLP-1 analogues.
Examples of GLP-1 analogues are exenatide and liraglutide. The
combination of an SGLT2 inhibitor, a DPPIV inhibitor and a GLP-1
analogue may achieve a superior glycemic control at lower doses of
the individual drugs. In addition, the body weight reducing
capability of the GLP-1 analogue is expected to be further enhanced
by the potential for body weight control of the DPPIV inhibitor and
the SGLT2 inhibitor. On the other hand, a reduction of side effects
(e.g. nausea, vomiting) may be obtained, when a reduced dose of the
GLP-1 analogue is applied in the combination with a DPP IV and a
SGLT2 inhibitor.
[0181] Each term of the group "exenatide" and "liraglutide" as
employed herein refers to the respective active drug or a
pharmaceutically acceptable salt thereof.
[0182] In a first embodiment E1 the pharmaceutical compositions,
methods and uses according to this invention preferably relate to
combinations wherein the SGLT2 inhibitor is selected from
glucopyranosyl-substituted benzene derivatives of the formula
(I)
##STR00014##
wherein R.sup.1, R.sup.2 and R.sup.3 are defined as hereinbefore.
Even more preferably the SGLT2 inhibitor is selected from group of
compounds (I.1) to (I.11) as defined hereinbefore. Most preferably
according to the first embodiment the SGLT2 inhibitor is the
compound (I.9). According to the first embodiment the DPPIV
inhibitor and the third antidiabetic agent are preferably selected
according to the entries in the Table 1.
TABLE-US-00002 TABLE 1 Embodiment DPPIV Inhibitor Third
Antidiabetic Agent E1.1 selected from the group G2 selected from
the group G3 E1.2 selected from the group G2 Metformin E1.3
selected from the group G2 Pioglitazone E1.4 selected from the
group G2 Rosiglitazone E1.5 selected from the group G2
Glibenclamide E1.6 selected from the group G2 Glimepiride E1.7
selected from the group G2 Gliquidone E1.8 selected from the group
G2 Nateglinide E1.9 selected from the group G2 Repaglinide E1.10
Linagliptin selected from the group G3 E1.11 Linagliptin Metformin
E1.12 Linagliptin Pioglitazone E1.13 Linagliptin Rosiglitazone
E1.14 Linagliptin Glibenclamide E1.15 Linagliptin Glimepiride E1.16
Linagliptin Gliquidone E1.17 Linagliptin Nateglinide E1.18
Linagliptin Repaglinide E1.19 Sitagliptin selected from the group
G3 E1.20 Sitagliptin Metformin E1.21 Sitagliptin Pioglitazone E1.22
Sitagliptin Rosiglitazone E1.23 Sitagliptin Glibenclamide E1.24
Sitagliptin Glimepiride E1.25 Sitagliptin Gliquidone E1.26
Sitagliptin Nateglinide E1.27 Sitagliptin Repaglinide E1.28
Vildagliptin selected from the group G3 E1.29 Vildagliptin
Metformin E1.30 Vildagliptin Pioglitazone E1.31 Vildagliptin
Rosiglitazone E1.32 Vildagliptin Glibenclamide E1.33 Vildagliptin
Glimepiride E1.34 Vildagliptin Gliquidone E1.35 Vildagliptin
Nateglinide E1.36 Vildagliptin Repaglinide E1.37 Alogliptin
selected from the group G3 E1.38 Alogliptin Metformin E1.39
Alogliptin Pioglitazone E1.40 Alogliptin Rosiglitazone E1.41
Alogliptin Glibenclamide E1.42 Alogliptin Glimepiride E1.43
Alogliptin Gliquidone E1.44 Alogliptin Nateglinide E1.45 Alogliptin
Repaglinide E1.46 Saxagliptin selected from the group G3 E1.47
Saxagliptin Metformin E1.48 Saxagliptin Pioglitazone E1.49
Saxagliptin Rosiglitazone E1.50 Saxagliptin Glibenclamide E1.51
Saxagliptin Glimepiride E1.52 Saxagliptin Gliquidone E1.53
Saxagliptin Nateglinide E1.54 Saxagliptin Repaglinide E1.55
Carmegliptin selected from the group G3 E1.56 Carmegliptin
Metformin E1.57 Carmegliptin Pioglitazone E1.58 Carmegliptin
Rosiglitazone E1.59 Carmegliptin Glibenclamide E1.60 Carmegliptin
Glimepiride E1.61 Carmegliptin Gliquidone E1.62 Carmegliptin
Nateglinide E1.63 Carmegliptin Repaglinide E1.64 Melogliptin
selected from the group G3 E1.65 Melogliptin Metformin E1.66
Melogliptin Pioglitazone E1.67 Melogliptin Rosiglitazone E1.68
Melogliptin Glibenclamide E1.69 Melogliptin Glimepiride E1.70
Melogliptin Gliquidone E1.71 Melogliptin Nateglinide E1.72
Melogliptin Repaglinide E1.73 Dutogliptin selected from the group
G3 E1.74 Dutogliptin Metformin E1.75 Dutogliptin Pioglitazone E1.76
Dutogliptin Rosiglitazone E1.77 Dutogliptin Glibenclamide E1.78
Dutogliptin Glimepiride E1.79 Dutogliptin Gliquidone E1.80
Dutogliptin Nateglinide E1.81 Dutogliptin Repaglinide
[0183] In a second embodiment E2 the pharmaceutical compositions,
methods and uses according to this invention preferably relate to
combinations wherein the DPPIV inhibitor is linagliptin. According
to the second embodiment the SGLT2 inhibitor and the third
antidiabetic agent are preferably selected according to the entries
in the Table 2.
TABLE-US-00003 TABLE 2 Embodiment SGLT2 Inhibitor Third
Antidiabetic Agent E2.1 selected from the group G1 selected from
the group G3 E2.2 selected from the group G1 Metformin E2.3
selected from the group G1 Pioglitazone E2.4 selected from the
group G1 Rosiglitazone E2.5 selected from the group G1
Glibenclamide E2.6 selected from the group G1 Glimepiride E2.7
selected from the group G1 Gliquidone E2.8 selected from the group
G1 Nateglinide E2.9 selected from the group G1 Repaglinide E2.10
Compound (I.9) selected from the group G3 E2.11 Compound (I.9)
Metformin E2.12 Compound (I.9) Pioglitazone E2.13 Compound (I.9)
Rosiglitazone E2.14 Compound (I.9) Glibenclamide E2.15 Compound
(I.9) Glimepiride E2.16 Compound (I.9) Gliquidone E2.17 Compound
(I.9) Nateglinide E2.18 Compound (I.9) Repaglinide E2.19
Dapagliflozin selected from the group G3 E2.20 Dapagliflozin
Metformin E2.21 Dapagliflozin Pioglitazone E2.22 Dapagliflozin
Rosiglitazone E2.23 Dapagliflozin Glibenclamide E2.24 Dapagliflozin
Glimepiride E2.25 Dapagliflozin Gliquidone E2.26 Dapagliflozin
Nateglinide E2.27 Dapagliflozin Repaglinide E2.28 Canagliflozin
selected from the group G3 E2.29 Canagliflozin Metformin E2.30
Canagliflozin Pioglitazone E2.31 Canagliflozin Rosiglitazone E2.32
Canagliflozin Glibenclamide E2.33 Canagliflozin Glimepiride E2.34
Canagliflozin Gliquidone E2.35 Canagliflozin Nateglinide E2.36
Canagliflozin Repaglinide E2.37 Atigliflozin selected from the
group G3 E2.38 Atigliflozin Metformin E2.39 Atigliflozin
Pioglitazone E2.40 Atigliflozin Rosiglitazone E2.41 Atigliflozin
Glibenclamide E2.42 Atigliflozin Glimepiride E2.43 Atigliflozin
Gliquidone E2.44 Atigliflozin Nateglinide E2.45 Atigliflozin
Repaglinide E2.46 Remogliflozin selected from the group G3 E2.47
Remogliflozin Metformin E2.48 Remogliflozin Pioglitazone E2.49
Remogliflozin Rosiglitazone E2.50 Remogliflozin Glibenclamide E2.51
Remogliflozin Glimepiride E2.52 Remogliflozin Gliquidone E2.53
Remogliflozin Nateglinide E2.54 Remogliflozin Repaglinide E2.55
Sergliflozin selected from the group G3 E2.56 Sergliflozin
Metformin E2.57 Sergliflozin Pioglitazone E2.58 Sergliflozin
Rosiglitazone E2.59 Sergliflozin Glibenclamide E2.60 Sergliflozin
Glimepiride E2.61 Sergliflozin Gliquidone E2.62 Sergliflozin
Nateglinide E2.63 Sergliflozin Repaglinide
[0184] Among the combinations according to the present invention
listed in Table 1 and Table 2, the combinations No. E1.1 to E1.18
and E2.1 to E2.18, in particular E1.10 to E1.18 and E2.10 to E2.18,
especially E1.11 and E2.11 are even more preferred.
[0185] The combination of an SGLT2 inhibitor, a DPPIV inhibitor and
a third antidiabetic agent according to this invention
significantly improves the glycemic control, in particular in
patients as described hereinafter, compared with a monotherapy
using either a SGLT2 inhibitor or a DPP IV inhibitor or the third
antidiabetic agent alone, for example with a monotherapy of
metformin. Furthermore the combination of an SGLT2 inhibitor, a
DPPIV inhibitor and a third antidiabetic agent according to this
invention improves the glycemic control, in particular in patients
as described hereinafter, compared with a combination therapy using
an SGLT2 inhibitor and a DPP IV inhibitor or using an SGLT2
inhibitor and the third antidiabetic agent or using a DPPIV
inhibitor and the third antidiabetic agent. The improved glycemic
control is determined as an increased lowering of blood glucose and
an increased reduction of HbA1c. With monotherapy in a patient, in
particular in patients as described hereinafter, the glycemic
control can usually not be further improved significantly by an
administration of the drug above a certain highest dose. In
addition, a long term treatment using a highest dose may be
unwanted in view of potential side effects. Therefore, a satisfying
glycemic control cannot be achieved in all patients via a
monotherapy using either the SLGT2 inhibitor or the DPP IV
inhibitor or the third antidiabetic agent alone. Even with
combination therapy using only two agents selected from the SGLT2
inhibitors, DPPIV inhibitors and third antidiabetic agents may not
yield in a full glycemic control in all patients and/or over a long
time. In such patients a progression of the diabetes mellitus may
continue and complications associated with diabetes mellitus may
occur, such as macrovascular complications. 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.
[0186] In addition, the combination of an SGLT2 inhibitor, a DPP IV
inhibitor and the third therapeutic agent according to this
invention allows a reduction in the dose of either the SGLT2
inhibitor, the DPP IV inhibitor or the third antidiabetic agent or
even of two or three of the active ingredients. A dose reduction is
beneficial for patients which otherwise would potentially suffer
from side effects in a therapy using a higher dose of one or more
of the active ingredients, in particular with regard to side effect
caused by the third antidiabetic agent. Therefore, the
pharmaceutical composition as well as the methods according to the
present invention, show less side effects, thereby making the
therapy more tolerable and improving the patients compliance with
the treatment.
[0187] A monotherapy using a DPP IV inhibitor or a combination
therapy using a DPPIV inhibitor and a third antidiabetic agent
according to the present invention is not independent from the
insulin secretory capacity or the insulin sensitivity of a patient.
On the other hand, a treatment with the administration of a SGLT2
inhibitor according the present invention does not depend on the
insulin secretory capacity or the insulin sensitivity of the
patient. Therefore, any patient independent of the prevailing
insulin levels or insulin resistance and/or hyperinsulinemia may
benefit from a therapy using a combination of a SGLT2 inhibitor
with a DPPIV inhibitor and a third antidiabetic agent according to
this invention. Independent of their prevailing insulin levels or
their insulin resistance or hyperinsulinemia these patients can
still be treated with a combination of the DPP IV inhibitor and the
third antidiabetic agent because of the combined or alternate
administration of the SGLT2 inhibitor.
[0188] A DPP IV inhibitor according to the present invention is
able--via the increases in active GLP-1 levels--to reduce the
glucagon secretion in a patient. This will therefore limit the
hepatic glucose production. Furthermore, the elevated active GLP-1
levels produced by the DPP IV inhibitor will have beneficial
effects on beta-cell regeneration and neogenesis. All these
features of DPP IV inhibitors render a combination with a SGLT2
inhibitor quite useful and therapeutically relevant.
[0189] When this invention refers to patients requiring treatment
or prevention, it relates primarily to treatment and prevention in
humans, but the pharmaceutical composition may also be used
accordingly in veterinary medicine in mammals. In the scope of this
invention adult patients are preferably humans of the age of 18
years or older. Also in the scope of this invention, 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. In addition it is
assumed that in an adolescent population, in particular in
overweight and/or obese patients, a pronounced weight loss can be
observed.
[0190] As described hereinbefore by the administration of the
pharmaceutical composition according to this invention and in
particular in view of the high SGLT2 inhibitory activity of the
SGLT2 inhibitors therein, excessive blood glucose is excreted
through the urine of the patient, so that no gain in weight or even
a reduction in body weight may result. Therefore, 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. In addition a treatment or prophylaxis according
to this invention is advantageously suitable in those patients in
which a weight increase is contraindicated. Any weight increasing
effect in the therapy, for example due to the administration of the
third antidiabetic agent, may be attenuated or even avoided
thereby.
[0191] 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). By administering a
pharmaceutical composition according to this invention, a reduction
of HbA1c equal to or greater than preferably 1.0%, more preferably
equal to or greater than 2.0%, even more preferably equal to or
greater than 3.0% can be achieved and the reduction is particularly
in the range from 1.0% to 3.0%.
[0192] Furthermore, the method and/or use according to this
invention is advantageously applicable in those patients who show
one, two or more of the following conditions: [0193] (a) a fasting
blood glucose or serum glucose concentration greater than 100 mg/dL
or 110 mg/dL, in particular greater than 125 mg/dL; [0194] (b) a
postprandial plasma glucose equal to or greater than 140 mg/dL;
[0195] (c) an HbA1c value equal to or greater than 6.5%, in
particular equal to or greater than 7.0%, especially equal to or
greater than 7.5%, even more particularly equal to or greater than
8.0%.
[0196] The present invention also discloses the use of the
pharmaceutical composition for improving glycemic control in
patients having type 2 diabetes or showing first signs of
pre-diabetes. Thus, 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.
[0197] Furthermore, 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. These
patients include patients with diabetes type 2 and patients with
diabetes type
[0198] Therefore, according to a preferred embodiment of the
present invention, there is provided a method for improving
glycemic control and/or for reducing of fasting plasma glucose, of
postprandial plasma glucose and/or of glycosylated hemoglobin HbA1c
in a patient in need thereof who is diagnosed with impaired glucose
tolerance (IGT), impaired fasting blood glucose (IFG) with insulin
resistance, with metabolic syndrome and/or with type 2 or type 1
diabetes mellitus characterized in that an SGLT2 inhibitor, a DPPIV
inhibitor and a third antidiabetic agent as defined hereinbefore
and hereinafter are administered, for example in combination or
alternation, to the patient.
[0199] According to another preferred embodiment of the present
invention, there is provided a method for improving glycemic
control in patients, in particular in adult patients, with type 2
diabetes mellitus as an adjunct to diet and exercise.
[0200] It can be found that by using 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 SGLT2
inhibitor or a DPPIV inhibitor or a combination of metformin with a
SGLT2 inhibitor or a combination of metformin with a DPPIV
inhibitor, in particular a SGLT2 inhibitor according to this
invention, or a DPP IV inhibitor according to this invention. A
maximal recommended or tolerated dose with regard to metformin is
for example 2000 mg per day, 1500 mg per day (for example in asian
countries) or 850 mg three times a day or any equivalent thereof. A
maximal recommended or tolerated dose with regard to a SGLT2
inhibitor according to this invention, in particular with regard to
the compound (I.9), is for example 100 mg or 50 mg or even 25 mg or
10 mg once per day or any equivalent thereof. A maximal recommended
or tolerated dose with regard to linagliptin is for example 10 mg,
preferably 5 mg once daily or any equivalent thereof. A maximal
recommended or tolerated dose with regard to sitagliptin is for
example 100 mg once daily or any equivalent thereof.
[0201] Therefore, the method and/or use according to this invention
is advantageously applicable in those patients who show one, two or
more of the following conditions: [0202] (a) insufficient glycemic
control with diet and exercise alone; [0203] (b) insufficient
glycemic control despite oral monotherapy with metformin, in
particular despite oral monotherapy at a maximal recommended or
tolerated dose of metformin; [0204] (c) insufficient glycemic
control despite oral monotherapy with the third antidiabetic agent,
in particular despite oral monotherapy at a maximal recommended or
tolerated dose of the third antidiabetic agent; [0205] (d)
insufficient glycemic control despite oral monotherapy with the
SGLT2 inhibitor, in particular despite oral monotherapy at a
maximal recommended or tolerated dose of the SGLT2 inhibitor;
[0206] (e) insufficient glycemic control despite oral monotherapy
with the DPPIV inhibitor, in particular despite oral monotherapy at
a maximal recommended or tolerated dose of the DPPIV inhibitor;
[0207] (f) insufficient glycemic control despite combination
therapy with two agents selected from the group of the SGLT2
inhibitor, the DPPIV inhibitor and the third antidiabetic agent;
[0208] (g) insufficient glycemic control despite oral combination
therapy with the SGLT2 inhibitor and the third antidiabetic agent
(for example metformin), in particular despite oral monotherapy at
a maximal recommended or tolerated dose of at least one of the
combination partners; [0209] (h) insufficient glycemic control
despite oral combination therapy with the DPPIV inhibitor and the
third antidiabetic agent (for example metformin), in particular
despite oral monotherapy at a maximal recommended or tolerated dose
of at least one of the combination partners.
[0210] The lowering of the blood glucose level by the
administration of an SGLT2 inhibitor according to this invention is
insulin-independent. Therefore, 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 [0211] insulin resistance, [0212]
hyperinsulinemia, [0213] pre-diabetes, [0214] type 2 diabetes
mellitus, particular having a late stage type 2 diabetes mellitus,
[0215] type 1 diabetes mellitus.
[0216] Furthermore, 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 [0217]
(a) obesity (including class I, II and/or III obesity), visceral
obesity and/or abdominal obesity, [0218] (b) triglyceride blood
level.gtoreq.150 mg/dL, [0219] (c) HDL-cholesterol blood
level<40 mg/dL in female patients and <50 mg/dL in male
patients, [0220] (d) a systolic blood pressure.gtoreq.130 mm Hg and
a diastolic blood pressure.gtoreq.85 mm Hg, [0221] (e) a fasting
blood glucose level.gtoreq.100 mg/dL.
[0222] It is assumed that patients diagnosed with impaired glucose
tolerance (IGT), impaired fasting blood glucose (IFG), with insulin
resistance and/or with 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 glycemic control according to this
invention may result in a reduction of the cardiovascular
risks.
[0223] Furthermore, the pharmaceutical composition and the methods
according to this invention are 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 [0224] (a) a higher age, in particular above
50 years, [0225] (b) male gender; [0226] (c) overweight, obesity
(including class I, II and/or III obesity), visceral obesity and/or
abdominal obesity, [0227] (d) pre-transplant diabetes, [0228] (e)
immunosuppression therapy.
[0229] Furthermore, the pharmaceutical composition and the methods
according to this invention are particularly suitable in the
treatment of patients who are diagnosed having one or more of the
following conditions: [0230] (a) hyponatremia, in particular
chronical hyponatremia; [0231] (b) water intoxication; [0232] (c)
water retention; [0233] (d) plasma sodium concentration below 135
mmol/L.
[0234] The patient may be a diabetic or non-diabetic mammal, in
particular human.
[0235] Furthermore, the pharmaceutical composition and the methods
according to this invention are particularly suitable in the
treatment of patients who are diagnosed having one or more of the
following conditions: [0236] (a) high serum uric acid levels, in
particular greater than 6.0 mg/dL (357 .mu.mol/L); [0237] (b) a
history of gouty arthritis, in particular recurrent gouty
arthritis; [0238] (c) kidney stones, in particular recurrent kidney
stones; [0239] (d) a high propensity for kidney stone
formation.
[0240] A pharmaceutical composition according to this invention, in
particular due to the SGLT2 inhibitor and the DPPIV inhibitor
therein, exhibits a good safety profile. Therefore, a treatment or
prophylaxis according to this invention is advantageously possible
in those patients for which the mono-therapy with another
antidiabetic drug, such as for example metformin, is
contraindicated and/or who have an intolerance against such drugs
at therapeutic doses. In particular, a treatment or prophylaxis
according to this invention may be advantageously possible in those
patients showing or having an increased risk for one or more of the
following disorders: renal insufficiency or diseases, cardiac
diseases, cardiac failure, hepatic diseases, pulmonal diseases,
catabolytic states and/or danger of lactate acidosis, or female
patients being pregnant or during lactation.
[0241] Furthermore, it can be found that the administration of 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.
[0242] 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.
[0243] The term "long term" as used hereinbefore and hereinafter
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.
[0244] Therefore, 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.
[0245] The effects mentioned above are observed both, when the
SGLT2 inhibitor, the DPP IV inhibitor and the third antidiabetic
agent are administered in combination, for example simultaneously
in one single or two or three separate formulations, and when they
are administered in alternation, for example successively in two or
three separate formulations.
[0246] It will be appreciated that 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. In general, however, the
SGLT2 inhibitor, the DPP IV inhibitor and the third antidiabetic
agent according to this invention are included in the
pharmaceutical composition or dosage form in an amount sufficient
that by their administration in combination and/or alternation the
glycemic control in the patient to be treated is improved.
[0247] For the treatment of hyperuricemia or hyperuricemia
associated conditions 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.
[0248] For the treatment or prevention of kidney stones 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.
[0249] For the treatment of hyponatremia and associated conditions
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.
[0250] In the following preferred ranges of the amount of the SGLT2
inhibitor, the DPP IV inhibitor and the third antidiabetic agent 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 ranges of the dosage and amounts are
calculated for the individual active moiety. Advantageously, the
combination therapy according to the present invention utilizes
lower dosages of the individual SGLT2 inhibitor, of the individual
DPP IV inhibitor and/or of the individual third antidiabetic agent
used in monotherapy or used in conventional therapeutics, thus
avoiding possible toxicity and adverse side effects incurred when
those agents are used as monotherapies.
[0251] Within the scope of the present invention, the
pharmaceutical composition is preferably administered orally. Other
forms of administration are possible and described hereinafter.
Preferably the one or more dosage forms comprising the SGLT2
inhibitor, the DPPIV inhibitor and/or the third antidiabetic agent
is oral or usually well known.
[0252] In general, the amount of the SGLT2 inhibitor in the
pharmaceutical composition and methods according to this invention
is preferably in the range from 1/5 to 1/1 of the amount usually
recommended for a monotherapy using said SGLT2 inhibitor.
[0253] 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. 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)
are for example 1, 2.5, 5, 7.5, 10, 12.5, 15, 20, or 50 mg of the
compound of the formula (I), in particular of the compound (I.9),
or of dapagliflozin. The application of the active ingredient may
occur up to three times a day, preferably one or two times a
day.
[0254] In general, the amount of the DPP IV inhibitor in the
pharmaceutical composition and methods according to this invention
is preferably in the range from 1/5 to 1/1 of the amount usually
recommended for a monotherapy using said DPP IV inhibitor.
[0255] A preferred dosage range of linagliptin when administered
orally is 0.5 mg to 10 mg per day, preferably 2.5 mg to 10 mg, most
preferably 1 mg to 5 mg per day. The preferred range of amounts in
the pharmaceutical composition is 0.5 to 10 mg, in particular 1 to
5 mg. Examples of particular dosage strengths are 1, 2.5, 5 or 10
mg. The application of the active ingredient may occur up to three
times a day, preferably one or two times a day. Suitable
formulations for linagliptin may be those formulations disclosed in
the application WO 2007/128724, the disclosure of which is
incorporated herein in its entirety.
[0256] A preferred dosage range of sitagliptin when administered
orally is from 10 to 200 mg, in particular 25 to 150 mg per day. A
recommended dose of sitagliptin is 100 mg calculated for the active
moiety (free base anhydrate) once daily or 50 mg twice daily. The
preferred range of amounts in the pharmaceutical composition is 10
to 150 mg, in particular 25 to 100 mg. Examples are 25, 50, 75 or
100 mg. The application of the active ingredient may occur up to
three times a day, preferably one or two times a day. Equivalent
amounts of salts of sitagliptin, in particular of the phosphate
monohydrate can be calculated accordingly. Adjusted dosages of
sitagliptin, for example 25 and 50 mg, are preferably used for
patients with renal failure.
[0257] A preferred dosage range of vildagliptin when administered
orally is from 10 to 150 mg daily, in particular from 25 to 150 mg,
25 and 100 mg or 25 and 50 mg or 50 and 100 mg daily. For example
the daily administration of vildagliptin is 50 or 100 mg. The
preferred range of amounts in the pharmaceutical composition is 10
to 150 mg, in particular 25 to 100 mg. Examples are 25, 50, 75 or
100 mg. The application of the active ingredient may occur up to
three times a day, preferably one or two times a day.
[0258] A preferred dosage range of alogliptin when administered
orally is from 5 to 250 mg daily, in particular from 10 to 150 mg
daily. The preferred range of amounts in the pharmaceutical
composition is 5 to 150 mg, in particular 10 to 100 mg. Examples
are 10, 12.5, 20, 25, 50, 75 and 100 mg. The application of the
active ingredient may occur up to three times a day, preferably one
or two times a day.
[0259] A preferred dosage range of saxagliptin when administered
orally is from 2.5 to 100 mg daily, in particular from 2.5 to 50 mg
daily. The preferred range of amounts in the pharmaceutical
composition is from 2.5 to 100 mg, in particular from 2.5 and 50
mg. Examples are 2.5, 5, 10, 15, 20, 30, 40, 50 and 100 mg. The
application of the active ingredient may occur up to three times a
day, preferably one or two times a day.
[0260] A preferred dosage range of dutogliptin when administered
orally is from 50 to 400 mg daily, in particular from 100 to 400 mg
daily. The preferred range of amounts in the pharmaceutical
composition is from 50 to 400 mg. Examples are 50, 100, 200, 300
and 400 mg. The application of the active ingredient may occur up
to three times a day, preferably one or two times a day.
[0261] In general, the amount of the third antidiabetic agent in
the pharmaceutical composition and methods according to this
invention is preferably in the range from 1/5 to 1/1 of the amount
usually recommended for a monotherapy using said antidiabetic
agent. Using lower dosages of the individual third antidiabetic
agent compared with monotherapy could avoid or minimize possible
toxicity and adverse side effects incurred when those agents are
used as monotherapies.
[0262] A preferred dosage range of metformin when administered
orally is 250 to 3000 mg, in particular 500 to 2000 mg per day. The
preferred range of amounts in the pharmaceutical composition is 250
to 1000, in particular 500 to 1000 mg or 250 to 850 mg
respectively. Examples are 500, 750, 850 or 1000 mg. Preferably the
administration of said amounts is once, twice or three times daily.
For example the amounts of 500, 750 and 850 mg preferably require
once-daily, twice-daily or three-times daily dosing and the amount
of 1000 mg preferably requires once-daily or twice-daily dosing.
Certain controlled or sustained release formulations allow a
once-daily dosing. Metformin can be administered for example in the
form as marketed under the trademarks GLUCOPHAGE.TM.,
GLUCOPHAGE-D.TM. or GLUCOPHAGE-XR.TM..
[0263] A preferred dosage range of pioglitazone when administered
orally is 5 to 50 mg per day. The preferred range of amounts in the
pharmaceutical composition is 5 to 50 mg, 10 to 45 mg and 15 to 45
mg respectively. Examples are 15, 30 or 45 mg. Preferably the
administration of said amounts is once or twice daily, in
particular once daily. Pioglitazone can be administered in the form
as it is marketed for example under the trademark ACTOS.TM..
[0264] A preferred dosage range of rosiglitazone when administered
orally is 1 mg to 10 mg per day. The preferred range of amounts in
the pharmaceutical composition is 1 to 10 mg, 2 to 8 mg, 4 to 8 mg
and 1 to 4 mg. Examples are 1, 2, 4 or 8 mg. Preferably the
administration of said amounts is once or twice daily. Preferably
the dose should not exceed 8 mg daily.
[0265] Rosiglitazone can be administered in the form as it is
marketed for example under the trademark AVANDIA.TM..
[0266] A preferred dosage range of a thiazolidindione (other than
pioglitazone or rosiglitazone as described above) when administered
orally is 2 to 100 mg per day. The preferred range of amounts in
the pharmaceutical composition for an administration once, twice or
three times daily is 2 to 100, 1 to 50 and 1 to 33 mg
respectively.
[0267] A preferred dosage range of glibenclamide when administered
orally is 0.5 to 15 mg, in particular 1 to 10 mg per day. The
preferred range of amounts in the pharmaceutical composition is 0.5
to 5 mg, in particular 1 to 4 mg. Examples are 1.0, 1.75 and 3.5
mg. Preferably the administration of said amounts is once, twice or
three-times daily. Glibenclamide can be administered in the form as
it is marketed for example under the trademark EUGLUCON.TM..
[0268] A preferred dosage range of glimepiride when administered
orally is 0.5 to 10 mg, in particular 1 to 6 mg per day. The
preferred range of amounts in the pharmaceutical composition is 0.5
to 10 mg, in particular 1 to 6 mg. Examples are 1, 2, 3, 4, and 6
mg. Preferably the administration of said amounts is once, twice or
three-times daily, preferably once daily. Glimepiride can be
administered in the form as it is marketed for example under the
trademark AMARYL.TM..
[0269] A preferred dosage range of gliquidone when administered
orally is 5 to 150 mg, in particular 15 to 120 mg per day. The
preferred range of amounts in the pharmaceutical composition is 5
to 120 mg, in particular 5 to 30 mg. Examples are 10, 20, 30 mg.
Preferably the administration of said amounts is once, twice,
three-times or four-times daily. Gliquidone can be administered in
the form as it is marketed for example under the trademark
GLURENORM.TM..
[0270] A preferred dosage range of glibornuride when administered
orally is 5 to 75 mg per day. The preferred range of amounts in the
pharmaceutical composition is 5 to 75 mg, in particular 10 to 50
mg. Preferably the administration of said amounts is once, twice or
three-times daily.
[0271] A preferred dosage range of gliclazide when administered
orally is 20 to 300 mg, in particular 40 to 240 mg per day. The
preferred range of amounts in the pharmaceutical composition is 20
to 240 mg, in particular 20 to 80 mg. Examples are 20, 30, 40 and
50 mg. Preferably the administration of said amounts is once, twice
or three-times daily.
[0272] A preferred dosage range of glisoxepide when administered
orally is 1 to 20 mg, in particular 1 to 16 mg per day. The
preferred range of amounts in the pharmaceutical composition is 1
to 8 mg, in particular 1 to 4 mg. Preferably the administration of
said amounts is once, twice, three-times or four-times daily.
[0273] A preferred dosage range of tolbutamide when administered
orally is 100 to 3000 mg, preferably 500 to 2000 mg per day. The
preferred range of amounts in the pharmaceutical composition is 100
to 1000 mg. Preferably the administration of said amounts is once
or twice daily.
[0274] A preferred dosage range of glipizide when administered
orally is 1 to 50 mg, in particular 2.5 to 40 mg per day. The
preferred range of amounts in the pharmaceutical composition for an
administration once, twice or three times daily is 1 to 50, 0.5 to
25 and 0.3 to 17 mg respectively.
[0275] A preferred dosage range of nateglinide when administered
orally is 30 to 500 mg, in particular 60 to 360 mg per day. The
preferred range of amounts in the pharmaceutical composition is 30
to 120 mg. Examples are 30, 60 and 120 mg. Preferably the
administration of said amounts is once, twice or three-times daily.
Nateglinide can be administered in the form as it is marketed for
example under the trademark STARLIX.TM..
[0276] A preferred dosage range of repaglinide when administered
orally is 0.1 to 16 mg, in particular 0.5 to 6 mg per day.
[0277] The preferred range of amounts in the pharmaceutical
composition is 0.5 to 4 mg. Examples are 0.5, 1, 2 or 4 mg.
Preferably the administration of said amounts is once, twice,
three-times or four-times daily. Repaglinide can be administered in
the form as it is marketed for example under the trademark
NOVONORM.TM..
[0278] A preferred dosage range of acarbose when administered
orally is 50 to 1000 mg, in particular 50 to 600 mg per day. The
preferred range of amounts in the pharmaceutical composition is 50
to 150 mg. Examples are 50 and 100 mg. Preferably the
administration of said amounts is once, twice, three-times or
four-times daily. Acarbose can be administered in the form as it is
marketed for example under the trademark Glucobay.TM..
[0279] A preferred dosage range of voglibose when administered
orally is 100 to 1000 mg, in particular 200 to 600 mg per day. The
preferred range of amounts in the pharmaceutical composition is 50
to 300 mg. Examples are 50, 100, 150, 200 and 300 mg. Preferably
the administration of said amounts is once, twice, three-times or
four-times daily. Voglibose can be administered in the form as it
is marketed for example under the trademark Basen.TM. or
Voglisan.TM..
[0280] A preferred dosage range of miglitol when administered
orally is 25 to 500 mg, in particular 25 to 300 mg per day. The
preferred range of amounts in the pharmaceutical composition is 25
to 100 mg. Examples are 25, 50 and 100 mg. Preferably the
administration of said amounts is once, twice, three-times or
four-times daily. Miglitol can be administered in the form as it is
marketed for example under the trademark Glyset.TM..
[0281] A preferred dosage range of GLP-1 analogues, in particular
of exenatide is 5 to 30 .mu.g, in particular 5 to 20 .mu.g per day.
The preferred range of amounts in the pharmaceutical composition is
5 to 10 .mu.g. Examples are 5 and 10 .mu.g. Preferably the
administration of said amounts is once, twice, three-times or
four-times daily by subcutaneous injection. Exenatide can be
administered in the form as it is marketed for example under the
trademark Byetta.TM.. A long acting formulation, preferably for a
once weekly subcutaneous injection, comprises an amount from 0.1 to
3.0 mg, preferably 0.5 to 2.0 mg exenatide. Examples are 0.8 mg and
2.0 mg. An example of a long acting formulation of exenatide is
Byetta LAR.TM..
[0282] A preferred dosage range of liraglutide is 0.5 to 3 mg, in
particular 0.5 to 2 mg per day. The preferred range of amounts in
the pharmaceutical composition is 0.5 to 2 mg. Examples are 0.6,
1.2 and 1.8 mg. Preferably the administration of said amounts is
once or twice daily by subcutaneous injection.
[0283] The amount of the SGLT2 inhibitor, the DPP IV inhibitor and
the third therapeutic agent in the pharmaceutical composition and
in the methods and uses according to this invention correspond to
the respective dosage ranges as provided hereinbefore. For example,
preferred dosage ranges in a pharmaceutical composition and in
methods and uses according to this invention are an amount of 1 to
50 mg (in particular 1 to 25 mg) of a SGLT2 inhibitor according to
the formula (I), in particular of the compound (I.9), an amount of
0.5 to 10 mg (in particular 1 to 5 mg) of linagliptin and an amount
of 250 to 1000 mg (in particular 250 to 850 mg) of metformin. An
oral administration once or twice daily is preferred.
[0284] Another example of preferred dosage ranges in a
pharmaceutical composition or in methods or uses according to this
invention are an amount of 1 to 50 mg (in particular 1 to 25 mg) of
a SGLT2 inhibitor according to the formula (I), in particular of
the compound (I.9), an amount of 0.5 to 10 mg (in particular 1 to 5
mg) of linagliptin and an amount of 5 to 50 mg (in particular 10 to
45 mg) of pioglitazone. An oral administration once daily is
preferred.
[0285] Another example of preferred dosage ranges in a
pharmaceutical composition or in methods or uses according to this
invention are an amount of 1 to 50 mg (in particular 1 to 25 mg) of
dapagliflozin, an amount of 0.5 to 10 mg (in particular 1 to 5 mg)
of linagliptin and an amount of 250 to 1000 mg (in particular 250
to 850 mg) of metformin. An oral administration once or twice daily
is preferred.
[0286] Another example of preferred dosage ranges in a
pharmaceutical composition or in methods or uses according to this
invention are an amount of 1 to 50 mg (in particular 1 to 25 mg) of
a SGLT2 inhibitor according to the formula (I), in particular of
the compound (I.9), an amount of 10 to 150 mg (in particular 25 to
100 mg) of vildagliptin and an amount of 250 to 1000 mg (in
particular 250 to 850 mg) of metformin. An oral administration once
or twice daily is preferred.
[0287] Another example of preferred dosage ranges in a
pharmaceutical composition or in methods or uses according to this
invention are an amount of 1 to 50 mg (in particular 1 to 25 mg) of
a SGLT2 inhibitor according to the formula (I), in particular of
the compound (I.9), an amount of 5 to 150 mg (in particular 10 to
100 mg) of alogliptin and an amount of 250 to 1000 mg (in
particular 250 to 850 mg) of metformin. An oral administration once
or twice daily is preferred.
[0288] Another example of preferred dosage ranges in a
pharmaceutical composition or in methods or uses according to this
invention are an amount of 1 to 50 mg (in particular 1 to 25 mg) of
a SGLT2 inhibitor according to the formula (I), in particular of
the compound (I.9), an amount of 2.5 to 100 mg (in particular 2.5
to 50 mg) of saxagliptin and an amount of 250 to 1000 mg (in
particular 250 to 850 mg) of metformin. An oral administration once
or twice daily is preferred.
[0289] In the methods and uses according to the present invention
the SGLT2 inhibitor and the DPP IV inhibitor and the third
therapeutic agent are administered in combination or
alternation.
[0290] The term "administration in combination" means that the
active ingredients are administered at the same time, i.e.
simultaneously, or essentially at the same time. The term
"administration in alternation" means that at first one or two
active ingredients are administered and after a period of time the
other two or one active ingredients are administered, i.e. at least
two of the three active ingredients are administered sequentially.
The period of time may be in the range from 30 min to 12 hours. The
administration which is in combination or in alternation may be
once, twice, three times or four times daily, preferably once or
twice daily.
[0291] With regard to the administration of the SGLT2 inhibitor and
the DPP IV inhibitor and the third antidiabetic agent, all three
active ingredients may be present in one single dosage form, for
example in one tablet or capsule, or one or two of the active
ingredients may be present in a separate dosage form, for example
in two different or identical dosage forms.
[0292] With regard to their administration in alternation, one or
two of the active ingredients are present in a separate dosage
form, for example in two different or identical dosage forms.
[0293] Therefore, the pharmaceutical composition according to this
invention may be present as single dosage forms which comprise the
SGLT2 inhibitor, the DPP IV inhibitor and the third antidiabetic
agent. Alternatively the pharmaceutical composition according to
this invention may be present as two separate dosage forms wherein
one dosage form comprises the SGLT2 inhibitor and the other dosage
form comprises the DPP IV inhibitor plus the third antidiabetic
agent or one dosage form comprises the SGLT2 inhibitor plus the
third antidiabetic agent and the other dosage form comprises the
DPP IV inhibitor. Alternatively the pharmaceutical composition
according to this invention may be present as three separate dosage
forms wherein one dosage form comprises the SGLT2 inhibitor and a
second dosage form comprises the DPP IV inhibitor and the third
dosage form comprises the third antidiabetic agent.
[0294] Therefore according to one embodiment the pharmaceutical
composition according to the invention is characterized in that the
SGLT2 inhibitor and the DPP IV inhibitor are present in a single
dosage form and the third antidiabetic agent is present in a
separate dosage form.
[0295] According to another embodiment the pharmaceutical
composition according to the invention is characterized in that the
SGLT2 inhibitor and the third antidiabetic agent are present in a
single dosage form and the DPPIV inhibitor is present in a separate
dosage form.
[0296] According to another embodiment the pharmaceutical
composition according to the invention is characterized in that the
DPPIV inhibitor and the third antidiabetic agent are present in a
single dosage form and the SGLT2 inhibitor is present in a separate
dosage form.
[0297] According to another embodiment the pharmaceutical
composition according to the invention is characterized in that the
SGLT2 inhibitor, the DPP IV inhibitor and the third antidiabetic
agent are present in a single dosage form.
[0298] According to another embodiment the pharmaceutical
composition according to the invention is characterized in that the
SGLT2 inhibitor, the DPP IV inhibitor and the third antidiabetic
agent are present each in a separate dosage form.
[0299] The case may arise in which one active ingredient has to be
administered more often, for example twice per day, than the other
active ingredients, which for example needs administration once
daily. Therefore the term "administration in combination or
alternation" also includes an administration scheme in which first
all active ingredients are administered in combination or
alternation and after a period of time only one active ingredient
is administered again or vice versa.
[0300] Therefore, the present invention also includes
pharmaceutical compositions which are present in separate dosage
forms wherein one dosage form comprises SGLT2 inhibitor, the DPP IV
inhibitor and the third therapeutic agent and the other dosage form
comprises the third therapeutic agent only.
[0301] A pharmaceutical composition which is present as a separate
or multiple dosage form, preferably as a kit of parts, is useful in
combination therapy to flexibly suit the individual therapeutic
needs of the patient.
[0302] According to a first embodiment a preferred kit of parts
comprises [0303] (a) a first containment containing a dosage form
comprising the SGLT2 inhibitor and at least one pharmaceutically
acceptable carrier, and [0304] (b) a second containment containing
a dosage form comprising the DPP IV inhibitor and at least one
pharmaceutically acceptable carrier, and [0305] (b) a second
containment containing a dosage form comprising the third
antidiabetic agent and at least one pharmaceutically acceptable
carrier.
[0306] According to a second embodiment a preferred kit of parts
comprises [0307] (a) a first containment containing a dosage form
comprising the SGLT2 inhibitor and the third antidiabetic agent and
at least one pharmaceutically acceptable carrier, and [0308] (b) a
second containment containing a dosage form comprising the DPP IV
inhibitor and at least one pharmaceutically acceptable carrier.
[0309] According to a third embodiment a preferred kit of parts
comprises [0310] (a) a first containment containing a dosage form
comprising the SGLT2 inhibitor and at least one pharmaceutically
acceptable carrier, and [0311] (b) a second containment containing
a dosage form comprising the DPP IV inhibitor and the third
antidiabetic agent and at least one pharmaceutically acceptable
carrier.
[0312] According to a fourth embodiment a preferred kit of parts
comprises [0313] (a) a first containment containing a dosage form
comprising the SGLT2 inhibitor and the DPPIV inhibitor and at least
one pharmaceutically acceptable carrier, and [0314] (b) a second
containment containing a dosage form comprising the third
antidiabetic agent and at least one pharmaceutically acceptable
carrier.
[0315] 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.
[0316] According to a first embodiment 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 may or is to be
administered, for example in combination or alternation, with a
medicament comprising a DPP IV inhibitor according to the present
invention and with a medicament comprising a third antidiabetic
agent according to the present invention or with a medicament
comprising both a DPPIV inhibitor and a third antidiabetic agent
according to the present invention.
[0317] According to a second embodiment a manufacture comprises (a)
a pharmaceutical composition comprising a DPP IV inhibitor
according to the present invention and (b) a label or package
insert which comprises instructions that the medicament may or is
to be administered, for example in combination or alternation, with
a medicament comprising a SGLT2 inhibitor according to the present
invention and a medicament comprising a third antidiabetic agent
according to the present invention or with a medicament comprising
both a SGLT2 inhibitor and a third antidiabetic agent according to
the present invention.
[0318] According to a third embodiment a manufacture comprises (a)
a pharmaceutical composition comprising a DPP IV inhibitor and a
third antidiabetic agent according to the present invention and (b)
a label or package insert which comprises instructions that the
medicament may or is to be administered, for example in combination
or alternation, with a medicament comprising a SGLT2 inhibitor
according to the present invention.
[0319] According to a fourth embodiment a manufacture comprises (a)
a pharmaceutical composition comprising a SGLT2 inhibitor and a
third antidiabetic agent according to the present invention and (b)
a label or package insert which comprises instructions that the
medicament may or is to be administered, for example in combination
or alternation, with a medicament comprising a DPPIV inhibitor
according to the present invention.
[0320] 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.
[0321] 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.
[0322] 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.
[0323] The pharmaceutical composition and the dosage forms
preferably comprises one or more pharmaceutical acceptable
carriers. Preferred carriers must be "acceptable" in the sense of
being compatible with the other ingredients of the formulation and
not deleterious to the recipient thereof. Examples of
pharmaceutically acceptable carriers are known to the one skilled
in the art.
[0324] Pharmaceutical 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.
[0325] The pharmaceutical composition 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. Alternatively, 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.
[0326] Pharmaceutical 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.
[0327] The pharmaceutical compositions and methods according to
this invention show advantageous effects in the treatment and
prevention of those diseases and conditions as described
hereinbefore compared with pharmaceutical compositions and methods
which comprise only one or two of the three active ingredients.
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.
[0328] Methods for the manufacture of SGLT2 inhibitors according to
this invention and of prodrugs thereof are known to the one skilled
in the art. Advantageously, the compounds according to this
invention can be prepared using synthetic methods as described in
the literature, including patent applications as cited
hereinbefore. Preferred methods of manufacture are described in the
WO 2006/120208 and WO 2007/031548. With regard to the preferred
compound (I.9) an advantageous crystalline form is described in the
international patent application WO 2006/117359 which hereby is
incorporated herein in its entirety.
[0329] With respect to linagliptin, the methods of synthesis are
known to the skilled person and as described in the literature, in
particular as described in WO 2002/068420, WO 2004/018468, or WO
2006/048427, the disclosures of which are incorporated herein.
Polymorphous crystal modifications and formulations of particular
DPP IV inhibitors are disclosed in WO 2007/128721 and WO
2007/128724, respectively, the disclosures of which are
incorporated herein in their entireties.
[0330] The methods of synthesis for the further DPP IV inhibitors
are described in the scientific literature and/or in published
patent documents, particularly in those cited hereinbefore.
[0331] The active ingredients, in particular the DPP IV inhibitor
and/or the third antidiabetic agent, 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.
[0332] 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.
[0333] Any of the above mentioned combinations and methods within
the scope of the invention may be tested by animal models known in
the art. In the following, in vivo experiments are described which
are suitable to evaluate pharmacologically relevant properties of
pharmaceutical compositions and methods according to this
invention:
[0334] Pharmaceutical compositions and methods according to this
invention can be tested in genetically hyperinsulinemic or diabetic
animals like db/db mice, ob/ob mice, Zucker Fatty (fa/fa) rats or
Zucker Diabetic Fatty (ZDF) rats. In addition, they can be tested
in animals with experimentally induced diabetes like HanWistar or
Sprague Dawley rats pretreated with streptozotocin.
[0335] The effect on glycemic control of the combinations according
to this invention can be tested after single dosing of the SGLT2
inhibitor and the DPP IV inhibitor and the third antidiabetic agent
alone and in combination in an oral glucose tolerance test in the
animal models described hereinbefore. The time course of blood
glucose is followed after an oral glucose challenge in overnight
fasted animals. The combinations according to the present invention
significantly improve glucose excursion compared to each
monotherapy or dual-combination therapy using a combination of only
two of the three active ingredients as measured by reduction of
peak glucose concentrations or reduction of glucose AUC. In
addition, after multiple dosing of the SGLT2 inhibitor and the DPP
IV inhibitor and the third therapeutic agent alone and in
combination in the animal models described hereinbefore, the effect
on glycemic control can be determined by measuring the HbA1c value
in blood. The combinations according to this invention
significantly reduce HbA1c compared to each monotherapy or compared
to a dual-combination therapy, i.e. using a combination of only two
of the three active ingredients, for example employing the SGLT2
inhibitor plus the third antidiabetic agent or the DPPIV inhibitor
and the third therapeutic agent.
[0336] The possible dose reduction of one or more of the SGLT2
inhibitor, the DPPIV inhibitor and the third antidiabetic agent can
be tested by the effect on glycemic control of lower doses of the
combinations and monotherapies or dual-combination therapies in the
animal models described hereinbefore. The combinations according to
this invention at the lower doses significantly improve glycemic
control compared to placebo treatment whereas the monotherapies or
dual-combination therapies at lower doses do not.
[0337] The improved independence from insulin of the treatment
according to this invention can be shown after single dosing in
oral glucose tolerance tests in the animal models described
hereinbefore. The time course of plasma insulin is followed after a
glucose challenge in overnight fasted animals. The SGLT2 inhibitor
in combination with the DPP IV inhibitor and the third antidiabetic
agent will exhibit lower insulin peak concentrations or insulin AUC
at lower blood glucose excursion than the DPP IV inhibitor
alone.
[0338] The increase in active GLP-1 levels by treatment according
to this invention after single or multiple dosing can be determined
by measuring those levels in the plasma of animal models described
hereinbefore in either the fasting or postprandial state. Likewise,
a reduction in glucagon levels in plasma can be measured under the
same conditions. The SGLT2 inhibitor in combination with the DPP IV
inhibitor and the third antidiabetic agent will exhibit higher
active GLP-1 concentrations and lower glucagon concentrations than
the SGLT2 inhibitor alone.
[0339] A superior effect of the combination of a SGLT2 inhibitor, a
DPP IV inhibitor and a third antidiabetic agent according to the
present invention on beta-cell regeneration and neogenesis can be
determined after multiple dosing in the animal models described
hereinbefore by measuring the increase in pancreatic insulin
content, or by measuring increased beta-cell mass by morphometric
analysis after immunhistochemical staining of pancreatic sections,
or by measuring increased glucose-stimulated insulin secretion in
isolated pancreatic islets.
PHARMACOLOGICAL EXAMPLES
[0340] The following examples show the beneficial effect on
glycemic control of the combination according to the present
invention.
Example 1
[0341] According to a first example an oral glucose tolerance test
is performed in overnight fasted male Zucker rats
(Crl:ZUC(Orl)Lepr.sup.fa) or Zucker Diabetic Fatty (ZDF) rats
(ZDF/Crl-Lepr.sup.fa/Crl). A pre-dose blood sample is obtained by
tail bleed. Blood glucose is measured with a glucometer, and the
animals are randomized for blood glucose (n=5/group). Subsequently,
the groups receive a single oral administration of either vehicle
alone (0.5% aqueous hydroxyethylcellulose containing 0.015%
Polysorbat 80) or vehicle containing either the SGLT2 inhibitor or
the DPPIV inhibitor or the third antidiabetic agent or the
combination of the SGLT2 inhibitor plus the DPP IV inhibitor plus
the third antidiabetic agent. Alternatively, the test can also be
performed after multiple administrations of the respective drugs to
account for anti-diabetic effects that need longer to become
evident like in the case of thiazolidindiones. The animals receive
an oral glucose load (2 g/kg) 30 min after compound administration.
Blood glucose is measured in tail blood 30 min, 60 min, 90 min, and
120 min after the glucose challenge. Glucose excursion is
quantified by calculating the glucose AUC. The data are presented
as mean.+-.SEM. The two-sided unpaired Student t-test is used for
statistical comparison of the control group and the active groups.
Statistical comparisons are conducted by Student's t test.
[0342] The following specific example shows the superior effect on
glycemic control of the combination of the SGLT2 inhibitor (I.9)
with the DPPIV inhibitor linagliptin and with metformin as a third
antidiabetic agent as compared to the respective monotherapies and
double combinations. All experimental protocols concerning the use
of laboratory animals were reviewed by a federal Ethics Committee
and approved by governmental authorities. An oral glucose tolerance
test was performed after single oral dosing in overnight fasted
male Zucker rats as described above. Control animals received
vehicle only. Compound A is the glucopyranosyl-substituted benzene
derivative (I.9) at a dose of 0.5 mg/kg body weight. Compound B is
linagliptin at a dose of 0.5 mg/kg body weight. Met is metformin at
a dose of 50 mg/kg body weight. In the combinations, the compounds
were administered together at the same doses as in the respective
monotherapies. The result is shown in FIG. 1.
[0343] P values for comparison versus control are indicated by
symbols above the bars. P values for comparison of the triple
combination of the glucopyranosyl-substituted benzene derivative,
linagliptin and metformin with the respective double combinations
and monotherapies are indicated below the figure (#, p<0.1; *,
p<0.05; **, p<0.01; ***, p<0.001). A p value below 0.05 is
considered as being statistically significant, and a p value
between 0.1 and 0.05 is regarded as showing a trend. A complete set
of p values for comparison of all groups is given in the following
Table 3.
TABLE-US-00004 A + A + B + A B Met A + Met B + Met B Met Control
n.s. n.s. n.s. # * * ** A n.s. n.s. * * ** *** B n.s. # # # * Met #
# * ** A + Met n.s. n.s. * B + Met n.s. * A + B *
[0344] None of the compounds used here as monotherapy at a low dose
had an effect on glucose tolerance. Surprisingly, it was found that
the triple combination of the glucopyranosyl-substituted benzene
derivative plus linagliptin plus metformin reduced glucose
excursion significantly by 16% versus control, and this reduction
in total glucose AUC was also statistically significant not only
when compared to each of the monotherapies, but also when compared
to each of the double combinations.
Example 2
[0345] According to a second example an oral glucose tolerance test
is performed in overnight fasted male Sprague Dawley rats
(Crl:CD(SD)) with a body weight of about 200 g. A pre-dose blood
sample is obtained by tail bleed. Blood glucose is measured with a
glucometer, and the animals are randomized for blood glucose
(n=5/group). Subsequently, the groups receive a single oral
administration of either vehicle alone (0.5% aqueous
hydroxyethylcellulose containing 0.015% Polysorbat 80) or vehicle
containing either the SGLT2 inhibitor or the DPPIV inhibitor or the
third antidiabetic agent or the combination of the SGLT2 inhibitor
plus the DPP IV inhibitor plus the third antidiabetic agent.
Alternatively the groups receive a single oral administration of
either vehicle alone or vehicle containing either the SGLT2
inhibitor or the DPPIV inhibitor plus the third antidiabetic agent
or the third antidiabetic agent or the combination of the SGLT2
inhibitor plus the DPP IV inhibitor plus the third antidiabetic
agent. Alternatively, the test can also be performed after multiple
administrations of the respective drugs to account for
anti-diabetic effects that need longer to become evident like in
the case of thiazolidindiones. The animals receive an oral glucose
load (2 g/kg) 30 min after compound administration. Blood glucose
is measured in tail blood 30 min, 60 min, 90 min, and 120 min after
the glucose challenge. Glucose excursion is quantified by
calculating the glucose AUC. The data are presented as
mean.+-.S.E.M. Statistical comparisons are conducted by Student's t
test.
Example 3
Treatment of Pre-Diabetes
[0346] The efficacy of a pharmaceutical composition according to
the invention in the treatment of pre-diabetes characterised by
pathological fasting glucose and/or impaired glucose tolerance can
be tested using clinical studies. In studies over a shorter period
(e.g. 2-4 weeks) the success of the treatment is examined by
determining the fasting glucose values and/or the glucose values
after a meal or after a loading test (oral glucose tolerance test
or food tolerance test after a defined meal) after the end of the
period of therapy for the study and comparing them with the values
before the start of the study and/or with those of a placebo group.
In addition, the fructosamine value can be determined before and
after therapy and compared with the initial value and/or the
placebo value. A significant drop in the fasting or non-fasting
glucose levels demonstrates the efficacy of the treatment. In
studies over a longer period (12 weeks or more) the success of the
treatment is tested by determining the HbA1c value, by comparison
with the initial value and/or with the value of the placebo group.
A significant change in the HbA1c value compared with the initial
value and/or the placebo value demonstrates the efficacy of the
combination according to the invention for treating
pre-diabetes.
Example 4
Preventing Manifest Type 2 Diabetes
[0347] Treating patients with pathological fasting glucose and/or
impaired glucose tolerance (pre-diabetes) is also in pursuit of the
goal of preventing the transition to manifest type 2 diabetes. The
efficacy of a treatment can be investigated in a comparative
clinical study in which pre-diabetes patients are treated over a
lengthy period (e.g. 1-5 years) with either a pharmaceutical
composition according to this invention or with placebo or with a
non-drug therapy or other medicaments. During and at the end of the
therapy, by determining the fasting glucose and/or a loading test
(e.g. oGTT), a check is made to determine how many patients exhibit
manifest type 2 diabetes, i.e. a fasting glucose level of >125
mg/dl and/or a 2 h value according to oGTT of >199 mg/dl. A
significant reduction in the number of patients who exhibit
manifest type 2 diabetes when treated with a combination according
to this invention as compared to one of the other forms of
treatment, demonstrates the efficacy in preventing a transition
from pre-diabetes to manifest diabetes.
Example 5
Treatment of Type 2 Diabetes
[0348] Treating patients with type 2 diabetes with the
pharmaceutical composition according to the invention, in addition
to producing an acute improvement in the glucose metabolic
situation, prevents a deterioration in the metabolic situation in
the long term. This can be observed is patients are treated for a
longer period, e.g. 3 months to 1 year or even 1 to 6 years, with
the pharmaceutical composition according to the invention and are
compared with patients who have been treated with other
antidiabetic medicaments. There is evidence of therapeutic success
compared with patients treated with other antidiabetic medicaments
if no or only a slight increase in the fasting glucose and/or HbA1c
value is observed. Further evidence of therapeutic success is
obtained if a significantly smaller percentage of the patients
treated with a pharmaceutical composition according to the
invention, compared with patients who have been treated with other
medicaments, undergo a deterioration in the glucose metabolic
position (e.g. an increase in the HbA1c value to >6.5% or
>7%) to the point where treatment with an additional oral
antidiabetic medicament or with insulin or with an insulin analogue
is indicated.
Example 6
Treatment of Insulin Resistance
[0349] In clinical studies running for different lengths of time
(e.g. 2 weeks to 12 months) the success of the treatment is checked
using a hyperinsulinaemic euglycaemic glucose clamp study. A
significant rise in the glucose infusion rate at the end of the
study, compared with the initial value or compared with a placebo
group, or a group given a different therapy, proves the efficacy of
a pharmaceutical composition according to the invention in the
treatment of insulin resistance.
Example 7
Treatment of Hyperglycaemia
[0350] In clinical studies running for different lengths of time
(e.g. 1 day to 24 months) the success of the treatment in patients
with hyperglycaemia is checked by determining the fasting glucose
or non-fasting glucose (e.g. after a meal or a loading test with
oGTT or a defined meal). A significant fall in these glucose values
during or at the end of the study, compared with the initial value
or compared with a placebo group, or a group given a different
therapy, proves the efficacy of a pharmaceutical composition
according to the invention in the treatment of hyperglycaemia.
Example 8
Prevention of Micro- or Macrovascular Complications
[0351] The treatment of type 2 diabetes or pre-diabetes patients
with a pharmaceutical composition according to the invention
prevents or reduces or reduces the risk of developing microvascular
complications (e.g. diabetic neuropathy, diabetic retinopathy,
diabetic nephropathy, diabetic foot, diabetic ulcer) or
macrovascular complications (e.g. myocardial infarct, acute
coronary syndrome, unstable angina pectoris, stable angina
pectoris, stroke, peripheral arterial occlusive disease,
cardiomyopathy, heart failure, heart rhythm disorders, vascular
restenosis). Type 2 diabetes or patients with pre-diabetes are
treated long-term, e.g. for 1-6 years, with a pharmaceutical
composition according to the invention or a combination of active
ingredients according to the invention and compared with patients
who have been treated with other antidiabetic medicaments or with
placebo. Evidence of the therapeutic success compared with patients
who have been treated with other antidiabetic medicaments or with
placebo can be found in the smaller number of single or multiple
complications. In the case of macrovascular events, diabetic foot
and/or diabetic ulcer, the numbers are counted by anamnesis and
various test methods. In the case of diabetic retinopathy the
success of the treatment is determined by computer-controlled
illumination and evaluation of the background to the eye or other
ophthalmic methods. In the case of diabetic neuropathy, in addition
to anamnesis and clinical examination, the nerve conduction rate
can be measured using a calibrated tuning fork, for example. With
regard to diabetic nephropathy the following parameters may be
investigated before the start, during and at the end of the study:
secretion of albumin, creatinine clearance, serum creatinin values,
time taken for the serum creatinine values to double, time taken
until dialysis becomes necessary.
Example 9
Treatment of Metabolic Syndrome
[0352] The efficacy of a pharmaceutical composition according to
the invention can be tested in clinical studies with varying run
times (e.g. 12 weeks to 6 years) by determining the fasting glucose
or non-fasting glucose (e.g. after a meal or a loading test with
oGTT or a defined meal) or the HbA1c value. A significant fall in
these glucose values or HbA1c values during or at the end of the
study, compared with the initial value or compared with a placebo
group, or a group given a different therapy, proves the efficacy of
an active ingredient or combination of active ingredients in the
treatment of Metabolic Syndrome. Examples of this are a reduction
in systolic and/or diastolic blood pressure, a lowering of the
plasma triglycerides, a reduction in total or LDL cholesterol, an
increase in HDL cholesterol or a reduction in weight, either
compared with the starting value at the beginning of the study or
in comparison with a group of patients treated with placebo or a
different therapy.
Example 10a
Prevention of NODAT and/or PTMS, and NODAT/PTMS Associated
Complications
[0353] Treatment of patients after organ transplantation with the
pharmaceutical composition according to the invention prevents the
development of NODAT and/or PTMS, and associated complications. The
efficacy of the treatment can be investigated in a comparative
clinical study in which patients before or immediately after
transplantation are treated over a lengthy period (e.g. 1-5 years)
with either a pharmaceutical composition according to this
intervention or with a placebo or with a non-drug therapy or other
medicaments. During and at the end of the therapy, the incidence of
NODAT, PTMS, micro- and macrovascular complications, graft
rejection, infection and death will be assessed. A significant
reduction in the number of patients experiencing these
complications demonstrates the efficacy in preventing development
of NODAT, PTMS, and associated complications.
Example 10b
Treatment of NODAT and/or PTMS with Prevention, Delay or Reduction
of Associated Complications
[0354] Treatment of patients with NODAT and/or PTMS with the
pharmaceutical composition according to the invention prevents,
delays or reduces the development of NODAT/PTMS associated
complications. The efficacy of the treatment can be investigated in
a comparative clinical study in which patients with NODAT and/or
PTMS are treated over a lengthy period (e.g. 1-5 years) with either
a pharmaceutical composition according to this intervention or with
a placebo or with a non-drug therapy or other medicaments. During
and at the end of the therapy, the incidence of micro- and
macrovascular complications, graft rejection, infection and death
will be assessed. A significant reduction in the number of patients
experiencing these complications demonstrates the efficacy in
preventing, delaying or reducing the development of NODAT and/or
PTMS associated complications.
Example 11a
Treatment of Gestational Diabetes
[0355] In clinical studies running for a shorter period (e.g. 2-4
weeks) the success of the treatment is checked by determining the
fasting glucose values and/or the glucose values after a meal or
after a loading test (oral glucose tolerance test or food tolerance
test after a defined meal) at the end of the therapeutic period of
the study and comparing them with the values before the start of
the study and/or with those of a placebo group. In addition, the
fructosamine value can be determined before and after treatment and
compared with the initial value and/or a placebo value. A
significant fall in the fasting or non-fasting glucose levels
demonstrates the pharmaceutical composition according to the
invention.
[0356] In longer-running studies (12 weeks or more) the success of
the treatment is checked by determining the HbA1c value (compared
with initial value and placebo group). A significant change in the
HbA1c value compared with the starting value and/or placebo value
demonstrates the efficacy of the pharmaceutical composition
according to the invention in the treatment of gestational
diabetes.
Example 11b
Treatment of Women who have had Gestational Diabetes
[0357] Patients with gestational diabetes have a significantly
increased risk of contracting manifest type 2 diabetes after the
pregnancy. Therapy may be provided with the objective of preventing
the transition to manifest type 2. For this purpose, women with a
history of gestational diabetes are treated either with a
pharmaceutical composition according to the invention or with
placebo or with a non-drug therapy or with other medicaments, over
a lengthy period (e.g. 1-4 years). During and at the end of the
treatment a check is carried out by determining the fasting glucose
and/or by a loading test (e.g. oGTT) to see how many patients have
developed manifest type 2 diabetes (fasting glucose level>125
mg/dl and/or 2 h value after oGTT>199 mg/dl). A significant
reduction in the number of patients who develop manifest type 2
diabetes when treated with a pharmaceutical composition according
to the invention compared with a different type of therapy, is
proof of the efficacy of a pharmaceutical composition in preventing
manifest diabetes in women with a history of gestational
diabetes.
Example 12
Treatment of Hyperuricemia
[0358] Patients with elevated levels of uric acid above the normal
range (above 8.3 mg/dL or 494 .mu.mol/L) or patients with a history
of gout or gouty arthritis with a uric acid level greater than 6.0
mg/dL or 357 .mu.mol/L have a significant risk of future episodes
of gout or gouty arthritis as well as having an increased risk of
cardiovascular disease. Therapy may be provided with the objective
of lowering serum levels of uric acid as a means of preventing
future episodes or flare-ups of gout or gouty arthritis.
Additionally, lowering serum uric acid levels may reduce the risk
of cardiovascular disease. For this purpose patients with an
elevated uric acid level or a history of gout or gouty arthritis
are treated either with a pharmaceutical composition according to
the invention or with placebo or with a non-drug therapy or with
other medicaments, over a lengthy period (e.g. 6 months to 4
years). During and at the end of the treatment a check is carried
out by determining the serum uric acid level and the number of
episodes of gout or gouty arthritis occurences. A reduction in uric
acid below 6.0 mg/dL and/or fewer episodes of gout or gouty
arthritis occurrence when treated with a pharmaceutical composition
according to the invention compared with a different type of
therapy, is proof of the efficacy of a pharmaceutical composition
in preventing episodic gout or gouty arthritis or treating
hyperuricemia.
Example 13
Treatment of Hyponatremia
[0359] Patients with hyponatremia and water intoxication whether
due to an increase in water resorption or an increase in water
intake, are at risk of central nervous system abnormalities and
possibly death. Therapy may be provided with the objective of
increasing the amount of free water to be excreted in the renal
filtrate without disturbing sodium balance with the objective of
increasing the overall sodium concentration of the interstitial
fluids. For this purpose, patients with a history of hyponatremia
are treated either with a pharmaceutical composition according to
the invention or with placebo or with a non-drug therapy or with
other medicaments, over a short period (e.g. 3 to 6 months), with
periodic assessment of serum sodium levels. An increase in sodium
levels into the normal range reported during this time period when
treated with a pharmaceutical composition according to the
invention compared with a different type of therapy, is proof of
the efficacy of a pharmaceutical composition in treating
hyponatremia.
Example 14
Treatment/Prevention of Kidney Stones
[0360] Patients with a history of kidney stones, particularly
calcium, mixed calcium, and uric acid stones frequently have a
history of hyperuricemia. These renal stones may relate to small
urate crystals forming a nidus in the renal filtrate upon which
further crystallization of urate or other crystallizing substances
in the solute can induce renal stone formation. These stones are
not related to renal stones caused by certain kidney infections
(such as staghorn-type stones). Therapy may be provided with the
objective of increasing the neutral solutes (for example glucose)
and free water content of the renal filtrate, making it difficult
for a urate nidus to form, despite a possible increase in the
absolute amounts of urate in the renal filtrate. These neutral
solutes and free water will also reduce the formation of stones
other than uric acid stones. For this purpose patients with a
history of kidney stones particularly calcium, mixed calcium, and
uric acid stones are treated either with a pharmaceutical
composition according to the invention or with placebo or with a
non-drug therapy or with other medicaments, over a lengthy period
(e.g. 6 months to 4 years). A reduction in the number of kidney
stones stones particularly calcium, mixed calcium, and uric acid
stones reported during this time period when treated with a
pharmaceutical composition according to the invention compared with
a different type of therapy, is proof of the efficacy of a
pharmaceutical composition in preventing kidney stones particularly
calcium, mixed calcium, and uric acid stones.
EXAMPLES OF FORMULATIONS
[0361] The following examples of formulations, which may be
obtained analogously to methods known in the art, serve to
illustrate the present invention more fully without restricting it
to the contents of these examples. The term "active ingredient"
denotes one or more compounds according to the invention, i.e.
denotes an SGLT2 inhibitor, DPP IV inhibitor or a third
antidiabetic compound according to this invention or a combination
of two or three of said active ingredients, for example selected
from the combinations as listed in the Table 1 or 2. Additional
suitable formulations for the DPP IV inhibitor linagliptin may be
those formulations disclosed in the application WO 2007/128724, the
disclosure of which is incorporated herein in its entirety.
Additional suitable formulations for the other DPP IV inhibitors
may be those formulations which are available on the market, or
formulations described in the patent applications cited above in
paragraph "background of the invention", or those described in the
literature, for example as disclosed in current issues of "Rote
Liste.RTM." (Germany) or of "Physician's Desk Reference".
Example 1
Dry Ampoule Containing 75 mg of Active Ingredient Per 10 ml
TABLE-US-00005 [0362] Composition: Active ingredient 75.0 mg
Mannitol 50.0 mg water for injections ad 10.0 ml
Preparation:
[0363] Active ingredient and mannitol are dissolved in water. After
packaging the solution is freeze-dried. To produce the solution
ready for use, the product is dissolved in water for
injections.
Example 2
Dry Ampoule Containing 35 mg of Active Ingredient Per 2 ml
TABLE-US-00006 [0364] Composition: Active ingredient 35.0 mg
Mannitol 100.0 mg water for injections ad 2.0 ml
Preparation:
[0365] Active ingredient and mannitol are dissolved in water. After
packaging, the solution is freeze-dried. To produce the solution
ready for use, the product is dissolved in water for
injections.
Example 3
Tablet Containing 50 mg of Active Ingredient
TABLE-US-00007 [0366] Composition: (1) Active ingredient 50.0 mg
(2) Mannitol 98.0 mg (3) Maize starch 50.0 mg (4)
Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate 2.0 mg 215.0
mg
Preparation:
[0367] (1), (2) and (3) are mixed together and granulated with an
aqueous solution of (4). (5) is added to the dried granulated
material. From this mixture tablets are pressed, biplanar, faceted
on both sides and with a dividing notch on one side.
[0368] Diameter of the tablets: 9 mm.
Example 4
Tablet Containing 350 mg of Active Ingredient
TABLE-US-00008 [0369] Preparation: (1) Active ingredient 350.0 mg
(2) Mannitol 136.0 mg (3) Maize starch 80.0 mg (4)
Polyvinylpyrrolidone 30.0 mg (5) Magnesium stearate 4.0 mg 600.0
mg
[0370] (1), (2) and (3) are mixed together and granulated with an
aqueous solution of (4). (5) is added to the dried granulated
material. From this mixture tablets are pressed, biplanar, faceted
on both sides and with a dividing notch on one side.
[0371] Diameter of the tablets: 12 mm.
Example 5
Tablet Containing 850 mg of Active Ingredient
TABLE-US-00009 [0372] Preparation: (1) Active ingredient 850.0 mg
(2) Mannitol 300.0 mg (3) Maize starch 200.0 mg (4)
Polyvinylpyrrolidone 70.0 mg (5) Magnesium stearate 10.0 mg 1430.0
mg
[0373] (1), (2) and (3) are mixed together and granulated with an
aqueous solution of (4). (5) is added to the dried granulated
material. From this mixture tablets are pressed, biplanar, faceted
on both sides and with a dividing notch on one side.
[0374] Diameter of the tablets: 12 mm.
Example 6
Capsules Containing 50 mg of Active Ingredient
TABLE-US-00010 [0375] Composition: (1) Active ingredient 50.0 mg
(2) Dried maize starch 58.0 mg (3) Mannitol 50.0 mg (4) Magnesium
stearate 2.0 mg 160.0 mg
Preparation:
[0376] (1) is triturated with (3). This trituration is added to the
mixture of (2) and (4) with vigorous mixing. This powder mixture is
packed into size 3 hard gelatin capsules in a capsule filling
machine.
Example 7
Capsules Containing 350 mg of Active Ingredient
TABLE-US-00011 [0377] Composition: (1) Active ingredient 350.0 mg
(2) Dried maize starch 46.0 mg (3) Mannitol 30.0 mg (4) Magnesium
stearate 4.0 mg 430.0 mg
[0378] Preparation:
[0379] (1) is triturated with (3). This trituration is added to the
mixture of (2) and (4) with vigorous mixing. This powder mixture is
packed into size 0 hard gelatin capsules in a capsule filling
machine.
* * * * *