U.S. patent application number 17/494543 was filed with the patent office on 2022-06-23 for methods for treating and pharmaceutical compositions.
The applicant listed for this patent is Boehringer Ingelheim International GmbH. Invention is credited to Delphine BEHR-ROUSSEL, Francois GIULIANO, Eric Williams MAYOUX.
Application Number | 20220193101 17/494543 |
Document ID | / |
Family ID | |
Filed Date | 2022-06-23 |
United States Patent
Application |
20220193101 |
Kind Code |
A1 |
MAYOUX; Eric Williams ; et
al. |
June 23, 2022 |
Methods for treating and Pharmaceutical compositions
Abstract
The invention relates to methods for improving glycemic control
and for treating erectile dysfunction in a patient diagnosed with
prediabetes, type 1 diabetes mellitus, type 2 diabetes mellitus or
metabolic syndrome wherein a SGLT2 inhibitor is administered to the
patient. Furthermore the invention relates to a method for
improving a treatment of erectile dysfunction in a male patient
diagnosed with prediabetes, type 1 diabetes mellitus or type 2
diabetes mellitus characterized in that in addition to the
treatment of erectile dysfunction a SGLT2 inhibitor is administered
to the patient. The invention also relates a pharmaceutical
composition comprising a SGLT2 inhibitor and a compounds selected
from the group consisting of PDE5 inhibitors or alprostadil.
Inventors: |
MAYOUX; Eric Williams;
(Neauphle-le-Vieux, FR) ; BEHR-ROUSSEL; Delphine;
(Viroflay, FR) ; GIULIANO; Francois; (Paris,
FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Boehringer Ingelheim International GmbH |
Ingelheim am Rhein |
|
DE |
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Appl. No.: |
17/494543 |
Filed: |
October 5, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16446109 |
Jun 19, 2019 |
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17494543 |
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15568602 |
Oct 23, 2017 |
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PCT/EP2016/059525 |
Apr 28, 2016 |
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16446109 |
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International
Class: |
A61K 31/7048 20060101
A61K031/7048; A61K 45/06 20060101 A61K045/06; A61K 31/5575 20060101
A61K031/5575; A61P 15/10 20060101 A61P015/10; A61P 3/10 20060101
A61P003/10 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 30, 2015 |
EP |
15166057.8 |
Claims
1. A method for improving glycemic control in a patient diagnosed
with prediabetes, type 1 diabetes mellitus, type 2 diabetes
mellitus or metabolic syndrome comprising administering a SGLT2
inhibitor to the patient, wherein the patient is a male patient
diagnosed with erectile dysfunction.
2. A method for treating erectile dysfunction in a male patient
diagnosed with prediabetes, type 1 diabetes mellitus, type 2
diabetes mellitus or metabolic syndrome comprising administering a
SGLT2 inhibitor to the patient.
3. The method according to claim 1, wherein the patient is a
poor-responder or a non-responder to a treatment with a PDE5
inhibitor.
4. The method according to claim 1, wherein the patient is over the
age of 60 years.
5. The method according to claim 1, wherein the patient has
insufficient glycemic control despite antidiabetic treatment with
one or more medicaments not including SGLT2 inhibitors.
6. The method according to claim 1, wherein in that in addition to
the administration of a SGLT2 inhibitor one or more antidiabetic
medicaments not belonging to the class of SGLT2 inhibitors are
administered to the patient.
7. The method according to claim 1, wherein the SGLT2 inhibitor is
empagliflozin.
8. The method according to claim 7, wherein empagliflozin is
administered in an amount of 2.5 to 25 mg.
9. A method for improving a treatment of erectile dysfunction in a
male patient diagnosed with prediabetes, type 1 diabetes mellitus,
type 2 diabetes mellitus or metabolic syndrome comprising
administering a SGLT2 inhibitor to the patient in addition to the
treatment of erectile dysfunction.
10. The method according to claim 9, wherein the treatment of
erectile dysfunction comprises the administration of one or more
medicaments selected from the group consisting of PDE5 inhibitors
or alprostadil.
11. The method according to claim 9, wherein l the SGLT2 inhibitor
is empagliflozin.
12. The method according to claim 11, wherein empagliflozin is
administered in an amount of 2.5 to 25 mg.
13. A pharmaceutical composition comprising a SGLT2 inhibitor and
one or more compounds selected from the group consisting of PDE5
inhibitors, apomorphin or alprostadil.
14. The pharmaceutical composition according to claim 13, wherein
the SGLT2 inhibitor is empagliflozin.
15. The pharmaceutical composition according to claim 13, wherein
the amount of empagliflozin is from 2.5 to 25 mg.
Description
TECHNICAL FIELD OF THE INVENTION
[0001] The invention relates to a method for improving glycemic
control in a male patient diagnosed with prediabetes, type 1
diabetes mellitus, type 2 diabetes mellitus or metabolic syndrome
and with erectile dysfunction. Furthermore the invention relates to
a method for treating erectile dysfunction in a male patient
diagnosed with prediabetes, type 1 diabetes mellitus, type 2
diabetes mellitus or metabolic syndrome. In addition the invention
relates to a method for improving a treatment of erectile
dysfunction in a male patient diagnosed with prediabetes, type 1
diabetes mellitus, type 2 diabetes mellitus or metabolic syndrome.
Furthermore the invention relates to a pharmaceutical composition
comprising a SGLT2 inhibitor and one or more compounds selected
from the group consisting of PDE5 inhibitors or alprostadil.
BACKGROUND OF THE INVENTION
[0002] The rising prevalences of obesity and type 2 diabetes
mellitus (T2DM) represent major challenges for global public
health. Worldwide, there are more than 220 million adults with type
2 diabetes mellitus, figures which are projected to rise to 366
million by 2030 (World Health Organisation 2010; International
Diabetes Federation 2010). According to the US Centers for Disease
Control and Prevention, rates of type 2 diabetes mellitus have
tripled in the past 30 years. Diabetes now affects an estimated
23.6 million people in the United States; another 57 million have
prediabetes. Prediabetes raises short-term absolute risk of type 2
diabetes mellitus five- to sixfold.
[0003] Type 2 diabetes mellitus 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 mellitus is associated
with a two to five fold increase in cardiovascular disease
risk.
[0004] After long duration of disease, most patients with type 2
diabetes mellitus will eventually fail on oral therapy and become
insulin dependent with the necessity for daily injections and
multiple daily glucose measurements.
[0005] 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, DPPIV inhibitors,
SGLT2 inhibitors, glinides, .alpha.-glucosidase inhibitors.
[0006] Erectile dysfunction is defined as the persistent inability
to attain or maintain a penile erection sufficient for satisfactory
sexual performance. Therefore erectile dysfunction has a
significant impact on the physical and psychosocial health aspects
of men and their partners. The prevalence of this condition
increases with age. In a large cross-sectional, community-based
study, 2 among men between the ages of 40 and 49 years, the
prevalence of complete or severe erectile dysfunction was 5%, while
among men between the ages of 70 and 79 years, these rates were 15%
and 34%, respectively. Erectile dysfunction affects about 30
million men in USA and it has been estimated that the worldwide
prevalence of erectile dysfunction will be 322 million cases by the
year 2025.
[0007] Erectile dysfunction (ED) is even more common in diabetic
populations. Studies of ED suggest that its prevalence in men with
diabetes ranges from 35-75% versus 26% in general population.
Moreover the onset of ED also occurs 10-15 years earlier in men
with diabetes than it does in sex-matched counterparts without
diabetes. Moreover, for patients with diabetes, the risk of
erectile dysfunction increase with the duration of the condition
and with increasing levels of glycated hemoglobin. Erectile
dysfunction can also be linked to other conditions common in men
with diabetes, such as high blood pressure and coronary artery
disease and metabolic syndrome. Coexistence of hypertension, CVD
and poor glycemic control worsens ED.
[0008] PDE5 inhibitors on demand or daily dosing (such as
tadalafil) are the recommended first-line treatment for ED.
However, their use is not recommended in men who have recent
history of stroke or myocardial infarction (within the last 6-8
weeks), or who have significantly low blood pressure, uncontrolled
high blood pressure, unstable angina, severe cardiac failure,
severe liver impairment or end-stage kidney disease requiring
dialysis. Furthermore diabetic men have displayed impaired response
rates in therapeutic trials with PDE5 inhibitors (Kendirci M,
Tanriverdi O, Trost L, Hellstrom W J. Management of sildenafil
treatment failures. Curr Opin Urol 2006; 16:449-459). In case of
failure of PDE5 inhibitors in diabetic patients complaining about
erectile dysfunction, on demand intracavernosal injections of
prostagandin E1 or alprostadil are recommended. Limitations of
intracavernosal injections of prostagandin E1 or alprostadil in
diabetic patients are their invasivesness and possible pain.
[0009] In view of the limitation of the existing therapies there is
still an unmet medical need to treat erectile dysfunction, in
particular in patients with diabetes mellitus.
[0010] Empagliflozin is a novel SGLT2 inhibitor that is described
for the treatment or improvement in glycemic control in patients
with type 2 diabetes mellitus, for example in WO 05/092877, WO
06/117359, WO 06/120208, WO 2010/092126, WO 2010/092123, WO
2011/039107, WO 2011/039108, WO 2014/161918, WO 2014/161919 and WO
2014/170383.
AIM OF THE PRESENT INVENTION
[0011] An aim of the present invention is to provide a method for
improving glycemic control in a patient diagnosed with prediabetes,
type 1 diabetes mellitus, type 2 diabetes mellitus or metabolic
syndrome in a male patient diagnosed with erectile dysfunction.
[0012] Another aim of the present invention is to provide a method
for treating erectile dysfunction in a male patient diagnosed with
prediabetes, type 1 diabetes mellitus, type 2 diabetes mellitus or
metabolic syndrome.
[0013] Yet another aim of the present invention is to provide a
pharmaceutical composition, in particular for improving glycemic
control in a patient diagnosed with prediabetes, type 1 diabetes
mellitus, type 2 diabetes mellitus or metabolic syndrome and for
treating erectile dysfunction.
[0014] 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
[0015] Within the scope of the present invention it has now been
found that an administration of a SGLT2 inhibitor improved the
erectile responses in diabetic animals. Beside its effect in
improving glycemic control the SGLT2 inhibitor has further
advantageous properties of clinical relevance, such as the insulin
independent mechanism, a weight-reducing effect and a lowering
effect on the blood-pressure. Therefore the observed pro-erectile
effect of an administration of the SGLT2 inhibitor could become a
highly valuable treatment option for diabetic patients suffering
from erectile dysfunction.
[0016] Therefore, in a first aspect the present invention provides
a method for improving glycemic control in a patient diagnosed with
prediabetes, type 1 diabetes mellitus, type 2 diabetes mellitus or
metabolic syndrome wherein a SGLT2 inhibitor is administered to the
patient characterized in that the patient is a male patient
diagnosed with erectile dysfunction.
[0017] According to another aspect the present invention provides a
method for treating erectile dysfunction in a male patient
diagnosed with prediabetes, type 1 diabetes mellitus, type 2
diabetes mellitus or metabolic syndrome characterized in that a
SGLT2 inhibitor is administered to the patient.
[0018] The observed pro-erectile effect of an administration of a
SGLT2 inhibitor may support or improve a treatment of erectile
dysfunction in a patient.
[0019] Therefore according to another aspect the present invention
provides a method for improving a treatment of erectile dysfunction
in a male patient diagnosed with prediabetes, type 1 diabetes
mellitus, type 2 diabetes mellitus or metabolic syndrome
characterized in that in addition to the treatment of erectile
dysfunction a SGLT2 inhibitor is administered to the patient.
[0020] Known treatments of erectile dysfunction include an
administration of compounds selected from the group consisting of
oral PDE5 inhibitors, or local i.e. intracavernosal, intraurethral
or any other penile route alprostadil. The combination with a SGLT2
inhibitor may be beneficial.
[0021] Therefore according to another aspect the present invention
provides a pharmaceutical composition comprising a SGLT2 inhibitor
and one or more compounds selected from the group consisting of
PDE5 inhibitors or alprostadil.
[0022] According to another aspect of the invention there is
provided the use of a SGLT2 inhibitor for the manufacture of a
medicament for a therapeutic method as described hereinbefore and
hereinafter.
[0023] According to another aspect of the invention there is
provided a SGLT2 inhibitor for use in a therapeutic method as
described hereinbefore and hereinafter.
[0024] According to another aspect of the invention there is
provided the use of a pharmaceutical composition according to this
invention for the manufacture of a medicament for a therapeutic
method as described hereinbefore and hereinafter.
[0025] According to another aspect of the invention there is
provided a pharmaceutical composition according to this invention
for use in a therapeutic method as described hereinbefore and
hereinafter.
DEFINITIONS
[0026] 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".
[0027] 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.
[0028] The term "erectile dysfunction" is defined as the persistent
inability to attain or maintain a penile erection sufficient for
satisfactory sexual performance.
[0029] 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.
[0030] 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.
[0031] 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).
[0032] 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).
[0033] 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.
[0034] 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).
[0035] 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).
[0036] The terms "insulin-sensitizing", "insulin
resistance-improving" or "insulin resistance-lowering" are
synonymous and used interchangeably.
[0037] The term "insulin resistance" is defined as a state in which
circulating insulin levels in excess of the normal response to a
glucose load are required to maintain the euglycemic state (Ford
ES, et al. JAMA. (2002) 287:356-9). A method of determining insulin
resistance is the euglycaemic-hyperinsulinaemic clamp test. The
ratio of insulin to glucose is determined within the scope of a
combined insulin-glucose infusion technique. There is found to be
insulin resistance if the glucose absorption is below the 25th
percentile of the background population investigated (WHO
definition). Rather less laborious than the clamp test are so
called minimal models in which, during an intravenous glucose
tolerance test, the insulin and glucose concentrations in the blood
are measured at fixed time intervals and from these the insulin
resistance is calculated. With this method, it is not possible to
distinguish between hepatic and peripheral insulin resistance.
[0038] Furthermore, insulin resistance, the response of a patient
with insulin resistance to therapy, insulin sensitivity and
hyperinsulinemia may be quantified by assessing the "homeostasis
model assessment to insulin resistance (HOMA-IR)" score, a reliable
indicator of insulin resistance (Katsuki A, et al. Diabetes Care
2001; 24: 362-5). Further reference is made to methods for the
determination of the HOMA-index for insulin sensitivity (Matthews
et al., Diabetologia 1985, 28: 412-19), of the ratio of intact
proinsulin to insulin (Forst et al., Diabetes 2003, 52(Suppl. 1):
A459) and to an euglycemic clamp study. In addition, plasma
adiponectin levels can be monitored as a potential surrogate of
insulin sensitivity. The estimate of insulin resistance by the
homeostasis assessment model (HOMA)-IR score is calculated with the
formula (Galvin P, et al. Diabet Med 1992; 9:921-8):
HOMA-IR=[fasting serum insulin (.mu.U/mL)].times.[fasting plasma
glucose(mmol/L)/22.5]
[0039] 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.
[0040] 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.
[0041] 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.
[0042] 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.
[0043] 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.
[0044] The terms "obesity" or "being obese" and the like are
defined as the condition wherein the individual has a BMI equal to
or greater than 30 kg/m.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.
[0045] The indication obesity includes in particular exogenic
obesity, hyperinsulinaemic obesity, hyperplasmic obesity,
hyperphyseal adiposity, hypoplasmic obesity, hypothyroid obesity,
hypothalamic obesity, symptomatic obesity, infantile obesity, upper
body obesity, alimentary obesity, hypogonadal obesity, central
obesity, visceral obesity, abdominal obesity.
[0046] The term "PDE5 inhibitor" is defined as a phosphodiesterase
type 5 inhibitor. A PDE5 inhibitor blocks the degradative action of
cGMP-specific phosphodiesterase type 5 on cyclic GMP in the smooth
muscle cells lining the blood vessels supplying the corpus
cavernosum of the penis. PDE5 inhibitors are used in the treatment
of erectile dysfunction inter alia. In a diabetic population
impaired response rates in therapeutic trials with PDE5 inhibitors
are observed (Hatzichristou DG. Sildenafil citrate: lessons learned
from 3 years of clinical experience. Int J Impotence Res 2002;
14:S43-S51). In the scope of this invention the terms
"poor-responder to a treatment with a PDE5 inhibitor" and
"non-responder to a treatment with a PDE5 inhibitor" are to be
understood as a patient with no sufficient result of a treatment of
erectile dysfunction despite administration of a PDE5 inhibitor
either on demand or daily.
[0047] Known PDE5 inhibitors include the compounds avanafil,
lodenafil, mirodenafil, sildenafil, tadalafil, vardenafil, udenafil
and benzamidenafil or its synthetic derivatives. The
beforementioned drugs include pharmaceutically acceptable salts
thereof or hydrates or solvates thereof.
[0048] The term "SGLT2 inhibitor" in the scope of the present
invention relates to a compound, in particular to a
glucopyranosyl-derivative, i.e. compound having a
glucopyranosyl-moiety, which shows an inhibitory effect on the
sodium-glucose transporter 2 (SGLT2), in particular the human
SGLT2. The inhibitory effect on hSGLT2 measured as IC.sub.50 is
preferably below 1000 nM, even more preferably below 100 nM, most
preferably below 50 nM. IC.sub.50 values of SGLT2 inhibitors are
usually above 0.01 nM, or even equal to or above 0.1 nM. The
inhibitory effect on hSGLT2 can be determined by methods known in
the literature, in particular as described in the application WO
2005/092877 or WO 2007/093610 (pages 23/24), which are incorporated
herein by reference in its entirety. The term "SGLT2 inhibitor"
also comprises any pharmaceutically acceptable salts thereof,
hydrates and solvates thereof, including the respective crystalline
forms. Examples of SGLT2 inhibitors are dapagliflozin,
canagliflozin, empagliflozin, ertugliflozin, ipragliflozin,
luseogliflozin, sotagliflozin, tofogliflozin, sergliflozin and
remogliflozin, including prodrugs, pharmaceutically acceptable
salts, hydrate and solvates thereof. Prodrugs thereof are for
example remogliflozin etabonate and sergliflozin etabonate.
[0049] 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.
[0050] The term "abdominal obesity" is usually defined as the
condition wherein the waist circumference is >40 inches or 102
cm in men, and is >35 inches or 94 cm in women. With regard to a
Japanese ethnicity or Japanese patients abdominal obesity may be
defined as waist circumference .gtoreq.85 cm in men and .gtoreq.90
cm in women (see e.g. investigating committee for the diagnosis of
metabolic syndrome in Japan).
[0051] "Prediabetes" or "pre-diabetes" is a general term that
refers to an intermediate stage between normal glucose tolerance
(NGT) and overt type 2 diabetes mellitus (T2DM), also referred to
as intermediate hyperglycaemia. As such, it represents 3 groups of
individuals, those with impaired glucose tolerance (IGT) alone,
those with impaired fasting glucose (IFG) alone or those with both
IGT and IFG. IGT and IFG usually have distinct pathophysiologic
etiologies, however also a mixed condition with features of both
can exist in patients. Therefore in the context of the present
invention a patient being diagnosed of having "prediabetes" is an
individual with diagnosed IGT or diagnosed IFG or diagnosed with
both IGT and IFG. Following the definition according to the
American Diabetes Association (ADA) and in the context of the
present invention a patient being diagnosed of having "prediabetes"
is an individual with:
a) a fasting plasma glucose (FPG) concentration <100 mg/dL [1
mg/dL=0.05555 mmol/L] and a 2-hour plasma glucose (PG)
concentration, measured by a 75-g oral glucose tolerance test
(OGTT), ranging between .gtoreq.140 mg/dL and <200 mg/dL (i.e.,
IGT); or b) a fasting plasma glucose (FPG) concentration between
.gtoreq.100 mg/dL and <126 mg/dL and a 2-hour plasma glucose
(PG) concentration, measured by a 75-g oral glucose tolerance test
(OGTT) of <140 mg/dL (i.e., IFG); or c) a fasting plasma glucose
(FPG) concentration between .gtoreq.100 mg/dL and <126 mg/dL and
a 2-hour plasma glucose (PG) concentration, measured by a 75-g oral
glucose tolerance test (OGTT), ranging between .gtoreq.140 mg/dL
and <200 mg/dL (i.e., both IGT and IFG).
[0052] Patients with "prediabetes" are individuals being
pre-disposed to the development of type 2 diabetes. Prediabetes
extends the definition of IGT to include individuals with a fasting
blood glucose within the high normal range .varies.100 mg/dL (J. B.
Meigs, et al. Diabetes 2003; 52:1475-1484). The scientific and
medical basis for identifying prediabetes 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).
[0053] The methods to investigate the function of pancreatic
beta-cells are similar to the above methods with regard to insulin
sensitivity, hyperinsulinemia or insulin resistance: An improvement
of beta-cell function can be measured for example by determining a
HOMA-index for beta-cell function (Matthews et al., Diabetologia
1985, 28: 412-19), the ratio of intact proinsulin to insulin (Forst
et al., Diabetes 2003, 52(Suppl. 1): A459), the insulin/C-peptide
secretion after an oral glucose tolerance test or a meal tolerance
test, or by employing a hyperglycemic clamp study and/or minimal
modeling after a frequently sampled intravenous glucose tolerance
test (Stumvoll et al., Eur J Clin Invest 2001, 31: 380-81).
[0054] The term "type 2 diabetes mellitus" or "T2DM" is defined as
the condition in which a subject has a fasting blood glucose or
serum glucose concentration greater than 125 mg/dL (6.94 mmol/L).
The measurement of blood glucose values is a standard procedure in
routine medical analysis. If a glucose tolerance test is carried
out, the blood sugar level of a diabetic will be in excess of 200
mg of glucose per dL (11.1 mmol/l) of plasma 2 hours after 75 g of
glucose have been taken on an empty stomach. In a glucose tolerance
test 75 g of glucose are administered orally to the patient being
tested after 10-12 hours of fasting and the blood sugar level is
recorded immediately before taking the glucose and 1 and 2 hours
after taking it. 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.
[0055] 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).
[0056] 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.
[0057] 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%.
[0058] 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: [0059] 1. Abdominal obesity, defined as waist
circumference >40 inches or 102 cm in men, and >35 inches or
94 cm in women; or with regard to a Japanese ethnicity or Japanese
patients defined as waist circumference .gtoreq.85 cm in men and
.gtoreq.90 cm in women; [0060] 2. Triglycerides: .gtoreq.150 mg/dL
[0061] 3. HDL-cholesterol <40 mg/dL in men [0062] 4. Blood
pressure .gtoreq.130/85 mm Hg (SBP .gtoreq.130 or DBP .gtoreq.85)
[0063] 5. Fasting blood glucose .gtoreq.100 mg/dL
[0064] 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.
[0065] 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.
[0066] The term "empagliflozin" refers to the SGLT2 inhibitor
1-chloro-4-(.beta.-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy-
)-benzyl]-benzene of the formula
##STR00001##
as described for example in WO 2005/092877. Methods of synthesis
are described in the literature, for example WO 06/120208 and WO
2011/039108. According to this invention, it is to be understood
that the definition of empagliflozin also comprises its hydrates,
solvates and polymorphic forms thereof, and prodrugs thereof. An
advantageous crystalline form of empagliflozin is described in WO
2006/117359 and WO 2011/039107 which hereby are incorporated herein
in their entirety. This crystalline form possesses good solubility
properties which enables a good bioavailability of the SGLT2
inhibitor. Furthermore, the crystalline form is physico-chemically
stable and thus provides a good shelf-life stability of the
pharmaceutical composition. Preferred pharmaceutical compositions,
such as solid formulations for oral administration, for example
tablets, are described in WO 2010/092126, which hereby is
incorporated herein in its entirety.
[0067] 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. The term treatment also encompasses prophylactically
treating, preventivally treating and preventing also. These terms
are used interchangeably and comprise a treatment of patients at
risk to develop a condition mentioned hereinbefore, thus reducing
said risk.
[0068] 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.
[0069] 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
[0070] FIG. 1 shows erectile responses elicited by cavernous nerve
stimulation at increasing stimulation frequencies in animals.
[0071] FIGS. 2a and 2b show show erectile responses in terms of
AUC.sub.45/MAP and AUC.sub.tot/MAP elicited by cavernous nerve
stimulation at increasing stimulation frequencies in anaesthetized
Wistar rats.
[0072] The FIG. 3 shows relaxant responses elicited by increasing
frequencies of EFS on PHE-induced contractions of CC strips from
Wistar rats
DETAILED DESCRIPTION
[0073] The aspects according to the present invention, in
particular the pharmaceutical compositions, methods and uses, refer
to a SGLT2 inhibitor as defined hereinbefore and hereinafter.
[0074] According to an embodiment of this invention the SGLT2
inhibitor is selected from the group consisting of dapagliflozin,
canagliflozin, empagliflozin, ertugliflozin, ipragliflozin,
luseogliflozin, sotagliflozin, tofogliflozin, sergliflozin and
remogliflozin, including prodrugs, pharmaceutically acceptable
salts, hydrate and solvates thereof. Prodrugs thereof are for
example remogliflozin etabonate and sergliflozin etabonate.
[0075] According to a particularly preferred embodiment the SGLT2
inhibitor is empagliflozin.
[0076] The aspects according to the present invention, in
particular the methods and uses, refer to a treatment of patients
diagnosed with prediabetes, type 1 diabetes mellitus, type 2
diabetes mellitus or metabolic syndrome as defined hereinbefore and
hereinafter.
[0077] According to an embodiment of this invention the patient is
diagnosed with type 2 diabetes mellitus.
[0078] According to another embodiment of this invention the
patient is diagnosed with type 1 diabetes mellitus.
[0079] According to a further embodiment of this invention the
patient is diagnosed with prediabetes.
[0080] According to a further embodiment of this invention the
patient is diagnosed with metabolic syndrome.
[0081] When this invention refers to patients requiring treatment
or prevention, it relates primarily to treatment and prevention in
male humans, in particular in adult male 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.
[0082] According to an embodiment of this invention the patient has
insufficient glycemic control with diet and exercise alone.
[0083] In view of the insulin-independent mode of action the
efficacy of a SGLT2 inhibitor is maintained even in patients with
decreased beta-cell activity. Thus in patients with insufficient
glycemic control under treatment with other antidiabetic drugs, a
treatment with a SGLT2 inhibitor still leads to a lowering of blood
glucose. Therefore according to an embodiment of this invention the
patient has insufficient glycemic control despite antidiabetic
treatment with one or more medicaments not including SGLT2
inhibitors. In particular the patient has insufficient glycemic
control despite oral treatment with one, two or more drugs selected
from the group consisting of metformin hydrochloride and
sulfonylureas. For example the patient has insufficient glycemic
control despite oral monotherapy with metformin hydrochloride, in
particular despite oral monotherapy at a maximal recommended or
tolerated dose of metformin hydrochloride.
[0084] According to an embodiment of this invention the patient is
over the age of 60 years. It is known that the frequency of
erectile dysfunction increases with age.
[0085] In a diabetic population impaired response rates in
therapeutic trials with PDE5 inhibitors are observed. In view of an
independent mode of action of SGLT2 inhibitors patients poorly or
not responding to a treatment with a PDE5 inhibitor may still
benefit from a pro-erectile effect resulting from an administration
of a SGLT2 inhibitor. Therefore according to an embodiment of this
invention the patient is a poor-responder or a non-responder to a
treatment with a PDE5 inhibitor, in particular to a treatment with
a compound selected from the group consisting of avanafil,
lodenafil, mirodenafil, sildenafil, tadalafil, vardenafil, udenafil
and benzamidenafil or a pharmaceutically acceptable salts thereof
or hydrates or solvates thereof.
[0086] SGLT2 inhibitors, in particular empagliflozin, were shown to
have a weight reducing effect. Therefore according to an embodiment
of this invention the patient is diagnosed of being overweight or
obese, including class I, II and/or III obesity, visceral obesity
and/or abdominal obesity.
[0087] According to an embodiment of this invention the patient is
diagnosed with type 2 diabetes and overweight or obese, including
class I, II and/or III obesity, visceral obesity and/or abdominal
obesity.
[0088] According to another embodiment of this invention the
patient is diagnosed with type 1 diabetes and overweight or obese,
including class I, II and/or III obesity, visceral obesity and/or
abdominal obesity.
[0089] According to a further embodiment of this invention the
patient is diagnosed with prediabetes and overweight or obese,
including class I, II and/or III obesity, visceral obesity and/or
abdominal obesity.
[0090] The present invention also discloses methods and uses for
improving glycemic control in patients being overweight or obese
and 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 are present in an overweight or obese
patient, the onset of manifest type 2 diabetes mellitus can be
delayed or prevented in this patient.
[0091] According to an embodiment of this invention the methods or
uses according to this invention are advantageously applicable in
those patients who show 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 7.0%, especially equal to or greater than 7.5%,
even more particularly equal to or greater than 8.0%.
[0092] According to an embodiment of this invention the methods or
uses according to this invention is particularly suitable in the
treatment of patients who are diagnosed of being overweight or
obese and having one or more of the following conditions
(a) triglyceride blood level .gtoreq.150 mg/dL, (b) HDL-cholesterol
blood level <40 mg/dL in female patients and <50 mg/dL in
male patients, (c) a systolic blood pressure .gtoreq.130 mm Hg and
a diastolic blood pressure .gtoreq.85 mm Hg, (d) a fasting blood
glucose level .gtoreq.100 mg/dL.
[0093] A method for treatment or use according to this invention is
particularly suitable as long term treatment or use as described
hereinbefore and hereinafter, in particular in patients diagnosed
with erectile dysfunction and diagnosed with prediabetes, type 1
diabetes mellitus or type 2 diabetes mellitus. 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 8
weeks, preferably longer than 12 weeks, more preferably longer than
25 weeks or longer than 1 year.
[0094] According to an aspect the present invention provides a
method for improving a treatment of erectile dysfunction in a male
patient diagnosed with prediabetes, type 1 diabetes mellitus, type
2 diabetes mellitus or metabolic syndrome characterized in that in
addition to the treatment of erectile dysfunction a SGLT2 inhibitor
is administered to the patient.
[0095] According to an embodiment of this aspect of the invention
the treatment of erectile dysfunction comprises an administration
of one or more medicaments selected from the group consisting of
PDE5 inhibitors, or alprostadil. The beforementioned drugs include
pharmaceutically acceptable salts thereof or hydrates or solvates
thereof.
[0096] According to an embodiment of this aspect of the invention
the PDE5 inhibitor is selected from the group consisting of
avanafil, lodenafil, mirodenafil, sildenafil, tadalafil,
vardenafil, udenafil, benzamidenafil or its synthetic derivatives.
Preferred PDE5 inhibitors are avanafil, sildenafil, tadalafil and
vardenafill. The beforementioned drugs include pharmaceutically
acceptable salts thereof or hydrates or solvates thereof.
[0097] Preferred SGLT2 inhibitors according to this aspect of the
invention are those as described hereinbefore. A particularly
preferred SGLT2 inhibitor is empagliflozin.
[0098] In the following, preferred ranges of the amount of active
ingredients to be employed in 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 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 .
[0099] A preferred amount of empagliflozin is in a range from 1 to
50 mg, even more preferably from 2.5 to 25 mg, even more preferably
5 to 25 mg for once daily oral administration. Preferred dosages of
empagliflozin are for example 2 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg,
15 mg, 20 mg and 25 mg for once daily oral administration. Most
preferred dosages of empagliflozin are 10 mg and 25 mg for once
daily oral administration. Tablet formulations of empagliflozin are
described in WO 2010/092126 which is incorporated herein by
reference. Empagliflozin tablet formulations are marketed under the
tradename JARDIANCE.
[0100] A preferred amount of dapagliflozin is in a range from 1 to
50 mg, even more preferably from 2.5 to 25 mg, even more preferably
5 to 20 mg for once daily oral administration. Preferred dosages of
dapagliflozin are for example 5 mg and 10 mg for once daily oral
administration. Tablet formulations of dapagliflozin are marketed
under the tradename FORXIGA.
[0101] A preferred amount of canagliflozin is in a range from 50 to
500 mg, even more preferably from 100 to 300 mg for once daily oral
administration. Preferred dosages of canagliflozin are for example
100 mg and 300 mg for once daily oral administration. Tablet
formulations of canagliflozin are marketed under the tradename
INVOKANA.
[0102] According to an embodiment of this invention the SGLT2
inhibitor is administered together with another antidiabetic drugs.
According to a preferred variant of this embodiment the SGLT2
inhibitor is administered together with metformin hydrochloride.
According to another variant of this embodiment the SGLT2 inhibitor
is administered together with a DPPIV inhibitor. Examples of DPPIV
inhibitors are linagliptin, sitagliptin, saxagliptin and
vildagliptin. The beforementioned drugs include pharmaceutically
acceptable salts thereof or hydrates or solvates thereof.
[0103] According to an example of this embodiment empagliflozin is
administered together with metformin hydrochloride. The
administration of empagliflozin may be an add-on to an existing
treatment with metformin hydrochloride or a fixed dose combination
of empagliflozin with metformin hydrochloride is administered.
Metformin hydrochloride may be administered as an immediate or
extended release formulation. Examples of individual amounts for a
combination of empagliflozin/metformin hydrochloride are 5 mg/500
mg, 5 mg/850 mg, 5 mg/1000 mg, 12.5 mg/500 mg, 12.5 mg/850 mg and
12.5 mg/1000 mg each for twice daily oral administration, wherein
metformin chloride is present in an immediate release formulation.
Tablet formulations of fixed dose combinations of empagliflozin
with metformin hydrochloride as immediate release formulation are
described in WO 2011/039337 which is incorporated herein by
reference. According to another example amounts for a combination
of empagliflozin/metformin hydrochloride are 10 mg/1000 mg and 25
mg/1000 mg each for once daily oral administration, wherein
metformin chloride is present in an extended release formulation.
According to yet another example amounts for a combination of
empagliflozin/metformin hydrochloride are 5 mg/1000 mg and 12.5
mg/1000 mg each for twice daily oral administration, wherein
metformin chloride is present in an extended release formulation.
Tablet formulations of fixed dose combinations of empagliflozin
with metformin hydrochloride as extended release formulation are
described in WO 2012/120040 and WO 2013/131967 which are
incorporated herein by reference.
[0104] According to another example of this embodiment
empagliflozin is administered together with the DPPIV inhibitor
linagliptin or a pharmaceutically acceptable salt thereof. The
administration of empagliflozin and linagliptin may be separately
in two separate dosage forms or a fixed dose combination of
empagliflozin with linagliptin. Examples of individual amounts for
a combination of empagliflozin/linagliptin are 10 mg/5 mg and 25
mg/5 mg each for once daily oral administration. Respective tablet
formulations are described in WO 2010/092124 which is incorporated
herein by reference.
[0105] According to another example of this embodiment
dapagliflozin is administered together with metformin
hydrochloride. The administration of dapagliflozin may be an add-on
to an existing treatment with metformin hydrochloride or a fixed
dose combination of dapagliflozin with metformin hydrochloride is
administered. Metformin hydrochloride may be administered as an
immediate or extended release formulation. Examples of individual
amounts for a combination of dapagliflozin/metformin hydrochloride
are 5 mg/850 mg and 5 mg/1000 mg each for twice daily oral
administration, wherein metformin chloride is present in an
immediate release formulation. Tablet formulations of dapagliflozin
together with metformin hydrochloride as immediate release
formulation are marketed under the tradename XIGDUO.
[0106] According to yet another example of this embodiment
canagliflozin is administered together with metformin
hydrochloride. The administration of canagliflozin may be an add-on
to an existing treatment with metformin hydrochloride or a fixed
dose combination of canagliflozin with metformin hydrochloride is
administered. Metformin hydrochloride may be administered as an
immediate or extended release formulation. Examples of individual
amounts for a combination of canagliflozin/metformin hydrochloride
are 50 mg/850 mg, 150 mg/850 mg, 50 mg/1000 mg and 150 mg/1000 mg
each for twice daily oral administration, wherein metformin
chloride is present in an immediate release formulation. Tablet
formulations of canagliflozin together with metformin hydrochloride
as immediate release formulation are marketed under the tradename
VOKANAMET.
[0107] According to another variant of the hereinbefore described
embodiment the SGLT2 inhibitor is administered together with an
insulin. The term insulin includes normal insulin, human insulin,
insulin derivatives, zinc insulins and insulin analogues, including
formulations thereof with modified release profiles. The term
insulin covers rapid-acting insulins, short-acting insulins,
intermediate-acting insulins and long-acting insulins. Patients
which may benefit from an administration of a SGLT2 inhibitor and
insulin according to this invention are patients diagnosed with
type 1 diabetes mellitus. Furthermore patients which may benefit
from an administration of a SGLT2 inhibitor and insulin according
to this invention are patients with type 2 diabetes mellitus, in
particular type 2 diabetes mellitus patients with insufficient
glycemic control despite therapy with one or more oral antidiabetic
drugs.
[0108] According to an embodiment of this aspect of the invention
the treatment of erectile dysfunction comprises an administration
of one or more medicaments selected from the group consisting of
PDE5 inhibitors or alprostadil, in particular selected from the
group consisting of avanafil, sildenafil, tadalafil and vardenafil.
The beforementioned drugs include pharmaceutically acceptable salts
thereof or hydrates or solvates thereof.
[0109] A preferred amount of sildenafil is in a range from 25 to
100 mg on demand for oral administration. Preferred dosages of
sildenafil are for example 25 mg, 50 mg and 100 mg. The dose is
taken as needed before sexual activity, for example approximately
one hour before sexual activity. Tablet formulations of sildenafil
are marketed under the tradename VIAGRA for example.
[0110] A preferred amount of tadalafil is in a range from 1 to 100
mg, even more preferably from 2.5 and 5 to 20 mg once per day for
oral administration. Preferred dosages of tadalafil are for example
2.5 mg, 5 mg, 10 mg and 20 mg. Tadalafil 2.5 and 5 mg are doses for
once a day treatment for erectile dysfunction. The dose is taken
prior to anticipated sexual activity. Tablet formulations of
tadalafil are marketed under the tradename CIALIS for example.
[0111] A preferred amount of vardenafil is in a range from 1 to 50
mg, even more preferably from 5 to 20 mg once per day for oral
administration. Preferred dosages of vardenafil are for example 5
mg, 10 mg and 20 mg. Vardenafil is provided preferably as a
pharmaceutically acceptable salt, in particular as the
hydrochloride. The dose is taken as needed before sexual activity,
for example approximately 25 to 60 minutes before sexual activity.
Tablet formulations of vardenafil are marketed under the tradename
LEVITRA or VIVANZA for example. There is also an oral dispersable
formulation for vardenafil (Levitra ODT).
[0112] Unless otherwise noted, the combination therapy according to
the invention may refer to first line, second line or third line
therapy, or initial or add-on combination therapy or replacement
therapy.
[0113] According to one embodiment SGLT2 inhibitor and the
medicament selected from the group consisting of PDE5 inhibitors
are administered in combination, i.e. simultaneously, for example
in one single formulation or dosage form or in two separate
formulations or dosage forms, or in alternation or sequentially,
for example successively in two separate formulations or dosage
forms. Hence, the administration of one combination partner, i.e.
the SGLT2 inhibitor or the PDE5 inhibitor, may be prior to,
concurrent to, or subsequent to the administration of the other
combination partner. In one embodiment, for the combination therapy
according to this invention the SGLT2 inhibitor and the PDE5
inhibitor are administered in different formulations or different
dosage forms. In another embodiment, for the combination therapy
according to this invention the SGLT2 inhibitor and the PDE5
inhibitor are administered in the same formulation or in the same
dosage form.
[0114] In the methods and uses according to the present invention
the SGLT2 inhibitor and the PDE5 inhibitor are administered in
combination or alternation or sequentially. The term
"administration in combination" means that the active ingredients
are administered at the same time, i.e. simultaneously, or
essentially at the same time. The term "administration in
alternation" means that at first one of the two active ingredients,
i.e. the SGLT2 inhibitor or the PDE5 inhibitor, is administered and
after a period of time the other active ingredient, i.e. the PDE5
inhibitor or the SGLT2 inhibitor, is administered whereby this
administration scheme may be repeated one or more times. The period
of time between the administration of the first and of the second
active ingredient may be in the range from 1 min to 12 hours. The
administration which is in combination or in alternation may be
once, twice, three times or four times daily, preferably once or
twice daily. The term "sequentially" means that to a patient the
first active ingredient is administered to the patient one or more
times in a first period of time followed by an administration of
the second active ingredient which is administered to the patient
one or more times in a second period of time.
[0115] According to an embodiment of the methods and uses of the
present invention the SGLT2 inhibitor is administered to the
patient once per day and the PDE5 inhibitor is administered before
sexual activity.
[0116] According to an aspect the present invention provides a
pharmaceutical composition comprising a SGLT2 inhibitor and one or
more compounds selected from the group consisting of PDE5
inhibitors or alprostadil.
[0117] Preferred SGLT2 inhibitors are as described hereinbefore.
The most preferred SGLT2 inhibitor is empagliflozin.
[0118] PDE5 inhibitors according to this invention are described
hereinbefore. Preferred PDE5 inhibitors are sildenafil, tadalafil,
vardenafil and avanafil. The beforementioned drugs include
pharmaceutically acceptable salts thereof or hydrates or solvates
thereof.
[0119] According to an embodiment of this invention the
pharmaceutical composition comprises one or more pharmaceutically
acceptable excipients.
[0120] According to an embodiment of the present invention there is
provided a pharmaceutical dosage form comprising empagliflozin and
a PDE5 inhibitor and one or more pharmaceutically acceptable
excipients.
[0121] The amount of the SGLT2 inhibitor in the pharmaceutical
compositions and pharmaceutical dosage forms according to this
invention are known to the one skilled in the art and/or correspond
to the respective dosage ranges as provided hereinbefore.
[0122] The amount of the PDE5 inhibitor in the pharmaceutical
compositions and pharmaceutical dosage forms according to this
invention are known to the one skilled in the art and/or correspond
to the respective dosage ranges as provided hereinbefore.
[0123] According to an embodiment the pharmaceutical composition or
the pharmaceutical dosage form is provided for oral
administration.
[0124] A pharmaceutical composition which is present as a separate
or multiple dosage form, for example as a kit of parts, is useful
in combination therapy to flexibly suit the individual therapeutic
needs of the patient. For example a pharmaceutical composition may
be present as a first pharmaceutical dosage form comprising the
SGLT2 inhibitor and one or more pharmaceutically excipients and a
second pharmaceutical dosage form comprising the PDE5 inhibitor,
apomorphin or alprostadil and one or more pharmaceutically
excipients
[0125] According to an embodiment of the invention a kit of parts
comprises
(a) a first containment containing a dosage form comprising the
SGLT2 inhibitor and one or more pharmaceutically acceptable
excipients, and (b) a second containment containing a dosage form
comprising the PDE5 inhibitor, apomorphin or alprostadil and one or
more pharmaceutically acceptable excipients.
[0126] Within the scope of the present invention, the SGLT2
inhibitor is preferably administered orally or by injection,
preferably orally. The PDE5 inhibitor is preferably administered
orally. Alprostadil is preferably administered by intracavernosal
injection. Other forms of administration are possible and described
for the respective drug in the literature.
[0127] The effects mentioned above are observed both, when SGLT2
inhibitor and the PDE5 inhibitor or alprostadil are administered in
combination, for example simultaneously in one single or two
separate pharmaceutical dosage forms, and when they are
administered in alternation, for example successively in two or
three separate pharmaceutical dosage forms.
[0128] 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. Furthermore in general, the PDE5 inhibitor
or alprostadil according to this invention are included in the
pharmaceutical composition or dosage form in an amount sufficient
that by their administration in combination with the SGLT2
inhibitor the erectile function in the patient to be treated is
improved.
[0129] The amount of the SGLT2 inhibitor and the PDE5 inhibitor or
alprostadil in the pharmaceutical compositions and pharmaceutical
dosage forms according to this invention correspond to the
respective dosage ranges as provided hereinbefore.
[0130] 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. Once daily administration is
preferred.
[0131] The pharmaceutical composition may be formulated for oral,
parenteral (including sub-cutaneous) or other routes of
administration in liquid or solid form. Oral administration of the
SGLT2 inhibitor 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
excipients, such as carriers, like liquid carriers or finely
divided solid carriers or both, or diluents, and then, if
necessary, shaping the product into the desired formulation.
Examples of pharmaceutical compositions and pharmaceutical dosage
forms comprising empagliflozin and one or more pharmaceutically
acceptable excipients are described in WO 2010/092126.
[0132] The pharmaceutical composition and the pharmaceutical dosage
form preferably comprises one or more pharmaceutical acceptable
excipients. Preferred excipients 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 excipients are known to the one skilled
in the art.
[0133] The pharmaceutical composition may be formulated in the form
of solutions, suspensions, emulsions, tablets, granules, fine
granules, powders, capsules, caplets, soft capsules, pills, oral
solutions, syrups, dry syrups, chewable tablets, troches,
effervescent tablets, drops, fast dissolving tablets, oral
fast-dispersing tablets, etc. According to a preferred embodiment
of the present invention there is provided a solid pharmaceutical
composition for oral administration. Preferred pharmaceutical
dosage form are tablets or capsules.
[0134] For further details on dosage forms, formulations and
administration of the SGLT2 inhibitor and/or the PDE5 inhibitor or
alprostadil, reference is made to scientific literature and/or
published patent documents, particularly to those cited herein.
[0135] The pharmaceutical composition or dosage form may be
packaged in a variety of ways. Generally, a manufacture or an
article for distribution includes one or more containers that
contain the one or more pharmaceutical dosage forms in an
appropriate form. Tablets are typically packed in an appropriate
primary package for easy handling, distribution and storage and for
assurance of proper stability of the composition at prolonged
contact with the environment during storage. Primary containers for
tablets may be bottles or blister packs.
[0136] The manufacture or article may further comprise a label or
package insert, which refers to instructions customarily included
in commercial packages of therapeutic products, that may contain
information about the indications, usage, dosage, administration,
contraindications and/or warnings concerning the use of such
therapeutic products. In one embodiment, the label or package
inserts indicates that the composition can be used for any of the
purposes described hereinbefore or hereinafter.
[0137] An aspect of the present invention is a manufacture
comprising the pharmaceutical composition being present as a
pharmaceutical dosage form comprising the SGLT2 inhibitor and a
PDE5 inhibitor or alprostadil and one or more pharmaceutically
acceptable excipients.
[0138] A further aspect of the present invention is a manufacture
comprising the pharmaceutical composition being present as a first
and a second pharmaceutical dosage form according to the present
invention and a label or package insert comprising instructions
that the first and the second pharmaceutical dosage forms are to be
administered in combination or alternation or sequentially. Herein
the first pharmaceutical dosage form comprises the SGLT2 inhibitor
and one or more pharmaceutically excipients and the second
pharmaceutical dosage form comprises a PDE5 inhibitor or
alprostadil and one or more pharmaceutically excipients.
[0139] According to a first embodiment a manufacture comprises (a)
a pharmaceutical composition, in particular a solid pharmaceutical
dosage form for oral administration, comprising the SGLT2 inhibitor
according to the present invention and one or more pharmaceutically
acceptable excipients and (b) a label or package insert which
comprises instructions that the pharmaceutical composition may or
is to be administered, for example in combination or alternation or
sequentially, with a medicament comprising a PDE5 inhibitor or
alprostadil according to the present invention.
[0140] According to a second embodiment a manufacture comprises (a)
a pharmaceutical composition comprising PDE5 inhibitor or
alprostadil and one or more pharmaceutically acceptable excipients
and (b) a label or package insert which comprises instructions that
the pharmaceutical composition may or is to be administered, for
example in combination or alternation or sequentially, with a
medicament comprising the SGLT2 inhibitor according to the present
invention according to the present invention.
[0141] The pharmaceutical compositions, dosage forms, methods and
uses according to this invention show advantageous effects in the
treatment and prevention of those diseases and conditions as
described hereinbefore compared with pharmaceutical compositions,
dosage forms, methods and uses which comprise only one of the two
active ingredients. Additional 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.
[0142] Any of the above mentioned combinations, methods and uses
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 methods, uses and pharmaceutical compositions
according to this invention:
[0143] Pharmaceutical compositions and methods according to this
invention can be tested in experimental model of erectile 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.
[0144] The effect on glycemic control of the combinations according
to this invention can be tested 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. In addition an improvement of glucose
excursion can be measured by reduction of peak glucose
concentrations or reduction of glucose AUC. The effect on glycemic
control can be determined by measuring the HbA1c value in
blood.
PHARMACOLOGICAL EXAMPLES
[0145] The following examples show the beneficial effect of
empagliflozin on erectile function in a well-established in vivo
model of erectile dysfunction (ED) associated to type II diabetes
i.e., Goto-kakizaki diabetic rats (GK rats).
Example 1: Animal In Vivo Experiments
Animals
[0146] Goto-Kakizaki (GK) rats has been shown to be a relevant
experimental model of type II diabetes mellitus-associated erectile
dysfunction. It was shown that erectile function in GK rats was
markedly impaired (Oger-Roussel S, Behr-Roussel D, Caisey S,
Kergoat M, Charon C, Audet A, Bernabe J, Alexandre L, Giuliano F.
Bladder and erectile dysfunctions in the Type 2 diabetic
Goto-Kakizaki rat. Am J Physiol Regul Integr Comp Physiol 2014;
306:R108-R117). In that model, the impaired erectile function was
partially improved by an acute single dose (0.3 mg/kg) of the PDE5
inhibitor sildenafil. Thus, GK rats represent a suitable model to
investigate the pathophysiology of type 2 diabetes-associated
erectile complications and to assess efficacy of new therapeutic
agents targeting diabetic ED.
Methods
[0147] Adult male Wistar (Charles River, France) and age-matched GK
rats (Metabrain Research, Chilly-Mazarin, France) were housed at
least 7 days prior to the beginning of the treatment with free
access to control diet and water and maintained on an inversed 12 h
dark/light cycle. At 15 weeks of age, treatments were started; n=12
Wistar (group I) rats and n=24 GK (group II) rats were fed with a
control diet, while n=24 GK rats (group III) were fed for 28 days
by a medicated diet i.e., control diet premixed with empagliflozin
300 ppm (parts per million corresponding to an average of 25.3
mg/kg body weight of empaglfilozin in that experiment).
[0148] On day 29.sup.th after starting treatment administration,
and approximately 16 hours after the last treatment administration,
fasted rats (19 weeks of age) underwent an in vivo evaluation of
their erectile function after electrical stimulation of the
cavernous nerve (ES CN), in comparison to acute dosing of
sildenafil.
[0149] Erectile responses were elicited by electric stimulation
(ES) of the cavernous nerve (CN) and measured by monitoring
intracavernous pressure (ICP) in anesthetized rats according to an
experimental procedure previously described and well-standardized.
After an overnight fasting period, rats were anesthetized (urethane
1.2 mg/kg) and their temperature maintained at 37.degree. C. using
a homoeothermic blanket. A tracheotomy was performed to prevent
aspiration of saliva and to perform, when required, artificial
ventilation. The carotid artery was catheterized with polyethylene
tubings filled with heparinized saline (25 UI/mI) to record blood
pressure (BP) via a pressure transducer (Elcomatic 750, Glasgow,
UK). Simultaneous computerized measure of BP and ICP was performed.
CN was exposed at the lateral aspect of the prostate, with the aid
of a dissecting microscope and mounted on a bipolar platinum
electrode connected to an electrical stimulator (AMS 2100, Phymep,
France). In some animals an acute dose of sildenafil (0.3 mg/kg) or
vehicle was intravenously injected. This dose of sildenafil has
previously been demonstrated to ameliorate erectile function in
anesthetized GK rats (ref OGER-ROUSSEL S., BEHR-ROUSSEL D., CAISEY
S., KERGOAT M., CHARON C., AUDET A., BERNABE J., ALEXANDRE L.,
GIULIANO F., Bladder and erectile dysfunctions in the type 2
diabetic Goto-Kakizaki rat, Am. J. Physiol. Regul. Integr. Comp.
Physiol. 2014; 306(2):R108-17). The CN was stimulated at 6V, 1 ms
for 45 s by different stimulation frequencies (0, 2.5, 5, 7.5, 10,
12.5 and 15 Hz) in a randomized manner in order to assess the
erectile responses. These different electrical stimulations on the
increase of ICP were repeated twice in view of establishing a
frequency-response curve for each animal.
[0150] Mean arterial pressure (MAP) and the amplitude of the
erectile responses elicited by each ES CN were quantified for each
rat and averaged for each experimental group by calculating: [0151]
ICP (mmHg)/MAP (mmHg).times.100 with .DELTA.ICP being the
difference between ICP in the flaccid state, i.e. before
stimulation and ICP during the plateau phase of the erectile
response, and MAP, the mean arterial pressure during the plateau
phase. [0152] AUC.sub.45/MAP with AUC.sub.45, the area under the
curve during the first 45 seconds after the beginning of the
electrical stimulation of the cavernous nerve and determined using
the ICP level in the flaccid state before the onset of the
stimulation. [0153] AUC.sub.tot/MAP with AUC.sub.tot, the area
under the curve during the entire erectile response, measured from
the beginning of the electrical stimulation until the end of the
erectile response and determined using the ICP level in the flaccid
state before the onset of the stimulation. [0154] ICP increase and
AUC were normalized with MAP to account for the close influence of
the systemic blood pressure in the amplitude of ICP increase during
the plateau phase of the erectile response.
[0155] In addition, to further evaluate erectile function, at the
end of the in vivo evaluation of the ED, the penis of 24 GK rats
(groups IIA & IIIA) and 12 wistar rats (group I) were
immediately harvested and the corpora cavernosa (CC) dissected for
ex vivo isometric tension studies. After extensive washings,
corporal strips were incubated in the presence of guanethidine (5
.mu.M) and atropine (1 .mu.M) that were also added to the organ
chambers for the remainder of the experiments. The corporal strips
were placed between two parallel platinum electrodes in the organ
baths. After equilibration (60 min), the electric field stimulation
(EFS) experiments were started. Firstly, a priming period was
observed where corporal strips from Wistar, GK (control) and
GK_Chronic empa were exposed to phenylephrine (PHE) (10.sup.-5 M)
followed by an EFS-induced relaxation at 1 ms, 10 s, 300 mA and 20
Hz. Then, after washings, frequency-response curves (FRC) to EFS
(1-2-4-8-16-32 Hz) was constructed on PHE-precontracted corporal
strips (PHE 10.sup.-5 M). Frequency response-curves (FRC) to EFS
were performed by successive stimulation of the corporal strips at
1 ms, 10 s, 300 mA and increasing frequencies (1, 2, 4,8,16 and
32Hz).
Statistical Analysis
[0156] All results are presented as mean.+-.SEM. Grubbs test was
used for the detection and exclusion of outliers. This statistical
method allowed determining when a value was unlikely to have come
from the same Gaussian population as the other values in the
group.
[0157] For erectile function evaluation, comparisons of
frequency-response curves were performed with a two-way ANOVA
statistical analysis test followed by a Bonferroni's post-test. In
case of significant interaction between the two factors (i.e.
frequency of ES CN and experimental group), the difference between
groups of rats was examined by the modified Student's t-test with
the Bonferroni's adjustment for multiple comparisons.
[0158] For organ bath experiments, the amplitude of EFS-induced
relaxations were expressed in percentage of inhibition of the
contractile response to PHE.
[0159] The results from duplicate determinations in one experiment
with CC from one rat were averaged and the data expressed as
mean.+-.SEM for N experiments using CC from N different rats.
[0160] Statistical comparisons FRCs were performed using a two-way
ANOVA statistical analysis test and Bonferroni's post-test.
[0161] Statistical analysis was performed with GraphPad Prism.RTM.
5.04 software. P values <0.05 are considered significant.
Results
[0162] In the following an effect of chronic treatment with
empagliflozin on in vivo erectile function in GK rats is described
in comparison to an acute administration of sildenafil.
[0163] The FIG. 1 shows erectile responses elicited by cavernous
nerve stimulation at increasing stimulation frequencies in
anaesthetized Wistar rats that received control diet and acute
injection of normal saline (WI, n=15), GK rats that received
control diet and acute injection of normal saline (GK, n=10) or
sildenafil at 0.3mg/kg (GK_Acute sil, n=12) and GK rats that
received medicated diet i.e., control diet premixed with
empagliflozin at 25.3.+-.0.9 mg/kg/day, and acute injection of
normal saline (GK_Chronic empa, n=11). All rats received control or
medicated diet for 4 weeks, and then received an acute i.v.
injection of either sildenafil or normal saline 4 minutes prior to
the in vivo evaluation of erectile function, respectively. Data are
mean.+-.SEM.
[0164] The FIGS. 2a and 2b show erectile responses in terms of
AUC.sub.45/MAP (FIG. 2a) and AUC.sub.tot/MAP (FIG. 2b) elicited by
cavernous nerve stimulation at increasing stimulation frequencies
in anaesthetized Wistar rats that received control diet and acute
injection of normal saline (WI, n=15), GK rats that received
control diet and either acute injection of normal saline (GK, n=10)
or sildenafil at 0.3 mg/kg (GK_Acute sil, n=12) and GK rats that
received medicated diet i.e., control diet premixed with
empagliflozin at 25.3.+-.0.9 mg/kg/day and acute injection of
normal saline (GK_Chronic empa, n=11). All rats received control or
medicated diet for 4 weeks, and then received an acute IV injection
of either sildenafil or normal saline 4 minutes prior to the in
vivo evaluation of erectile function, respectively. Data are
mean.+-.SEM.
[0165] The in vivo erectile responses elicited by electrical
stimulation at increasing frequencies of the cavernous nerve
characterized by .DELTA.ICP/MAP (FIG. 1) as well as both
AUC.sub.45/MAP (FIG. 2a), and AUC.sub.tot/MAP (FIG. 2b) were
significantly reduced in diabetic GK rats compared with age-matched
Wistar rats.
[0166] Intravenous injection of sildenafil (0.3 mg/kg)
significantly increased the erectile response to ES CN in diabetic
GK rats in terms of .DELTA.ICP/MAP (p<0.0001, 2-way ANOVA, FIG.
1), AUC.sub.45/MAP (p<0.0001, 2-way ANOVA, FIG. 2a) and
AUC.sub.tot/MAP (p<0.0001, 2-way ANOVA, FIG. 2b).
[0167] The FIG. 3 shows relaxant responses elicited by increasing
frequencies of EFS on PHE-induced contractions of CC strips from
Wistar rats and diabetic GK rats that received control diet and
diabetic GK rats that received medicated diet i.e., control diet
premixed with empagliflozin at 25.3.+-.0.9 mg/kg/d. All rats
received control or medicated diet for 4 weeks.
[0168] Chronic administration of empagliflozin premixed with diet
at an average daily dose of 25.3.+-.0.9 mg/kg/day for 4 weeks
improved the erectile responses to ES CN in diabetic GK rats in
terms of AUC.sub.45/MAP (p<0.05, FIG. 2a) and AUC.sub.tot/MAP
(p<0.05, FIG. 2b) compared to those observed in diabetic GK rats
that received control diet. When examining the results obtained for
.DELTA.ICP/MAP, chronic empagliflozin seems to improve erectile
responses compared to diabetic GK rats that received control diet,
although no difference could be statistically detected (p=0.08,
2-way ANOVA, FIG. 1).
[0169] In the following in vitro nitrergic non-adrenergic
non-cholinergic neurogenic relaxation responses of isolated
corporal strips to EFS (electric field stimulation) are
described.
[0170] In diabetic GK rats, the relaxation induced by EFS on PHE
precontracted cavernosal strips was slightly but significantly
improved by a 4-week treatment of empagliflozin at 25.3.+-.0.9
mg/kg/d (p<0.05, 2-way ANOVA, FIG. 3). although the maximal
relaxation induced by EFS at 32 Hz was not significantly different
between treated and untreated diabetic rats (-42.0.+-.2.9% versus
-48.7.+-.6.6%).
[0171] In conclusion, the impairment of erectile responses in GK
rats and partially improvement with single dose sildenafil (0.3
mg/kg) is consistent with previous studies (ref A). In this model
of ED in diabetic GK rats, chronic treatment with empagliflozin at
25.3.+-.0.9 mg/kg/day slightly but consistently improved erectile
function, even though only the ratios of AUC.sub.45/MAP and
AUC.sub.tot/MAP showed a statistically significant improvement.
This observed pro-erectile facilitator effect of chronic
empaglfilozin remained slightly but significantly lower that an
acute IV dose of sildenafil at 0.3 mg/kg. Moreover, chronic
administration of empagliflozin slightly but significantly improved
nitrergic dysfunction in corporal strips of diabetic GK rats
Example of Pharmaceutical Composition and Dosage Form
[0172] The following example of solid pharmaceutical compositions
and dosage forms for oral administration serves to illustrate the
present invention more fully without restricting it to the contents
of the example. Further examples of compositions and dosage forms
for oral administration, are described in WO 2010/092126. The term
"active substance" denotes empagliflozin according to this
invention, especially its crystalline form as described in WO
2006/117359 and WO 2011/039107.
[0173] Tablets containing 2.5 mg, 5 mg, 10 mg, 25 mg of active
substance
TABLE-US-00001 2.5 mg/ 5 mg/ 10 mg/ 25 mg/ Active substance per
tablet per tablet per tablet per tablet Wet granulation active
substance 2.5000 5.000 10.00 25.00 Lactose 40.6250 81.250 162.50
113.00 Monohydrate Microcrystalline 12.5000 25.000 50.00 40.00
Cellulose Hydroxypropyl 1.8750 3.750 7.50 6.00 Cellulose
Croscarmellose 1.2500 2.500 5.00 4.00 Sodium Purified Water q.s.
q.s. q.s. q.s. Dry Adds Microcrystalline 3.1250 6.250 12.50 10.00
Cellulose Colloidal silicon 0.3125 0.625 1.25 1.00 dioxide
Magnesium stearate 0.3125 0.625 1.25 1.00 Total core 62.5000
125.000 250.00 200.00 Film Coating Film coating system 2.5000 4.000
7.00 6.00 Purified Water q.s. q.s. q.s. q.s. Total 65.000 129.000
257.00 206.00
[0174] Details regarding the manufacture of the tablets, the active
pharmaceutical ingredient, the excipients and the film coating
system are described in WO 2010/092126, in particular in the
Examples 5 and 6, which hereby is incorporated herein in its
entirety.
* * * * *