U.S. patent application number 16/446086 was filed with the patent office on 2020-03-05 for pharmaceutical composition, methods for treating and uses thereof.
The applicant listed for this patent is Boehringer Ingelheim International GmbH. Invention is credited to Uli Christian BROEDL, Peter EICKELMANN, Rolf GREMPLER, Michael MARK, Leo John SEMAN, Leo THOMAS.
Application Number | 20200069713 16/446086 |
Document ID | / |
Family ID | 42008536 |
Filed Date | 2020-03-05 |
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United States Patent
Application |
20200069713 |
Kind Code |
A1 |
EICKELMANN; Peter ; et
al. |
March 5, 2020 |
PHARMACEUTICAL COMPOSITION, METHODS FOR TREATING AND USES
THEREOF
Abstract
The invention relates to the treatment or prevention of one or
more conditions selected from type 1 diabetes mellitus, type 2
diabetes mellitus, impaired glucose tolerance and hyperglycemia
using a SGLT-2 inhibitor. 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 an
der Riss, DE) ; SEMAN; Leo John; (Cheshire, CT)
; THOMAS; Leo; (Biberach an der Riss, DE) ;
BROEDL; Uli Christian; (Oakville, CA) ; GREMPLER;
Rolf; (Mittelbiberach, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Boehringer Ingelheim International GmbH |
Ingelheim am Rhein |
|
DE |
|
|
Family ID: |
42008536 |
Appl. No.: |
16/446086 |
Filed: |
June 19, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15286017 |
Oct 5, 2016 |
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16446086 |
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15046653 |
Feb 18, 2016 |
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15286017 |
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14046109 |
Oct 4, 2013 |
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15046653 |
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13439324 |
Apr 4, 2012 |
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14046109 |
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12704062 |
Feb 11, 2010 |
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13439324 |
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61152318 |
Feb 13, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2018 20130101;
A61P 1/18 20180101; A61P 43/00 20180101; A61K 31/7034 20130101;
A61K 31/7048 20130101; A61P 3/00 20180101; A61P 37/06 20180101;
A61P 19/06 20180101; A61P 9/00 20180101; A61P 9/06 20180101; A61P
9/08 20180101; A61P 3/10 20180101; A61K 9/2027 20130101; A61K
9/4866 20130101; A61K 47/26 20130101; A61P 3/08 20180101; A61P
13/12 20180101; A61P 9/10 20180101; A61K 9/0019 20130101; A61P
11/00 20180101; A61P 9/04 20180101; A61P 25/00 20180101; A61P 3/04
20180101; A61P 27/12 20180101; A61P 27/02 20180101; A61P 5/50
20180101; A61P 3/06 20180101 |
International
Class: |
A61K 31/7034 20060101
A61K031/7034; A61K 31/7048 20060101 A61K031/7048 |
Claims
1. 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 a pharmaceutical composition comprising an SGLT2 inhibitor is
administered to the patient, wherein the SGLT2 inhibitor is a
glucopyranosyl-substituted benzene derivative of the formula (I)
##STR00005## wherein R.sup.1 denotes Cl, 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.
2. Method according to claim 1 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 100 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 8.0%; 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.
3. Method according to claim 1, wherein the SGLT2 inhibitor is
selected from the group consisting of the group of compounds (I.1)
to (I.11): (I.1)
6-(4-ethylbenzyl)-4-(.beta.-D-glucopyranos-1-yl)-2-methoxy-benzonit-
rile, (I.2)
2-(4-ethylbenzyl)-4-(.beta.-D-glucopyranos-1-yl)-5-methoxy-benzonitrile,
(I.3)
1-cyano-2-(4-ethylbenzyl)-4-(.beta.-D-glucopyranos-1-yl)-5-methyl-b-
enzene, (I.4)
2-(4-ethylbenzyl)-4-(.beta.-D-glucopyranos-1-yl)-5-hydroxy-benzonitrile,
(I.5)
2-(4-ethyl-benzyl)-4-(.beta.-D-glucopyranos-1-yl)-benzonitrile,
(I.6)
2-(4-cyclopropyl-benzyl)-4-(.beta.-D-glucopyranos-1-yl)-benzonitril-
e, (I.7)
1-chloro-4-(.beta.-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benz-
ene, (I.8)
1-chloro-4-(.beta.-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofur-
an-3-yloxy)-benzyl]-benzene, (I.9)
1-chloro-4-(.beta.-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy-
)-benzyl]-benzene, (I.10)
1-methyl-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-4-(.beta.-D-glucopyra-
nos-1-yl)-benzene, and (I.11)
1-methyl-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-4-(.beta.-D-glucopyra-
nos-1-yl)-benzene.
4. Method according to claim 1 wherein the pharmaceutical
composition additionally comprises one or more pharmaceutically
acceptable carriers.
5. 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 a pharmaceutical composition comprising an
SGLT2 is administered to the patient, wherein the SGLT2 inhibitor
is a glucopyranosyl-substituted benzene derivative of the formula
(I) ##STR00006## wherein R.sup.1 denotes Cl, 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.
6. Method according to claim 5 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 100 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 8.0%; 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.
7. Method according to claim 5, wherein the SGLT2 inhibitor is
selected from the group consisting of the group of compounds (I.1)
to (I.11): (I.1)
6-(4-ethylbenzyl)-4-(.beta.-D-glucopyranos-1-yl)-2-methoxy-benzonit-
rile, (I.2)
2-(4-ethylbenzyl)-4-(.beta.-D-glucopyranos-1-yl)-5-methoxy-benzonitrile,
(I.3)
1-cyano-2-(4-ethylbenzyl)-4-(.beta.-D-glucopyranos-1-yl)-5-methyl-b-
enzene, (I.4)
2-(4-ethylbenzyl)-4-(.beta.-D-glucopyranos-1-yl)-5-hydroxy-benzonitrile,
(1.5)
2-(4-ethyl-benzyl)-4-(.beta.-D-glucopyranos-1-yl)-benzonitrile,
(I.6)
2-(4-cyclopropyl-benzyl)-4-(.beta.-D-glucopyranos-1-yl)-benzonitril-
e, (I.7)
1-chloro-4-(.beta.-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benz-
ene, (I.8)
1-chloro-4-(.beta.-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofur-
an-3-yloxy)-benzyl]-benzene, (I.9)
1-chloro-4-(.beta.-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy-
)-benzyl]-benzene, (I.10)
1-methyl-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-4-(.beta.-D-glucopyra-
nos-1-yl)-benzene, and (I.11)
1-methyl-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-4-(.beta.-D-glucopyra-
nos-1-yl)-benzene.
8. Method according to claim 5 wherein the pharmaceutical
composition additionally comprises one or more pharmaceutically
acceptable carriers.
9. 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 a pharmaceutical composition comprising an SGLT2 inhibitor is
administered to the patient, wherein the SGLT2 inhibitor is a
glucopyranosyl-substituted benzene derivative of the formula (I)
##STR00007## wherein R.sup.1 denotes Cl, 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.
10. Method according to claim 9 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 100 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 8.0%; 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.
11. Method according to claim 9, wherein the SGLT2 inhibitor is
selected from the group consisting of the group of compounds (I.1)
to (I.11): (I.1)
6-(4-ethylbenzyl)-4-(.beta.-D-glucopyranos-1-yl)-2-methoxy-benzonit-
rile, (I.2)
2-(4-ethylbenzyl)-4-(.beta.-D-glucopyranos-1-yl)-5-methoxy-benzonitrile,
(I.3) 1-cyano-2-(4-ethylbenzyl)-4-(.beta.-D-glucopyranos-1-yl)-5
-methyl-benzene, (I.4)
2-(4-ethylbenzyl)-4-(.beta.-D-glucopyranos-1-yl)-5-hydroxy-benzonitrile,
(I.5)
2-(4-ethyl-benzyl)-4-(.beta.-D-glucopyranos-1-yl)-benzonitrile,
(I.6)
2-(4-cyclopropyl-benzyl)-4-(.beta.-D-glucopyranos-1-yl)-benzonitril-
e, (I.7)
1-chloro-4-(.beta.-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benz-
ene, (I.8)
1-chloro-4-(.beta.-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofur-
an-3-yloxy)-benzyl]-benzene, (I.9)
1-chloro-4-(.beta.-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy-
)-benzyl]-benzene, (I.10)
1-methyl-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-4-(.beta.-D-glucopyra-
nos-1-yl)-benzene, and (I.11)
1-methyl-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-4-(.beta.-D-glucopyra-
nos-1-yl)-benzene.
12. Method according to claim 9 wherein the pharmaceutical
composition additionally comprises one or more pharmaceutically
acceptable carriers.
13. 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 a pharmaceutical
composition comprising an SGLT2 inhibitor is administered to the
patient, wherein the SGLT2 inhibitor is a
glucopyranosyl-substituted benzene derivative of the formula (I)
##STR00008## wherein R.sup.1 denotes Cl, 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.
14. Method according to claim 13 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 100 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 8.0%; 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.
15. Method according to claim 13, wherein the SGLT2 inhibitor is
selected from the group consisting of the group of compounds (I.1)
to (I.11): (I.1)
6-(4-ethylbenzyl)-4-(.beta.-D-glucopyranos-1-yl)-2-methoxy-benzonit-
rile, (I.2)
2-(4-ethylbenzyl)-4-(.beta.-D-glucopyranos-1-yl)-5-methoxy-benzonitrile,
(I.3)
1-cyano-2-(4-ethylbenzyl)-4-(.beta.-D-glucopyranos-1-yl)-5-methyl-b-
enzene, (I.4)
2-(4-ethylbenzyl)-4-(.beta.-D-glucopyranos-1-yl)-5-hydroxy-benzonitrile,
(I.5)
2-(4-ethyl-benzyl)-4-(.beta.-D-glucopyranos-1-yl)-benzonitrile,
(I.6)
2-(4-cyclopropyl-benzyl)-4-(.beta.-D-glucopyranos-1-yl)-benzonitril-
e, (I.7)
1-chloro-4-(.beta.-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benz-
ene, (I.8)
1-chloro-4-(.beta.-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofur-
an-3-yloxy)-benzyl]-benzene, (I.9)
1-chloro-4-(.beta.-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy-
)-benzyl]-benzene, (I.10)
1-methyl-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-4-(.beta.-D-glucopyra-
nos-1-yl)-benzene, and (I.11)
1-methyl-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-4-(.beta.-D-glucopyra-
nos-1-yl)-benzene.
16. Method according to claim 13 wherein the pharmaceutical
composition additionally comprises one or more pharmaceutically
acceptable carriers.
17. 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 a pharmaceutical composition
comprising an SGLT2 inhibitor is administered to the patient,
wherein the SGLT2 inhibitor is a glucopyranosyl-substituted benzene
derivative of the formula (I) ##STR00009## wherein R.sup.1 denotes
Cl, 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.
18. Method according to claim 17 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 100 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 8.0%; 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
>130 mm Hg and a diastolic blood pressure .gtoreq.85 mm Hg, (e)
a fasting blood glucose level .gtoreq.100 mg/dL.
19. Method according to claim 17, wherein the SGLT2 inhibitor is
selected from the group consisting of the group of compounds (I.1)
to (I.11): (I.1)
6-(4-ethylbenzyl)-4-(.beta.-D-glucopyranos-1-yl)-2-methoxy-benzonit-
rile, (I.2)
2-(4-ethylbenzyl)-4-(.beta.D-glucopyranos-1-yl)-5-methoxy-benzonitrile,
(I.3) 1-cyano-2-(4-ethylbenzyl)-4-(.beta.D-glucopyranos- 1-yl)-5
-methyl-benzene, (I.4)
2-(4-ethylbenzyl)-4-(.beta.D-glucopyranos-1-yl)-5-hydroxy-benzonitrile,
(I.5)
2-(4-ethyl-benzyl)-4-(.beta.D-glucopyranos-1-yl)-benzonitrile,
(I.6)
2-(4-cyclopropyl-benzyl)-4-(.beta.-D-glucopyranos-1-yl)-benzonitril-
e, (I.7)
1-chloro-4-(.beta.-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benz-
ene, (I.8) 1-chloro-4-(.beta.-D-glucopyranos-1-yl)-2-
[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, (I.9)
1-chloro-4-(.beta.-D-glucopyranos-1-yl)-2-
[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, (I.10)
1-methyl-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-4-(.beta.-D-glucopyra-
nos-1-yl)-benzene, and (I.11)
1-methyl-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-4-(.beta.-D-glucopyra-
nos-1-yl)-benzene.
20. Method according to claim 17 wherein the pharmaceutical
composition additionally comprises one or more pharmaceutically
acceptable carriers.
21.-36. (canceled)
Description
[0001] This application is a Continuation of U.S. patent
application Ser. No. 15/286,017 filed on Oct. 5, 2016, which is a
Continuation of U.S. patent application Ser. No. 15/046,653 filed
on Feb. 18, 2016, which is a Continuation of U.S. patent
application Ser. No. 14/046,109 filed on Oct. 4, 2013, which is a
Continuation of U.S. patent application Ser. No. 13/439,324 filed
on Apr. 4, 2012, which is a Continuation of U.S. patent application
Ser. No. 12/704,062 filed on Feb. 11, 2010, which claims benefit
from U.S. Provisional Application No. 61/152,318, filed on Feb. 13,
2009, the content of which are incorporated herein in their
entireties.
TECHNICAL FIELD OF THE INVENTION
[0002] The invention relates to a pharmaceutical composition
comprising an SGLT2-inhibitor 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 a
pharmaceutical composition comprising an SGLT2 inhibitor as defined
hereinafter is administered.
[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] 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
[0019] 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.
[0020] 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.
[0021] 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.
[0022] Oral antidiabetic drugs conventionally used in therapy (such
as e.g. first- or second-line, and/or mono- or (initial or add-on)
combination therapy) include, without being restricted thereto,
metformin, sulphonylureas, thiazolidinediones, glinides and
a-glucosidase inhibitors.
[0023] 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.
[0024] 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.
[0025] 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.
[0026] 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.
Aim of the Present Invention
[0027] 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.
[0028] 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.
[0029] 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.
[0030] 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.
[0031] 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.
[0032] 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.
[0033] Another aim of the present invention is to provide a
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.
[0034] 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
[0035] Within the scope of the present invention it has now
surprisingly been found that a pharmaceutical composition
comprising a SGLT2 inhibitor 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.
[0036] Therefore, in a first aspect the present invention provides
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 as defined
hereinbefore and hereinafter is administered to the patient.
[0037] 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 as defined
hereinbefore and hereinafter is administered to the patient.
[0038] 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.
[0039] 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 as defined hereinbefore
and hereinafter is administered to the patient.
[0040] 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.
[0041] 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 as
defined hereinbefore and hereinafter is administered 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.
[0042] 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 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.
[0043] 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 as
defined hereinbefore and hereinafter is administered to the
patient.
[0044] 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.
[0045] 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 as
defined hereinbefore and hereinafter is administered to the
patient.
[0046] By the administration of a 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 liver fat, in a
patient in need thereof characterized in that an SGLT2 inhibitor as
defined hereinbefore and hereinafter is administered 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.
[0047] 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 as defined hereinbefore
and hereinafter is administered to the patient.
[0048] 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).
[0049] 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.
[0050] 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. The
patient may be a diabetic or non-diabetic patient.
[0051] 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.
[0052] According to a further aspect of the invention, there is
provided a method for treating hyponatremia, water retention and
water intoxication. 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.
[0053] According to another aspect of the invention there is
provided the use of an SGLT2 inhibitor for the manufacture of a
medicament for [0054] 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 [0055]
improving glycemic control and/or for reducing of fasting plasma
glucose, of postprandial plasma glucose and/or of glycosylated
hemoglobin HbA1c; or [0056] 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 [0057]
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,; or [0058] 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 [0059] 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
[0060] preventing, slowing, delaying or treating diseases or
conditions attributed to an abnormal accumulation of ectopic fat;
or [0061] maintaining and/or improving the insulin sensitivity
and/or for treating or preventing hyperinsulinemia and/or insulin
resistance; [0062] preventing, slowing progression of, delaying, or
treating new onset diabetes after transplantation (NODAT) and/or
post-transplant metabolic syndrome (PTMS); [0063] preventing,
delaying, or reducing NODAT and/or PTMS associated complications
including micro- and macrovascular diseases and events, graft
rejection, infection, and death; [0064] treating hyperuricemia and
hyperuricemia associated conditions; [0065] treating or prevention
kidney stones; [0066] treating hyponatremia; in a patient in need
thereof characterized in that the SGLT2 inhibitor is administered,
as defined hereinbefore and hereinafter.
[0067] 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.
[0068] Definitions
[0069] The term "active ingredient" of a pharmaceutical composition
according to the present invention means the SGLT2 inhibitor
according to the present invention. An "active ingredient is also
sometimes referred to herein as an "active substance".
[0070] 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.
[0071] 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.
[0072] 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.
[0073] 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.
[0074] 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 85 cm in men and 90 cm in women (see
e.g. investigating committee for the diagnosis of metabolic
syndrome in Japan).
[0075] 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.
[0076] 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.
[0077] 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).
[0078] 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).
[0079] 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.
[0080] 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).
[0081] 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).
[0082] The terms "insulin-sensitizing", "insulin
resistance-improving" or "insulin resistance-lowering" are
synonymous and used interchangeably.
[0083] 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 E
S, et al. JAMA. (2002) 287:356-9). A method of determining insulin
resistance is the euglycaemic-hyperinsulinaemic clamp test. The
ratio of insulin to glucose is determined within the scope of a
combined insulin-glucose infusion technique. There is found to be
insulin resistance if the glucose absorption is below the 25th
percentile of the background population investigated (WHO
definition). 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.
[0084] 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):
[0085] HOMA-IR=[fasting serum insulin (.mu.U/mL)].times.[fasting
plasma glucose(mmol/L)/22.5]
[0086] 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.
[0087] 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.
[0088] 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(SuppL1): 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).
[0089] 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).
[0090] 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.
[0091] 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.
[0092] 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).
[0093] 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.
[0094] 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%.
[0095] 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: [0096] 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 85 cm in men and .gtoreq.90
cm in women; [0097] 2. Triglycerides: .gtoreq.150 mg/dL [0098] 3.
HDL-cholesterol <40 mg/dL in men [0099] 4. Blood pressure
.gtoreq.130/85 mm Hg (SBP.gtoreq.130 or DBP.gtoreq.85) [0100] 5.
Fasting blood glucose.gtoreq.100 mg/dL
[0101] 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.
[0102] 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.
[0103] 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.
[0104] 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.
[0105] 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.
[0106] 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
kown 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.
[0107] 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.
[0108] The term "SGLT2 inhibitor" in the scope of the present
invention relates to compounds, in particular to
glucopyranosyl-derivatives, i.e. compounds having a
glucopyranosyl-moiety, which show an inhibitory effect on the
sodium-glucose transporter 2 (SGLT2), in particular the human
SGLT2. The inhibitory effect on hSGLT2 measured as 1050 is prerably
below 1000 nM, even more preferably below 100 nM, most preferably
below 50 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.
[0109] 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.
[0110] 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.
[0111] The term "tablet" comprises tablets without a coating and
tablets with one or more coatings. Furthermore the "term" tablet
comprises tablets having one, two, three or even more layers and
press-coated tablets, wherein each of the beforementioned types of
tablets may be without or with one or more coatings. The term
"tablet" also comprises mini, melt, chewable, effervescent and
orally disintegrating tablets.
[0112] The terms "pharmacopoe" and "pharmacopoeias" refer to
standard pharmacopoeias such as the "USP 31-NF 26 through Second
Supplement" (United States Pharmacopeial Convention) or the
"European Pharmacopoeia 6.3" (European Directorate for the Quality
of Medicines and Health Care, 2000-2009).
BRIEF DESCRIPTION OF THE FIGURES
[0113] FIG. 1 shows an X-ray powder diffractogram of the
crystalline form (I.9X) of the compound (1.9).
[0114] FIG. 2 shows the thermoanalysis and determination of the
melting point via DSC of the crystalline form (I9.X) of the
compound (1.9).
[0115] FIGS. 3A and 3B show the blood glucose level and blood
glucose AUC results of the administration of a compound of the
invention to ZDF rats.
[0116] FIG. 4A shows the results of the body weight analysis in the
administration of a compound of the invention to Wistar rats.
[0117] FIG. 4B shows the results of the body fat content analysis
in the administration of a compound of the invention to Wistar
rats.
DETAILED DESCRIPTION
[0118] The aspects according to the present invention, in
particular the pharmaceutical compositions, methods and uses, refer
to SGLT2 inhibitors as defined hereinbefore and hereinafter.
[0119] Preferably the SGLT2 inhibitor is selected from a
glucopyranosyl-substituted benzene derivative of the formula
(I)
##STR00001##
wherein R.sup.1 denotes Cl, 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.
[0120] 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.
[0121] In the above glucopyranosyl-substituted benzene derivatives
of the formula (I) the following definitions of the substituents
are preferred.
[0122] Preferably R.sup.1 denotes chloro or cyano; in particular
chloro.
[0123] Preferably R.sup.2 denotes H.
[0124] 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.
[0125] Preferred glucopyranosyl-substituted benzene derivatives of
the formula (I) are selected from the group of compounds (I.1) to
(I.11):
##STR00002## ##STR00003## ##STR00004##
[0126] 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). Even more preferred
glucopyranosyl-substituted benzene derivatives of the formula (I)
are selected from the compounds (I.8) and (I.9).
[0127] 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 applciation 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 applciation 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.
[0128] 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.
[0129] A preferred crystalline form (I.9X) of the compound (I.9)
can be characterized by an X-ray powder diffraction pattern that
comprises peaks at 18.84, 20.36 and 25.21 degrees 20 (.+-.0.1
degrees 2.THETA.), wherein said X-ray powder diffraction pattern
(XRPD) is made using CuK.sub..alpha.1 radiation.
[0130] In particular said X-ray powder diffraction pattern
comprises peaks at 14.69, 18.84, 19.16, 19.50, 20.36 and 25.21
degrees 2.THETA. (.+-.0.1 degrees 2.THETA.), wherein said X-ray
powder diffraction pattern is made using CuK.sub..alpha.1
radiation.
[0131] In particular said X-ray powder diffraction pattern
comprises peaks at 14.69, 17.95, 18.43, 18.84, 19.16, 19.50, 20.36,
22.71, 23.44, 24.81, 25.21 and 25.65 degrees 2.THETA. (.+-.0.1
degrees 2.THETA.), wherein said X-ray powder diffraction pattern is
made using CuK.sub..alpha.1 radiation.
[0132] More specifically, the crystalline form (I.9X) is
characterised by an X-ray powder diffraction pattern, made using
CuK.sub..alpha.1 radiation, which comprises peaks at degrees
2.THETA. (.+-.0.1 degrees 2.THETA.) as contained in Table 1.
TABLE-US-00001 TABLE 1 X-ray powder diffraction pattern of the
crystalline form (I.9X) (only peaks up to 30.degree. in 2.THETA.
are listed): 2.THETA. d-value Intensity I/I.sub.0 [.degree.]
[.ANG.] [%] 4.46 19.80 8 9.83 8.99 4 11.68 7.57 4 13.35 6.63 14
14.69 6.03 42 15.73 5.63 16 16.20 5.47 8 17.95 4.94 30 18.31 4.84
22 18.43 4.81 23 18.84 4.71 100 19.16 4.63 42 19.50 4.55 31 20.36
4.36 74 20.55 4.32 13 21.18 4.19 11 21.46 4.14 13 22.09 4.02 19
22.22 4.00 4 22.71 3.91 28 23.44 3.79 27 23.72 3.75 3 24.09 3.69 3
24.33 3.66 7 24.81 3.59 24 25.21 3.53 46 25.65 3.47 23 26.40 3.37 2
26.85 3.32 8 27.26 3.27 17 27.89 3.20 2 28.24 3.16 3 29.01 3.08 4
29.41 3.03 18
[0133] Even more specifically, the crystalline form (I.9X) is
characterised by an X-ray powder diffraction pattern, made using
CuK.sub..alpha.1 radiation, which comprises peaks at degrees
2.THETA. (.+-.0.1 degrees 2.THETA.) as shown in FIG. 1.
[0134] Furthermore the crystalline form (I.9X) is characterised by
a melting point of about 149.degree. C..+-.3.degree. C. (determined
via DSC; evaluated as onset-temperature; heating rate 10 K/min).The
obtained DSC curve is shown in FIG. 2.
[0135] The X-ray powder diffraction patterns are recorded, within
the scope of the present invention, using a STOE--STADI
P-diffractometer in transmission mode fitted with a
location-sensitive detector .quadrature.(OED) and a Cu-anode as
X-ray source (CuK.alpha.1 radiation, .quadrature..lamda.=1,54056
.ANG., 40 kV, 40 mA). In the Table 1 above the values "2.THETA.
[.degree.]" denote the angle of diffraction in degrees and the
values "d [.ANG.]" denote the specified distances in .ANG. between
the lattice planes. The intensity shown in the FIG. 1 is given in
units of cps (counts per second).
[0136] In order to allow for experimental error, the above
described 2.THETA. values should be considered accurate to .+-.0.1
degrees 2.THETA., in particular .+-.0.05 degrees 2.THETA.. That is
to say, when assessing whether a given sample of crystals of the
compound (I.9) is the crystalline form in accordance with the
invention, a 2.THETA. value which is experimentally observed for
the sample should be considered identical with a characteristic
value described above if it falls within .+-.0.1 degrees 2.THETA.
of the characteristic value, in particular if it falls within
.+-.0.05 degrees 2.THETA. of the characteristic value.
[0137] The melting point is determined by DSC (Differential
Scanning calorimetry) using a DSC 821 (Mettler Toledo).
[0138] In one embodiment, a pharmaceutical composition or dosage
form according to the present invention comprises the compound
(I.9), wherein at least 50% by weight of the compound (I.9) is in
the form of its crystalline form (I.9X) as defined hereinbefore.
Preferably in said composition or dosage form at least 80% by
weight, more preferably at least 90% by weight of the compound
(I.9) is in the form of its crystalline form (I.9X) as defined
hereinbefore.
[0139] Regarding the active pharmaceutical ingredients it can be
found that the dissolution properties of the pharmaceutical
composition and dosage form is affected inter alia by the particle
size and particle size distribution of the respective active
pharmaceutical ingredient. In the pharmaceutical composition and
pharmaceutical dosage form according to the invention the active
pharmaceutical ingredients preferably have a particle size
distribution such that at least 90% of the respective active
pharmaceutical ingredient particles, with regard to the
distribution by volume, has a particle size smaller than 200 .mu.m,
i.e. X90<200 .mu.m.
[0140] In particular, with regard to the glucopyranosyl-substituted
benzene derivative of the formula (I), in particular the compound
(I.9) or its crystalline form (I.9X), it was found that the
particle size influence the manufacturability, in particular that
too small particles influence the manufacturability by sticking or
filming. On the other hand too large particles negatively affect
the dissolution properties of the pharmaceutical composition and
dosage form and thus the bioavailability. In the following
preferred ranges of the particle size distribution are
described.
[0141] Therefore, in one aspect, in the pharmaceutical composition
and pharmaceutical dosage form according to the invention the
glucopyranosyl-substituted benzene derivative of the formula (I),
in particular the compound (I.9), preferably its crystalline form
(I9.X), preferably has a particle size distribution (by volume)
such that at least 90% of the respective active pharmaceutical
ingredient has a particle size smaller than 200 .mu.m, i.e.
X90<200 .mu.m, preferably X90 150 .mu.m. More preferably the
particle size distribution is such that X90.ltoreq.100 .mu.m, even
more preferably X90.ltoreq.90 .mu.m. In addition the particle size
distribution is preferably such that X90.gtoreq.1 .mu.m, more
preferably X90.gtoreq.5 .mu.m, even more preferably X90.gtoreq.10
.mu.m. Therefore preferred particle size distributions are such
that 1 .mu.m.ltoreq.X90.ltoreq.200 .mu.m, particularly 1
.mu.m.ltoreq.X90.ltoreq.150 .mu.m, more preferably 5
.mu.m.ltoreq.X90.ltoreq.150 .mu.m, even more preferably 5
.mu.m.ltoreq.X90.ltoreq.100 .mu.m, even more preferably 10
.mu.m.ltoreq.X90.ltoreq.100 .mu.m. A preferred example
X90.ltoreq.75 .mu.m. Another preferred example is 20
.mu.m.ltoreq.X90.ltoreq.50 .mu.m.
[0142] Furthermore in the pharmaceutical composition and
pharmaceutical dosage form according to the invention the
glucopyranosyl-substituted benzene derivative of the formula (I),
in particular the compound (I.9), preferably its crystalline form
(I9.X), preferably has a particle size distribution (by volume)
such that X50.ltoreq.90 .mu.m, more preferably X50.ltoreq.75 .mu.m,
even more preferably X50.ltoreq.50 .mu.m, most preferably
X50.ltoreq.40 .mu.m. In addition the particle size distribution is
preferably such that X50.gtoreq.1 .mu.m, more preferably
X50.gtoreq.5 .mu.m, even more preferably X50.gtoreq.8 .mu.m.
Therefore preferred particle size distributions are such that 1
.mu.m.ltoreq.X50.ltoreq.90 .mu.m, particularly 1
.mu.m.ltoreq.X50.ltoreq.75 .mu.m, more preferably 5
.mu.m.ltoreq.X50.ltoreq.75 .mu.m, even more preferably 5
.mu.m.ltoreq.X50.ltoreq.50 .mu.m. A preferred example is 8
.mu.m.ltoreq.X50.ltoreq.40 .mu.m.
[0143] Furthermore in the pharmaceutical composition and
pharmaceutical dosage form according to the invention the
glucopyranosyl-substituted benzene derivative of the formula (I),
in particular the compound (I.9), preferably its crystalline form
(I9.X), preferably has a particle size distribution (by volume)
such that X10.ltoreq.0.1 .mu.m, more preferably X10.ltoreq.0.5
.mu.m, even more preferably X10.ltoreq.1 .mu.m, in particular
X10.ltoreq.2 .mu.m.
[0144] Therefore a pharmaceutical composition or pharmaceutical
dosage form according to this invention may preferably be
characterized by the above specified particle size distributions
X90, X50 and/or X10 or one of the following embodiments:
TABLE-US-00002 Glucopyranosyl-substituted benzene derivative, in
particular of Embodiment the compound (I.9) 1 X90 < 200 .mu.m 2
1 .mu.m .ltoreq. X90 .ltoreq. 150 .mu.m 3 5 .mu.m .ltoreq. X90
.ltoreq. 150 .mu.m 4 10 .mu.m .ltoreq. X90 .ltoreq. 100 .mu.m 5 X90
.ltoreq.150 .mu.m 1 .mu.m .ltoreq. X50 .ltoreq. 75 .mu.m 6 X90
.ltoreq. 150 .mu.m 5 .mu.m .ltoreq. X50 .ltoreq. 50 .mu.m 7 X90
.ltoreq. 150 .mu.m 1 .mu.m .ltoreq. X50 .ltoreq. 75 .mu.m X10
.gtoreq.0.1 .mu.m 8 X90 .ltoreq.150 .mu.m 5 .mu.m .ltoreq. X50
.ltoreq. 50 .mu.m X10 .gtoreq. 0.5 .mu.m
[0145] The value X90 refers to the 90% value of the volume
distribution measured using a laser diffractometer. In other words,
for the purposes of the present invention, the X90 value denotes
the particle size below which 90% of the quantity of particles is
found based on the volume distribution. Analogously the value X50
refers to the 50% value (median) of the volume distribution
measured using a laser diffractometer. In other words, for the
purposes of the present invention, the X50 value denotes the
particle size below which 50% of the quantity of particles is found
based on the volume distribution. Analogously the value X10 refers
to the 10% value of the volume distribution measured using a laser
diffractometer. In other words, for the purposes of the present
invention, the X10 value denotes the particle size below which 10%
of the quantity of particles is found based on the volume
distribution.
[0146] Preferably all X90, X50, X10 values hereinbefore and
hereinafter are by volume and determined by laser-diffraction
method, in particular low angle laser light scattering, i.e.
Fraunhofer diffraction. A preferred test is described in the
experimental section. The laser diffraction method is sensitive to
the volume of a particle and provides a volume-average particle
size, which is equivalent to the weight-average particle size if
the density is constant. The skilled artesian knows that the
results of the particle size distribution determination by one
technique can be correlated with that from another technique, for
example on an empirical basis by routine experimentation.
Alternatively the particle size distribution in the pharmaceutical
composition or dosage form can be determined by microscopy, in
particular electron microscopy or scanning electron microscopy.
[0147] In the following the suitable excipients and carriers in the
pharmaceutical compositions according to the invention are
described in further detail.
[0148] A pharmaceutical composition according to the invention
typically comprises one or more diluents, one or more disintegrants
and optionally one or more binders. Some of the excipients may have
two or more functions at the same time, e.g. act as a filler and a
binder.
[0149] Suitable diluents according to the invention are for
example, lactose, in particular lactose monohydrate, cellulose and
derivatives, such as powdered cellulose, microcrystalline or
silicified microcrystalline cellulose, cellulose acetate, starches
and derivatives such as pregelatinized starch, corn starch, wheat
starch, rice starch, potato starch, sterilizable maize, sodium
chloride, calcium carbonate, calcium phosphate, particularly
dibasic calcium phosphate, calcium sulphate, dicalcium or
tricalcium phosphate, magnesium carbonate, magnesium oxide, sugars
and derivatives such as confectioner's sugar, fructose, sucrose,
dextrates, dextrin, D-sorbitol sulfobutylether B-cyclodextrin,
dextrose, polydextrose, trehalose, maltose, maltitol, mannitol,
maltodextrin, sorbitol, inulin, xylitol, erythritol, isomalt,
kaolin and lactitol. Preferred diluents are lactose monohydrate and
microcrystalline cellulose.
[0150] Suitable disintegrants according to the invention are for
example powdered cellulose, crospovidone, croscarmellose sodium,
docusate sodium, low-substituted hydroxypropyl cellulose, magnesium
aluminum silicate, microcrystalline cellulose, polacrilin
potassium, sodium starch glycolate, starch, particularly
pregelatinized starch and corn starch. A preferred disintegrant is
croscarmellose sodium.
[0151] Any binder usually employed in pharmaceutical compositions
may be used in the context of the instant invention. Binders are
for example naturally occurring or partially or totally synthetic
polymers selected from acacia, agar, alginic acid, carbomers,
carmellose sodium, carrageenan, cellulose acetate phthalate,
ceratonia, chitosan, confectionar's sugar, copovidone, povidone,
cottonseed oil, dextrate, dextrin, dextrose, polydextrose,
maltodextrin, maltose, cellulose and derivatives thereof such as
microcrystalline cellulose, methylcellulose, ethylcellulose,
hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl
celluloses, carboxymethylcelluloses, hypromelloses (cellulose
hydroxypropyl methyl ether), starch and derivatives thereof, such
as pregelatinized starch, hydroxypropylstarch, corn starch,
gelatin, glyceryl behenate, tragacanth, guar gum, hydrogenated
vegetable oils, inulin, poloxamer, polycarbophils, polyethylene
oxide, polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and
vinyl acetate, polymethacrylates, polyethylene glycols, alginates
such as sodium alginate, gelatin, sucrose, sunflower oil, zein as
well as derivatives and mixtures thereof. Preferred binders are
microcrystalline cellulose and hydroxypropyl cellulose.
[0152] The pharmaceutical composition according to the present
invention may also comprise one or more lubricants. Suitable
lubricants according to the invention are stearic acid as well as
salts thereof including talc, sodium stearate, calcium stearate,
zinc stearate, magnesium stearate, sodium stearyl fumarate,
glyceryl monostearate, particularly magnesium stearate,
polyethylene glycols, in particular polyethylene glycol with a
molecular weight in a range from about 4400 to about 9000,
hydrogenated castor oil, fatty acid, for example fumaric acid, and
salts of fatty acids, in particular the calcium, magnesium, sodium
or pottasium salts thereof, for example calcium behenate, calcium
stearate, sodium stearyl fumarate or magnesium stearate (for
example (e.g. HyQual.RTM., Mallinckrodt), glycerides such as
glyceryl behenate (Compritol.RTM. 888), Dynasan.RTM. 118 or
Boeson.RTM. VP.
[0153] The pharmaceutical composition according to the present
invention may also comprise one or more glidants. Suitable glidants
according to the invention are silicon dioxide, particularly
colloidal silicon dioxide (e.g. Aerosil.RTM., Cab-O-Sil.RTM.),
stearic acid as well as salts thereof including sodium stearate,
calcium stearate, zinc stearate, magnesium stearate, magnesium
silicate, calcium silicate, magnesium trisilicate and talc.
Preferred glidants are colloidal silicon dioxide and talc.
[0154] In another embodiment, a pharmaceutical composition
according to the instant invention comprises
TABLE-US-00003 Amount (% by weight) Active ingredient 0.5-25 One or
more diluents 65-93 One or more binders 1-5 One or more
disintegrants 1-4 Optionally additional additives ad 100%
[0155] In one aspect, the active ingredient is a compound of the
formula (I), for example of the formula (I.9) or its crystalline
form (I.9X).
[0156] In another embodiment, a pharmaceutical composition
according to the instant invention comprises
TABLE-US-00004 Amount (% by weight) Active ingredient 0.5-25 One or
more diluents 65-90 One or more binders 1-5 One or more
disintegrants 1-3 Optionally additional additives ad 100%
[0157] The active ingredient is a compound of the formula (I), for
example of the formula (I.9) or its crystalline form (I.9X).
[0158] In another embodiment, a pharmaceutical composition
according to the instant invention comprises
TABLE-US-00005 Amount (% by weight) Active ingredient 0.5-25
Lactose monohydrate 28-70 Microcrystalline cellulose 20-50
Hydroxypropyl cellulose 1-5 Croscarmellose sodium 1-4 Optionally
additional additives ad 100%
[0159] In one aspect, the active ingredient is a compound of the
formula (I), for example of the formula (I.9) or its crystalline
form (I.9X).
[0160] In another embodiment, a pharmaceutical composition
according to the instant invention comprises
TABLE-US-00006 Amount (% by weight) Active ingredient 0.5-25
Lactose monohydrate 35-90 Microcrystalline cellulose 0-30
Hydroxypropyl cellulose 1-5 Croscarmellose sodium 1-3 Additional
additives ad 100%
[0161] The active ingredient is a compound of the formula (I), for
example of the formula (I.9) or its crystalline form (I.9X).
[0162] In one embodiment, the ratio of said disintegrant to said
binder in a pharmaceutical composition of the present invention is
between 1.5:3.5 and 1:1.
[0163] In one embodiment, the active ingredient represents 25% or
less of the weight of the pharmaceutical composition. Preferably,
the active ingredient represents 0.5% to 25% of the weight of the
pharmaceutical composition. More preferably, the active ingredient
represents 1.0% to 20% of the weight of the pharmaceutical
composition. Even more preferably, the active ingredient represents
2.0% to 15% of the weight of the pharmaceutical composition.
[0164] In the following, preferred ranges of the amount of the
glucopyranosyl-substituted benzene derivative to be employed in the
pharmaceutical dosage form 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 active ingredient.
[0165] A preferred amount of the glucopyranosyl-substituted benzene
derivative, in particular the compound (I.9) or its crystalline
form (I.9X) is in a range from 0.5 to 100 mg, preferably from 0.5
to 50 mg, even more preferably from 1 to 25 mg, even more
preferably 5 to 25 mg. Preferred dosages of the
glucopyranosyl-substituted benzene derivative are for example 1 mg,
2 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg and
50 mg.
[0166] A pharmaceutical composition according to the present
invention may be comprised in a tablet, a capsule or a film-coated
tablet,
[0167] In one embodiment, a tablet comprising a pharmaceutical
composition according to the present invention comprises a
lubricant, such as magnesium stearate. Such lubricant may be
present in a concentration of 0.25-2% in said tablet.
[0168] In one embodiment, a tablet comprising a pharmaceutical
composition according to the present invention comprises a glidant,
such as colloidal silicon dioxide. Such glidant may be present in a
concentration of 0.25-2% in said tablet.
[0169] A tablet according to the invention may be film-coated.
Typically a film coat represents 2-5% by weight of the total
composition and comprises preferably a film-forming agent, a
plasticizer, a glidant and optionally one or more pigments. An
exemplary coat composition may comprise
hydroxypropylmethyl-cellulose (HPMC), polyethylene glycol (PEG),
talc, titanium dioxide and optionally iron oxide, including iron
oxide red and/or yellow.
[0170] In one embodiment, the pharmaceutical dosage form according
to the invention has dissolution properties such that after 45
minutes at least 75%, preferably at least 90% by weight of the
pharmaceutical active ingredient is dissolved. In another
embodiment after 30 minutes at least 75%, preferably at least 90%
by weight of the pharmaceutical active ingredien is dissolved. In
another embodiment after 15 minutes at least 75%, preferably at
least 90% by weight of the pharmaceutical active ingredient is
dissolved. The dissolution properties can be determined in a
standard dissolution test, for example as described in
pharmacopoeias, such as the USP31-NF26 S2, chapter 711
(dissolution).
[0171] In one embodiment, the pharmaceutical dosage form according
to the invention has disintegration properties such that within 40
minutes, alternatively within 30 minutes, preferably within 20
minutes, more preferably within 15 minutes the pharmaceutical
dosage form is disintegrated. The disintegration properties can be
determined in a standard disintegration test, for example as
described in pharmacopoeias, such as the USP31-NF26 S2, chapter 701
(disintegration).
[0172] In one embodiment, the pharmaceutical dosage form according
to the invention has a high content uniformity, preferably within a
range from 85 to 115%, more preferably from 90 to 110%, even more
preferably from 95 to 105% by weight with regard to the
pharmaceutical ingredient. The content uniformity can be determined
in a standard test using for example randomly 10 selected
pharmaceutical dosage forms, for example as described in
pharmacopoeias.
[0173] A dosage form according to this invention, such as a tablet,
capsule or film-coated tablet, may be prepared by methods
well-known to the one skilled in the art.
[0174] Suitable methods of manufacturing a tablet include
compression of the pharmaceutical composition in the form of a
powder, i.e. direct compression, or compression of the
pharmaceutical composition in the form of granules, and if needed
with additional excipients.
[0175] Granules of the pharmaceutical composition according to the
invention may be prepared by methods well-known to the one skilled
in the art. Preferred methods for the granulation of the active
ingredients together with the excipients include wet granulation,
for example high shear wet granulation and fluidized bed wet
granulation, dry granulation, also called roller compaction.
[0176] In the wet granulation process the granulation liquid are
the solvent alone or a preparation of one or more binders in a
solvent or mixture of solvents. Suitable binders are described
hereinbefore. Examples are hypromellose, hydroxypropyl cellulose,
povidone and copovidone. Suitable solvents are for example purified
water, ethanol, methanol, isopropanol, acetone, preferably purified
water, including mixtures thereof. The solvent is a volatile
component, which does not remain in the final product. The one or
more active ingredients and the other excipients, in particular the
one or more diluents and the one or more disintegrants, usually
with exception of the lubricant, are premixed and granulated with
the granulation liquid, for example using a high shear granulator.
The wet granulation step is usually followed by one or more drying
and sieving steps. For example a drying oven or a fluid bed dryer
can then be used for drying.
[0177] The dried granules are sieved through an appropriate sieve.
After optional addition of the other excipients, in particular
disintegrant, binder, filler and/or glidant, with exception of the
lubricant the mixture is blended in a suitable blender, for example
a free fall blender, followed by addition of the one or more
lubricants, for example magnesium stearate, and final blending in
the blender.
[0178] An exemplary wet granulation process for making a
pharmaceutical composition according to the instant invention
comprises the steps of: [0179] (1) Premixing the active ingredient
and the main portion of the excipients including the binder in a
mixer to obtain a pre-mixture; [0180] (2) granulating the
pre-mixture of step (1) by adding the granulation liquid,
preferably purified water; [0181] (3) drying the granules of step
(2) in a fluidized bed dryer or a drying oven; [0182] (4)
optionally dry sieving of the dried granules of step (3); [0183]
(5) mixing the dried granules of step (4) with the remaining
excipients like filler, binder, disintegrant and/or glidant in a
mixer to obtain the main mixture; [0184] (6) mixing the main
mixture of step (5) with the lubricnat in a mixer to obtain the
final mixture; [0185] (7) tableting the final mixture of step (6)
by compressing it on a suitable tablet press to produce tablets
cores; [0186] (8) optionally film-coating of the tablet cores of
step (7) with a non-functional coat.
[0187] The present invention also provides a pharmaceutical
composition obtainable by the above process.
[0188] An exemplary direct compression process according to the
present invention for making a pharmaceutical composition comprises
the steps of: [0189] (1) Premixing the active ingredient and the
main portion of the excipients in a mixer to obtain a pre-mixture;
[0190] (2) optionally dry screening the pre-mixture through a
screen in order to segregate cohesive particles and to improve
content uniformity; [0191] (3) mixing the pre-mixture of step (1)
or (2) in a mixer, optionally by adding remaining excipients to the
mixture and continuing mixing; [0192] (4) tableting the final
mixture of step (3) by compressing it on a suitable tablet press to
produce the tablet cores; [0193] (5) optionally film-coating of the
tablet cores of step (4) with a non-functional coat.
[0194] The present invention also provides a pharmaceutical
composition obtainable by the above process.
[0195] An exemplary dry granulation process according to the
present invention for making a pharmaceutical composition comprises
the steps of: [0196] (1) mixing the active ingredient or a
pharmaceutically acceptable salt thereof with either all or a
portion of the excipients in a mixer; [0197] (2) compaction of the
mixture of step (1) on a suitable roller compactor; [0198] (3)
reducing the ribbons obtained during step (2) to small granules by
suitable milling or sieving steps; [0199] (4) optionally mixing the
granules of step (3) with the remaining excipients in a mixer to
obtain the final mixture; [0200] (5) tabletting the granules of
step (3) or the final mixture of step (4) by compressing it on a
suitable tablet press to produce the tablet cores; [0201] (6)
optionally film-coating of the tablet cores of step (5) with a
non-functional coat.
[0202] In one embodiment, the size of the granules according to the
present invention is in the range from 25 to 800 .mu.m, for example
from 40 .mu.m to 500 .mu.m. The size of the granules may be
measured via sieve analysis, for example with a sonic sifter. In
one embodiment, at least 80%, at least 90%, or at least 95% by
weight of the granules is in the given range.
[0203] 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.
[0204] 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. 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.
[0205] 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 0.5%, even more
preferably equal to or greater than 1.0% can be achieved and the
reduction is particularly in the range from 1.0% to 2.0%.
[0206] 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: [0207] (a) a fasting
blood glucose or serum glucose concentration greater than 100
mg/dL, in particular greater than 125 mg/dL; [0208] (b) a
postprandial plasma glucose equal to or greater than 140 mg/dL;
[0209] (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%.
[0210] 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.
[0211] 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 1.
[0212] 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 as
defined hereinbefore and hereinafter is administered to the
patient.
[0213] According to another preferred embodiment of the present
invention, there is provided a method for improving gycemic control
in patients, in particular in adult patients, with type 2 diabetes
mellitus as an adjunct to diet and exercise.
[0214] 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 maximal
recommended dose with regard to metformin is for example 2000 mg
per day or 850 mg three times a day or any equivalent thereof.
[0215] 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:
[0216] (a) insufficient glycemic control with diet and exercise
alone;
[0217] (b) insufficient glycemic control despite oral monotherapy
with metformin, in particular despite oral monotherapy at a maximal
tolerated dose of metformin;
[0218] (c) insufficient glycemic control despite oral monotherapy
with another antidiabetic agent, in particular despite oral
monotherapy at a maximal tolerated dose of the other antidiabetic
agent.
[0219] 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 [0220] insulin resistance, [0221]
hyperinsulinemia, [0222] pre-diabetes, [0223] type 2 diabetes
mellitus, particular having a late stage type 2 diabetes mellitus,
[0224] type 1 diabetes mellitus.
[0225] 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
[0226] (a) obesity (including class I, II and/or III obesity),
visceral obesity and/or abdominal obesity,
[0227] (b) triglyceride blood level .gtoreq.150 mg/dL,
[0228] (c) HDL-cholesterol blood level <40 mg/dL in female
patients and <50 mg/dL in male patients,
[0229] (d) a systolic blood pressure .gtoreq.130 mm Hg and a
diastolic blood pressure .gtoreq.85 mm Hg,
[0230] (e) a fasting blood glucose level .gtoreq.100 mg/dL.
[0231] 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.
[0232] Furthermore, a pharmaceutical composition according to this
invention is particularly suitable in the treatment of patients
after organ transplantation, in particular those patients who are
diagnosed having one or more of the following conditions
[0233] (a) a higher age, in particular above 50 years,
[0234] (b) male gender;
[0235] (c) overweight, obesity (including class I, II and/or III
obesity), visceral obesity and/or abdominal obesity,
[0236] (d) pre-transplant diabetes,
[0237] (e) immunosuppression therapy.
[0238] 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:
[0239] (a) hyponatremia, in particular chronical hyponatremia;
[0240] (b) water intoxication;
[0241] (c) water retention;
[0242] (d) plasma sodium concentration below 135 mmol/L.
[0243] The patient may be a diabetic or non-diabetic mammal, in
particular human.
[0244] 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:
[0245] (a) high serum uric acid levels, in particular greater than
6.0 mg/dL (357 .mu.mol/L);
[0246] (b) a history of gouty arthritis, in particular recurrent
gouty arthritis;
[0247] (c) kidney stones, in particular recurrent kidney
stones;
[0248] (d) a high propensity for kidney stone formation.
[0249] A pharmaceutical composition according to this invention
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.
[0250] 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.
[0251] 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.
[0252] 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.
[0253] 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.
[0254] 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 according to this invention is included in the
pharmaceutical composition or dosage form in an amount sufficient
that by its administration the glycemic control in the patient to
be treated is improved.
[0255] 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.
[0256] 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.
[0257] 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.
[0258] In the following preferred ranges of the amount of the SGLT2
inhibitor to be employed in the pharmaceutical composition and the
methods and uses according to this invention are described. These
ranges refer to the amounts to be administered per day with respect
to an adult patient, in particular to a human being, for example of
approximately 70 kg body weight, and can be adapted accordingly
with regard to an administration 2, 3, 4 or more times daily and
with regard to other routes of administration and with regard to
the age of the patient.
[0259] 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 is oral or usually well known.
[0260] In general, the amount of the SGLT2 inhibitor in the
pharmaceutical composition and methods according to this invention
is preferably the amount usually recommended for a monotherapy
using said SGLT2 inhibitor.
[0261] 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, 25 or 50 mg of
the SGLT2 inhibitor, such as a compound of the formula (I), in
particular of the compound (1.9) or its crystalline form (I.9X).
The application of the active ingredient may occur up to three
times a day, preferably one or two times a day, most preferably
once a day.
[0262] 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.
[0263] According to a first embodiment a preferred kit of parts
comprises a containment containing a dosage form comprising the
SGLT2 inhibitor and at least one pharmaceutically acceptable
carrier.
[0264] 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.
[0265] 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 is to be
administered.
[0266] 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.
[0267] 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.
[0268] 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..
[0269] The pharmaceutical composition and the dosage forms
preferably comprises one or more pharmaceutical acceptable carriers
which must be "acceptable" in the sense of being compatible with
the other ingredients of the formulation and not deleterious to the
recipient thereof. Examples of pharmaceutically acceptable carriers
are known to the one skilled in the art.
[0270] 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.
[0271] 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.
[0272] 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.
[0273] 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. 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..
[0274] 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 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.
[0275] The active ingredients may be present in the form of a
pharmaceutically acceptable salt. Pharmaceutically acceptable salts
include, without being restricted thereto, such as salts of
inorganic acid like hydrochloric acid, sulfuric acid and phosphoric
acid; salts of organic carboxylic acid like oxalic acid, acetic
acid, citric acid, malic acid, benzoic acid, maleic acid, fumaric
acid, tartaric acid, succinic acid and glutamic acid and salts of
organic sulfonic acid like methanesulfonic acid and
p-toluenesulfonic acid. The salts can be formed by combining the
compound and an acid in the appropriate amount and ratio in a
solvent and decomposer. They can be also obtained by the cation or
anion exchange from the form of other salts.
[0276] 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.
[0277] Any of the above mentioned pharmaceutical compositions 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.
[0278] 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.
[0279] The effect on glycemic control according to this invention
can be tested after single dosing of the SGLT2 inhibitor 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 pharmaceutical
compositions according to the present invention significantly
improve glucose excursion, for example compared to another
monotherapy, as measured by reduction of peak glucose
concentrations or reduction of glucose AUC. In addition, after
multiple dosing of the SGLT2 inhibitor in the animal models
described hereinbefore, the effect on glycemic control can be
determined by measuring the HbA1c value in blood. The
pharmaceutical compositions according to this invention
significantly reduce HbA1c, for example compared to another
monotherapy or compared to a dual-combination therapy.
[0280] 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.
[0281] 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.
[0282] The effect of a SGLT2 inhibitor 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
[0283] The following examples show the beneficial effect on
glycemic control of the pharmaceutical compositions according to
the present invention.
Example 1
[0284] According to a first example an oral glucose tolerance test
is performed in overnight fasted 9-weeks old male Zucker Diabetic
Fatty (ZDF) rats (ZDF/Crl-Lepr.sup.fa). 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 3 mM HCl and 0.015% Polysorbat 80)
or vehicle containing the SGLT2 inhibitor. 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, 120
min, and 180 min after the glucose challenge. Glucose excursion is
quantified by calculating the reactive 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.
[0285] A representative experiment is shown in FIGS. 3A and 3B.
Compound (1.9)
(1-chloro-4-(.beta.-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran--
3-yloxy)-benzyl]-benzene) was orally administered to ZDF rats at
doses of 0.3 mg/kg, 3 mg/kg or 30 mg/kg body weight. The animals
then received an oral glucose bolus and the resulting glucose-time
profile is shown in FIG. 3A. The baseline-corrected area under the
glucose-time curves are shown in FIG. 3B. Compound (1.9) reduced
glucose excursion by 15% at 0.3 mg/kg (not significant), by 62% at
3 mg/kg (p<0.001) and by 89% at 30 mg/kg (p<0.001).
Example 2
[0286] 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 the SGLT2 inhibitor. 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 reactive 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
[0287] 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
pharmaceutical composition according to the invention for treating
pre-diabetes.
Example 4
Preventing Manifest Type 2 Diabetes
[0288] 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 2h 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 pharmaceutical
composition 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
[0289] 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
[0290] 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
[0291] 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
[0292] 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 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, creatinin clearance, serum creatinin values,
time taken for the serum creatinin values to double, time taken
until dialysis becomes necessary.
Example 9
Treatment of Metabolic Syndrome
[0293] 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 substance 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
[0294] 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
[0295] 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
[0296] 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 compositon according to the
invention.
[0297] 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
[0298] 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
[0299] Patients with elevated levels of uric acid above the normal
range (above 8.3 mg/dL or 494 pmol/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.
[0300] In a twelve week study of patients with manifest type 2
diabetes mellitus serum uric acid levels were measured at baseline
and every 4 weeks in patients randomized to an administration of
the compound (1.9) of 5 mg, 10 mg, or 25 mg or placebo or metformin
2000 mg, daily for 12 weeks. When compared to baseline, patients
receiving all doses of the compound (1.9) had a reduction in their
serum uric acid levels of 0.5 to 0.7 mg/dL when compared to
baseline, while serum uric acid levels increased in patients
randomized to either metformin or placebo.
TABLE-US-00007 Cpd. (I.9) Cpd. (I.9) Cpd. (I.9) Metformin 5 mg 10
mg 25 mg 2000 mg placebo baseline 5.5 mg/dL 5.3 mg/dL 5.4 mg/dL 5.6
mg/dL 5.4 mg/dL 12 weeks 5.0 mg/dL 4.7 mg/dL 4.7 mg/dL 6.2 mg/dL
5.6 mg/dL
Example 13
Treatment of Hyponatremia
[0301] 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
[0302] 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 crystalization of urate or other crystalizing 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.
Example 15
Body Weight and Body Fat Reduction
[0303] The following example shows the beneficial effect of the
compound (I.9) on body weight and total body fat content. All
experimental procedures concerning the use of laboratory animals
were carried out under a Home Office Certificate of Designation. An
animal model of obesity was used to study the effect of the
compound (I.9) on body weight and total body fat content. For this,
female Wistar rats were made obese by exposure to a simplified
cafeteria diet containing high fat chow, chocolate and ground
peanuts for approximately 24 weeks. Following the induction of
obesity, rats were given vehicle (0.5% aqueous
hydroxyethyl-cellulose) for 7 days and then dosed orally once daily
with either vehicle or 3 mg/kg or 10 mg/kg compound (I.9) for 28
days. For the duration of the study rats were maintained on the
cafeteria diet. Body weight was monitored daily and the final body
weight after 28 day treatment is given in the FIG. 4A. Therein "Cpd
A" denotes the glucopyranosyl-substituted benzene derivative (I.9)
at a dose of 3 mg/kg or 10 mg/kg. Results are means (adjusted for
differences between the body weights of the different treatment
groups at baseline (Day 1)).+-.SEM (calculated from the residuals
of the statistical model), n=10. After 28 day daily oral treatment
with the compound (I.9) a reduced body weight compared to the
vehicle-treated control group was observed. Body weight data was
analysed by analysis of covariance with body weights on Day 1 as
covariate. P values versus vehicle control are indicated by symbols
above the bars (*, p<0.05) Multiple comparisons against the
vehicle control group were performed by Williams' test for the two
freely-feeding "Cpd A" groups. The glucopyranosyl-substituted
benzene derivative (1.9) reduced the body weight by 4.1% at 3 mg/kg
and significantly by 6.9% at 10 mg/kg.
[0304] At the end of the study on Day 34 (24 hours after the last
treatment on Day 33) all rats were terminated, the body
exsanguinated and the following tissues removed: the caudate liver
lobe, the pancreas, the left kidney and one soleus muscle. Body
composition (body fat, protein and water) was determined using the
FoodScan NIR (near infra-red) meat analyser (Foss UK). This machine
has AOAC (Association of Official Analytical Chemists) approval as
reference method for the analysis of moisture, fat and protein in
meat. The carcasses were milled under liquid nitrogen and a portion
of the milled carcass was analysed in the FoodScan Analyser. The
results of the determination of body fat content are given in FIG.
4B. Therein "Cpd A" denotes the glucopyranosyl-substituted benzene
derivative (I.9) at a dose of 3 mg/kg or 10 mg/kg. After 33 day
daily oral treatment with the compound (I.9) a reduced body fat
content compared to the control group was observed. Means (n=9-10)
are adjusted for differences between treatment groups in body
weight at baseline (Day 1). Carcasses from all animals were
analysed less terminal bleeds (exsanguination), pancreas and
caudate lobe of the liver whilst 4-5 animals per group additionally
had the left kidney and one soleus muscle removed. Statistical
analysis was by robust regression and included Day 1 body weight as
a covariate. Standard errors of the mean (SEM) are calculated from
the residuals of the statistical model. Comparisons against the
vehicle-treated control group on the cafeteria diet were by
Williams' tests for the freely feeding "Cpd A" animals (3 mg/kg and
10 mg/kg). Significant differences are denoted by *p<0.05. The
total body fat content (expressed as weight per rat) was
significantly lower after treatment with 10 mg/kg of the compound
(1.9) in comparison to vehicle-treated animals.
Examples of Formulations
[0305] 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 substance"
denotes a SGLT-2 inhibitor according to this invention, especially
a compound of the formula (I), for example a compound of the
formula (I.9) or its crystalline form (I.9X).
[0306] The active pharmaceutical ingredient or active sustance,
i.e. the compound (I.9), preferably in the crystalline form (I9.X),
is milled with a suitable mill like pin- or jet-mill in order to
obtain the desired particle size distribution before manufacturing
of the pharmaceutical composition or dosage form.
[0307] Examples of typical particle size distribution values X90,
X50 and X10 for the preferred active pharmaceutical ingredient
according to the invention are shown in the table below.
[0308] Typical particle size distribution results
TABLE-US-00008 Active Active substance substance Batch 1 Batch 2
X10 1.8 .mu.m 1.7 .mu.m X50 18.9 .mu.m 12.1 .mu.m X90 45.3 .mu.m
25.9 .mu.m
Example 1
Dry Ampoule Containing 50 mg of Active Substance Per 10 ml
Composition
TABLE-US-00009 [0309] Active substance 50.0 mg Mannitol 50.0 mg
water for injections ad 10.0 ml
[0310] Preparation:
[0311] Active substance 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 25 mg of Active Substance Per 2 ml
Composition
TABLE-US-00010 [0312] Active substance 25.0 mg Mannitol 100.0 mg
water for injections ad 2.0 ml
[0313] Preparation:
[0314] Active substance 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 Substance Composition
TABLE-US-00011 [0315] (1) Active substance 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
[0316] Preparation:
[0317] (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.
[0318] Diameter of the tablets: 9 mm.
Example 4
Capsules Containing 50 mg of Active Substance Composition
TABLE-US-00012 [0319] (1) Active substance 50.0 mg (2) Dried maize
starch 58.0 mg (3) Mannitol 50.0 mg (4) Magnesium stearate 2.0 mg
160.0 mg
[0320] Preparation:
[0321] (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 5
Tablets Containing 2.5mg, 5mg, 10mg, 25mg, 50mg of Active
Substance
TABLE-US-00013 [0322] 2.5 mg 5 mg 10 mg 25 mg 50 mg Mg/per Mg/per
Mg/per Mg/per Mg/per Active substance tablet tablet tablet tablet
tablet Wet granulation active substance 2.5000 5.000 10.00 25.00
50.00 Lactose 40.6250 81.250 162.50 113.00 226.00 Monohydrate
Microcrystalline 12.5000 25.000 50.00 40.00 80.00 Cellulose
Hydroxypropyl 1.8750 3.750 7.50 6.00 12.00 Cellulose Croscarmellose
1.2500 2.500 5.00 4.00 8.00 Sodium Purified Water q.s. q.s. q.s.
q.s. q.s. Dry Adds Microcrystalline 3.1250 6.250 12.50 10.00 20.00
Cellulose Colloidal silicon 0.3125 0.625 1.25 1.00 2.00 dioxide
Magnesium stearate 0.3125 0.625 1.25 1.00 2.00 Total core 62.5000
125.000 250.00 200.00 400.00 Film Coating Film coating system
2.5000 4.000 7.00 6.00 9.00 Purified Water q.s. q.s. q.s. q.s. q.s.
Total 65.000 129.000 257.00 206.00 409.00
Example 6
[0323] Manufacturing Process for Tablets
Example 7
Pharmaceutical Composition Containing Other Fillers
[0324] Copovidone is dissolved in purified water at ambient
temperature to produce a granulation liquid. A
glucopyranosyl-substituted benzene derivative according to the
present invention, mannitol, pregelatinized starch and corn starch
are blended in a suitable mixer, to produce a pre-mix. The pre-mix
is moistened with the granulation liquid and subsequently
granulated. The moist granulate is sieved through a suitable sieve.
The granulate is dried at about 60.degree. C. inlet air temperature
in a fluid bed dryer until a loss on drying value of 1-4% is
obtained. The dried granulate is sieved through a sieve with a mesh
size of 1.0 mm.
[0325] Magnesium stearate is passed through a sieve for delumping
and added to the granulate. Subsequently the final blend is
produced by final blending in a suitable blender for three minutes
and compressed into tablet cores.
[0326] Hydroxypropyl methylcellulose, polyethylene glycol, talc,
titanium dioxide and iron oxide are suspended in purified water in
a suitable mixer at ambient temperature to produce a coating
suspension. The tablet cores are coated with the coating suspension
to a weight gain of about 3% to produce film-coated tablets. The
following formulation variants can be obtained:
TABLE-US-00014 mg/ mg/ mg/ mg/ mg/ Ingredient tablet tablet tablet
tablet tablet Active substance 2.5 5.0 10.0 25.0 50.0 Mannitol
133.4 130.9 125.9 110.9 221.8 Pregelatinised starch 18.0 18.0 18.0
18.0 36.0 Maize starch 18.0 18.0 18.0 18.0 36.0 Copovidone 5.4 5.4
5.4 5.4 10.8 Magnesium stearate 2.7 2.7 2.7 2.7 5.4 Film coat 5.0
5.0 5.0 5.0 10.0 Total 185.0 185.0 185.0 185.0 370.0
Example 8
Pharmaceutical Composition Containg Other Disintegrant
[0327] Copovidone is dissolved in purified water at ambient
temperature to produce a granulation liquid. An
glucopyranosyl-substituted benzene derivative according to the
present invention, mannitol, pregelatinized starch and corn starch
are blended in a suitable mixer, to produce a pre-mix. The pre-mix
is moistened with the granulation liquid and subsequently
granulated. The moist granulate is sieved through a suitable sieve.
The granulate is dried at about 60.degree. C. inlet air temperature
in a fluid bed dryer until a loss on drying value of 1-4% is
obtained. The dried granulate is sieved through a sieve with a mesh
size of 1.0 mm.
[0328] Crospovidone is added to the dried granulate and mixed for 5
minutes to produce the main blend. Magnesium stearate is passed
through a sieve for delumping and added to main blend. Subsequently
the final blend is produced by final blending in a suitable blender
for three minutes and compressed into 8 mm round tablet cores with
a compression force of 16 kN.
[0329] Hydroxypropyl methylcellulose, polyethylene glycol, talc,
titanium dioxide and iron oxide are suspended in purified water in
a suitable mixer at ambient temperature to produce a coating
suspension. The tablet cores are coated with the coating suspension
to a weight gain of about 3% to produce film-coated tablets. The
following formulation variants can be obtained:
TABLE-US-00015 mg/ mg/ mg/ mg/ mg/ Ingredient tablet tablet tablet
tablet tablet Active substance 2.5 5.0 10.0 25.0 50.0 Mannitol
127.5 125.0 120.0 105.0 210.0 Microcrystalline Cellulose 39.0 39.0
39.0 39.0 78.0 Crospovidone 2.0 2.0 2.0 2.0 4.0 Copovidone 5.4 5.4
5.4 5.4 10.8 Magnesium stearate 3.6 3.6 3.6 3.6 7.2 Film coat 5.0
5.0 5.0 5.0 10.0 Total 185.0 185.0 185.0 185.0 370.0
[0330] The tablet hardness, the friability, the content uniformity,
the disintegration time and the dissolution properties are
determined as described hereinbefore.
Example 9
Direct Compression Formulation
[0331] 1. Screen the active ingredient, microcrystalline cellulose,
croscarmellose.sodium and either hydroxypropyl cellulose or
polyethylene glycol powder through a 20 mesh hand screen.
[0332] 2. Add the above items into the high shear mixer and mix for
two minutes.
[0333] 3. Make a premix (.about.1/1) of the lactose and colloidal
silicon dioxide.
[0334] 4. Screen the premix through a 20 mesh hand screen and add
to the mixer.
[0335] 5. Screen the remaining lactose through a 20 mesh hand
screen and add to the mixer.
[0336] 6. Mix in components in the mixer for 2 minutes.
[0337] 7. Screen the magnesium stearate through a 30 mesh hand
screen and add to the mixer.
[0338] 8. Mix for 1 minute 30 seconds to obtain the final
blend.
[0339] 9 Tabletting of the final blend on a suitable tabletting
press.
[0340] 10. Optionally film coating of the tablet cores.
TABLE-US-00016 mg/ mg/ mg/ mg/ mg/ Ingredient tablet tablet tablet
tablet tablet Active substance 2.5000 5.000 10.00 25.0 50.0 Lactose
Monohydrate 43.7500 87.500 175.00 74.0 148.0 Microcrystalline
12.5000 25.000 50.00 80.0 160.0 Cellulose Polyethylene glycol -- --
-- 10.0 20.0 Croscarmellose sodium 1.2500 2.500 5.00 8.0 16.0
Hydroxypropyl cellulose 1.8750 3.750 7.50 -- -- Colloidal Silicon
dioxide 0.3125 0.625 1.25 1.0 2.0 Magnesium stearate 0.3125 0.625
1.25 2.0 4.0 Film coat 2.5000 4.000 7.00 6.00 9.00 Purified water
q.s. q.s. q.s. q.s. q.s. Total 65.000 129.000 257.00 206.00
409.00
Example 10
Tablets Containing 0.5mg, 5mg, 25mg, 100mg of Active Substance
TABLE-US-00017 [0341] 100 mg 0.5 mg 5 mg 25 mg mg/per Active
substance mg/per tablet mg/per tablet mg/per tablet tablet Wet
granulation active substance 2.5000 5.000 25.00 100.00 Lactose
60.00 55.00 42.00 168.00 Monohydrate Microcrystalline 20.00 20.00
38.00 152.00 Cellulose Hydroxypropyl 5.00 5.00 7.50 30.00 Cellulose
Croscarmellose 4.00 4.00 6.00 24.00 Sodium Purified Water q.s. q.s.
q.s. q.s. Dry Adds Microcrystalline 10.00 10.00 30.00 120.00
Cellulose Colloidal silicon -- 0.50 0.75 3.00 dioxide Magnesium
stearate 0.50 0.50 0.75 3.00 Total 100.00 100.00 150.00 600.00
[0342] The active substance, e.g. the compound (I.9), preferably in
the crystalline form (I.9X), hydroxypropyl cellulose, and
croscarmellose sodium are mixed in a blender. This premix is mixed
with lactose monohydrate and a portion of microcrystalline
cellulose. The resulting blend is granulated with purified water.
Multiple granulation subparts may be produced for an individual
tablet batch, as needed, depending on the batch size and equipment
used. The granulation is discharged onto dryer trays and dried. The
granulation is then milled. The remainder of the microcrystalline
cellulose is added (as a premix with the colloidal silicon dioxide
for all strengths other than the 0.5 mg) to the milled granulation,
and mixed. The magnesium stearate is premixed with a portion of the
blend, screened into the remainder of the granulation, and
mixed.
[0343] The final tablet blend is compressed into tablets using a
tablet press. The finished tablets are packaged using a suitable
container closure system.
Example 11
Tablets Containing 1 mg, 5mg, 25mg of Active Substance
TABLE-US-00018 [0344] 1 mg 5 mg 25 mg Active substance mg/per
tablet mg/per tablet mg/per tablet Wet granulation active substance
1.00 5.00 25.00 Lactose 63.00 59.00 39.00 Monohydrate
Microcrystalline 20.00 20.00 20.00 Cellulose Hydroxypropyl 3.00
3.00 3.00 Cellulose Croscarmellose 2.00 2.00 2.00 Sodium Purified
Water q.s. q.s. q.s. Dry Adds Microcrystalline 10.00 10.00 10.00
Cellulose Colloidal silicon 0.50 0.50 0.50 dioxide Magnesium
stearate 0.50 0.50 0.50 Total 100.00 100.00 100.00
[0345] The active substance, e.g. the compound (I.9), preferably in
the crystalline form (I.9X), is passed through a screen and added
to a blender or a high shear granulator. The hydroxypropyl
cellulose and croscarmellose