U.S. patent application number 10/885057 was filed with the patent office on 2004-12-02 for use of organic compounds.
Invention is credited to Emmons, Rebecca, Guitard, Christiane, Mueller, Beate.
Application Number | 20040242647 10/885057 |
Document ID | / |
Family ID | 8239709 |
Filed Date | 2004-12-02 |
United States Patent
Application |
20040242647 |
Kind Code |
A1 |
Guitard, Christiane ; et
al. |
December 2, 2004 |
Use of organic compounds
Abstract
The invention relates to the use of a hypolipidemic agent or a
pharmaceutically acceptable salt thereof for the manufacture of a
medicament for the prevention or delay of the progression to overt
diabetes, especially type 2, prevention or reduction of
microvascular complications (eg, retinopathy, neurophathy,
nephropathy), prevention or reduction of excessive cardiovascular
morbidity (eg, myocardial infarction, arterial occlusive disease,
atherosclerosis and stroke) and cardiovascular mortality,
prevention of cancer and reduction of cancer deaths. Additionally,
the invention relates to the use of a treatment for diseases and
conditions that are associated with IGM, IGT or IFG.
Inventors: |
Guitard, Christiane;
(Hegenheim, FR) ; Mueller, Beate; (Haenner,
DE) ; Emmons, Rebecca; (Riehen, CH) |
Correspondence
Address: |
NOVARTIS
CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 430/2
EAST HANOVER
NJ
07936-1080
US
|
Family ID: |
8239709 |
Appl. No.: |
10/885057 |
Filed: |
July 6, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10885057 |
Jul 6, 2004 |
|
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09731139 |
Dec 6, 2000 |
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Current U.S.
Class: |
514/342 ;
514/369 |
Current CPC
Class: |
A61P 27/02 20180101;
A61K 31/198 20130101; A61P 9/10 20180101; Y10S 514/866 20130101;
A61P 3/08 20180101; A61K 31/40 20130101; A61P 3/10 20180101; A61P
5/50 20180101; A61P 9/12 20180101; A61P 13/12 20180101; A61P 3/06
20180101; A61K 31/175 20130101; A61P 35/00 20180101; A61K 31/426
20130101; A61P 7/00 20180101; A61P 13/06 20180101; A61K 31/195
20130101; A61P 3/04 20180101; A61P 25/00 20180101; A61P 3/00
20180101; A61P 19/06 20180101; A61P 9/00 20180101; A61P 13/02
20180101 |
Class at
Publication: |
514/342 ;
514/369 |
International
Class: |
A61K 031/4439; A61K
031/426 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 23, 1999 |
EP |
99125761.9 |
Claims
1. A method for treating or preventing conditions or diseases
associated with IGT or IFG comprising administering repaglinide or
a pharmaceutically acceptable salt thereof to subjects in need
thereof.
2. The method of claim 1 for the prevention or delay of progression
to overt diabetes mellitus type 2; for the prevention, reduction or
delay in onset of a condition selected from the group consisting of
increased microvascular complications; increased cardiovascular
morbidity; excess cerebrovascular diseases; increased
cardiovascular mortality and sudden death; higher incidences and
mortality rates of malignant neoplasms; and other metabolic
disturbances that are associated with IGM.
3. The method of claim 1 for the prevention of cancer and reduction
of cancer deaths.
4. The method of claim 1 for the prevention, reduction or delay in
onset of a condition selected from the group e.g. consisting of
retinopathy, other ophthalmic complications of diabetes,
nephropathy, neuropathy, peripheral angiopathy, peripheral
angiopathy or gangrene, myocardial infarctions, coronary heart
disease, atherosclerosis, other acute and subacute forms of
coronary ischemia, stroke, dyslipidemia, hyperuricemia,
hypertension, angina pectoris, microangiopathic changes that result
in amputation, cancer, cancer deaths, obesity, uricemia, insulin
resistance, arterial occlusive disease, and atherosclerosis.
5. The method of claim 1 for the treatment of diseases or
conditions associated with isolated prandial hyperglycemia and/or
IFG.
6. The method of claim 1 for the prevention of diseases or
conditions associated with IGT in subjects with prandial glucose
excursions having 2 hour plasma glucose values between 7.8 to 11.1
mmol/L after an OGTT or casual glucose test.
7. (canceled)
8. (canceled)
9. (canceled)
10. (canceled)
11. The method of claim 5 wherein the disease and condition
associated with isolated prandial hyperglycemia and/or IFG is
selected from the group consisting of obesity, increased age,
family history of diabetes, diabetes during pregnancy,
dyslipidemia, high blood pressure, uricemia, insulin resistance,
arterial occlusive disease, atherosclerosis, retinopathy,
nephropathy, angina pectoris, myocardial infarction, and stroke.
Description
[0001] Impaired Glucose Metabolism (IGM) is defined by blood
glucose levels that are above the normal range but are not high
enough to meet the diagnostic criteria for type 2 diabetes
mellitus. The incidence of IGM varies from country to country, but
usually occurs 2-3 times more frequently than overt diabetes. Until
recently, individuals with IGM were felt to be pre-diabetics, but
data from several epidemiologic studies argue that subjects with
IGM are heterogeneous with respect to their risk of diabetes and
their risk of cardiovascular morbidity and mortality. The data
suggest that subjects with IGM, in particular IGT, do not always
develop diabetes, but whether they are diabetic or not, they are,
nonetheless, at high risk for cardiovascular morbidity and
mortality.
[0002] Among subjects with IGM, about 58% have Impaired Glucose
Tolerance (IGT), another 29% have Impaired Fasting Glucose (IFG),
and 13% have both abnormalities (IFG/IGT). IGT is characterized by
elevated postprandial (post-meal) hyperglycemia while IFG has been
defined by the ADA (see Table below) on the basis of fasting
glycemic values.
[0003] The categories of Normal Glucose Tolerance (NGT), IGM and
type 2 diabetes mellitus were defined by the ADA in 1997 as
follows:
1 Type 2 Diabetes NGT IGM mellitus IFG FPG level <6.1 mmol/L
6.1-7 mmol/L >7 mmol/L (<110 mg/dl) (110-126 mg/dl) >126
mg/dl) And and/or or IGT 2 h postprandial <7.8 mmol/l 7.8-11.1
mmol/L >11.1 mmol/L glucose (<140 mg/dl) (140-220 mg/dl)
(>200 mg/dl) level (75 g OGTT*.sup.)) *.sup.)These criteria were
defined using the WHO recommended conditions for administration of
an oral glucose tolerance test (OGTT), i.e., the oral
administration of a glucose load containing the equivalent of 75 g
of anyhydrous glucose dissolved in water with a blood sample taken
2 hours later to analyze the post-prandial glucose.
[0004] Individuals with IGM, especially those with the subcategory
IFG, are known to have a significantly higher rate of progression
to diabetes than normoglycemic individuals and are known to be high
at cardiovascular risk, especiallly if they develop diabetes.
Interestingly, subjects with IGM, more specifically those with the
subcategory IGT, have a high incidence of cancer, cardiovascular
diseases and mortality even if they never develop diabetes.
Therefore, IGM and more specifically, the subgroup IFG, appears to
be at high cardiovascular risk, especially after patients become
overtly diabetic. IGT, on the other hand, is associated with a high
risk for cancer, cardiovascular disease and mortality in
nondiabetics and diabetics. The increased risk associated with IGT
is independent of all other known cardiovascular risk factors
including age, sex, hypertension, low HDL and high LDL cholesterol
levels [Lancet 1999; 354: 617-621].
[0005] One mechanism through which IGM, and more specifically, IGT,
has been linked to micro- and macroangiopathic complications in the
absence of the abnormal FPG characteristic of diabetics, is
postprandial hyperglycemia. Isolated postprandial hyperglycemia,
even in nondiabetics, has been shown to reduce the natural
free-radical trapping agents (TRAP) that are present in serum.
Decreasing the level of TRAP has been shown, under experimental
conditions, to be associated with an increase in free radical
formation and increased oxidative stress. These free radicals have
been implicated in the pathological microvascular and macrovascular
changes associated with atherosclerosis, cardiovascular morbidity
and mortality, and cancer [Ceriello, A, Diabetic Medicine 15:
188-193, 1998]. The decrease of natural antioxidants like TRAP
during postprandial hyperglycemia may explain the increased
cardiovascular risk in subjects with IGM, and specifically IGT,
that do not develop diabetes. The fact that IGT is an independent
risk factor in non-diabetics as well as diabetics justifies it as a
new indication, separate from diabetes, for prevention and
treatment of cardiovascular morbidity and mortality as well as
cancer.
[0006] IGM is associated with following potential diseases or
conditions: 1.) progression to overt diabetes mellitus type 2 (Code
250.2 of the International Classification of Diseases 9.sup.th
version=ICD-9 Code 250.2) [Diabetes Research and Clinical Practice
1998; 40: S1-S2]; 2.) increased microvascular complications of
diabetes especially retinopathy and other ophthalmic complications
of diabetes (ICD-9 code 250.5), nephropathy (ICD-9 code 250.4),
neuropathy (ICD-9 code 250.6) [Diabetes Care 2000; 23: 1113-1118],
and peripheral angiopathy or gangrene (ICD-9 code 250.7); 3.)
increased cardiovascular morbidity (ICD-9 codes 410-414) especially
myocardial infarctions (ICD-9 code 410), coronary heart disease or
atherosclerosis (ICD-9 code 414) and other acute and subacute forms
of coronary ischemia (ICD-9 code 411); 4.) excess cerebrovascular
diseases like stroke (ICD-9 codes 430-438) [Circulation 1998; 98:
2513-2519]); 5.) increased cardiovascular mortality (ICD-9 codes
390-459) [Lancet 1999; 354: 617-621], and sudden death (ICD-9 code
798.1); 6.) higher incidences and mortality rates of malignant
neoplasms (ICD-9 codes 140-208) [Am J Epidemiol. 1990; 131:
254-262, Diabetologia 1999; 42: 1050-1054]. Other metabolic
disturbances that are associated with IGM include dyslipidemia
(ICD-9 code 272), hyperuricemia (ICD-9 code 790.6) as well as
hypertension (ICD-9 codes 401-404) and angina pectoris (ICD-9 code
413.9) [Ann Int Med 1998; 128: 524-533].
[0007] Clearly, the broad spectrum of diseases and conditions that
are linked to IGM, and especially IGT, represents an area of
tremendous medical need. Many of the same diseases and conditions
have been associated with both IGM and diabetes, but only recently
has it been possible to identify that that the nondiabetic
population that has IGM, and especially IGT, should be an
indication for prevention and treatment. Accordingly, in subjects
with IGM and especially IGT and/or IFG, the restoration of early
phase insulin secretion and/or the reduction of prandial
hyperglycemia should help to prevent or delay the progression to
overt diabetes and to prevent or reduce microvascular complications
associated with diabetes by preventing the development of the overt
diabetes. In addition, in individuals with IGM and especially those
with IGT and/or IFG, the restoration of early phase insulin
secretion and/or reduction of postprandial hyperglycemia should
also prevent or reduce the excessive cardiovascular morbidity and
mortality, and prevent cancer or reduce its mortality in
individuals.
[0008] Thus the stage between normoglycemia and type 2 diabetes
mellitus, especially the glycemic stage, is becoming of major
interest and there is a strong need for a method to inhibit or
delay the progression to type 2 diabetes mellitus, and also the
variety of cardiovascular and microvascular conditions and diseases
as well as cancer that have been associated with IGM and especially
IFG and/or IGT.
[0009] It has unexpectedly been found that hypoglycemic agents such
as insulin secretion enhancers can be used to prevent or delay the
progression to overt diabetes, to reduce microvascular
complications of diabetes, to reduce vascular, especially
cardiovascular, mortality and morbidity, especially cardiovascular
morbidity and mortality, and to reduce increased mortality related
to cancer in individuals with IGT and/or IFG.
[0010] Hypoglycemic agents comprise, for example, an insulin
secretion enhancer or an insulin sensitivity enhancer (insulin
resistance deblocker) or insulin of, if appropriate, in each case a
pharmaceutically acceptable salt thereof.
[0011] Insulin secretion enhancers are active ingredients that have
the property to promote the secretion of insulin from pancreatic
.beta.-cells.
[0012] An insulin secretion enhancer (also called insulin
secretogogue and insulinotropic agent) is, for example, a
shortacting or a long-acting hypoglycemic agent.
[0013] A short-acting hypoglycemic is, for example, a phenylacetic
acid derivative, furthermore gliquidone.
[0014] A corresponding phenylalanine derivative is, for example,
nateglinide
[N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine] (cf. EP
196222 and EP 526171) of the formula 1
[0015] and repaglinide
[(S)-2-ethoxy4-{2-[[3-methyl-1-[2-(1-piperidinyl)ph-
enyl]butyl]amino]-2-oxoethyl}benzoic acid]; and in free form or, if
appropriate, in each case a pharmaceutically acceptable salt
thereof.
[0016] The term nateglinide likewise comprises crystal
modifications such as disclosed in EP 0526171 B1 or U.S. Pat. No.
5,488,510, respectively, the subject matter of which, especially
with respect to the identification, manufacture and
characterization of crystal modifications, is herewith incorporated
by reference to this application, especially the subject matter of
claims 8 to 10 of said U.S. patent (referring to H-form crystal
modification) as well as the corresponding references to the B-type
crystal modification in EP 196222 B1 the subject matter of which,
especially with respect to the identification, manufacture and
characterization of the B-form crystal modification. Preferably, in
the present invention, the B- or H-type, more preferably the
H-type, is used.
[0017] A longacting hypoglycemic is, for example, a biguanide
derivative or a sulphonyl urea derivative.
[0018] An approriate biguanide is, for example, metformin or, if
appropriate, a pharmaceutically acceptable salt thereof, especially
the hydrochloride thereof.
[0019] Examples of sulfonylurea derivatives (SU) are, especially
those which promote the secretion of insulin from pancreatic
.beta.-cells by transmitting signals of insulin secretion via SU
receptors in the cell membrane, including (but are not limited to)
tolbutamide; chlorpropamide; tolazamide; acetohexamide;
4-chloro-N-[(1-pyrolidinylamino)carbonyl]-benz- ensulfonamide
(glycopyramide); glibenclamide (glyburide); gliclazide;
1-butyl-3-metanilylurea; carbutamide; glibonuride; glipizide;
gliquidone; glisoxepid; glybuthiazole; glibuzole; glyhexamide;
glymidine; glypinamide; phenbutamide; and tolylcyclamide, or, if
appropriate, in each case a pharmaceutically acceptable salt
thereof.
[0020] Insulin secretion enhancers furthermore include the
representatives of the new generation of SUs such as calcium
(2S)-2-benzyl-3-(cis-hexahyd- ro-2-isoindolinlycarbonyl)-propionate
dihydrate (KAD-1229) and glimepiride (Hoe 490); and in free or
pharmaceutically acceptable salt form.
[0021] Insulin secretion enhancers likewise include DPP-IV
inhibitors, GLP1 and GLP1 agonists.
[0022] DPP-IV is a serine protease and catalyses cleavage of
N-terminal Xaa-Pro or XaaAla dipeptide residues omcluding
glucagon-like protein-1 (GLP-1). Corresponding inhibitors of DPP-IV
increase circulating concentrations of GLP-1 and therefore
increasing insulin secretion.
[0023] Representatives of DPP-IV inhibitors are described in
WO98/19998 and WO00/34241. Preferred is
1-{2-[(5-cyanopyridin-2-yl)amino]ethylamino}-
acetyl-2(S)-cyano-pyrrolidine dihydrochloride (cf. example 3 of
WO98/19998) and
(S)1-[(3-hydroxy-1-adamantyl)amino]-acetyl-2-cyano-pyrrol- idine
(cf. example 1 of W00/34241).
[0024] GLP-1 and GLP-1 agonists likewise enhance insulin
secretion.
[0025] A preferred insulin secretion enhancer is repaglinide and
metformin, most preferred is nateglinide.
[0026] An insulin sensitivity enhancer restores impaired insulin
receptor function to reduce insulin resistance and consequently
enhance the insulin sensitivity.
[0027] An appropriate insulin sensitivity enhancer is, for example,
an appropriate hypoglycemic thiazolidinedione derivative
(glitazone).
[0028] An appropriate glitazone is, for example,
(S)-((3,4-dihydro-2-(phen-
yl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolidine-2,4-dione
(englitazone),
5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxopropyl)-pheny-
l]-methyl}-thiazolidine-2,4-dione (darglitazone),
5-{[4-(1-methyl-cyclohex-
yl)methoxy)-phenyl]methyl}-thiazolidine-2,4-dione (ciglitazone),
5-{[4-(2-(1-indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione
(DRF2189),
5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy)]benzyl}-thiazol-
idine-2,4-dione (BM-13.1246),
5-(2-naphthylsulfonyl)-thiazolidine-2,4-dion- e (AY-31637),
bis{4-[(2,4-dioxo-5-thiazolidinyl)methyl]phenyl}methane (YM268),
5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]benzyl}-t-
hiazolidine-2,4-dione (AD-5075),
5-[4-(1-phenyl-1-cyclopropanecarbonylamin-
o)-benzyl]-thiazolidine-2,4-dione (DN-108)
5-{[4-(2-(2,3-dihydroindol-1-yl-
)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione,
5-[3-(4-chloro-phenyl])-2-p-
ropynyl]-5-phenylsulfonyl)thiazolidine-2,4-dione,
5-[3-(4-chlorophenyl])-2-
-propynyl]-5-(4-fluorophenyl-sulfonyl)thiazolidine-2,4-dione,
5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,-
4-dione (rosiglitazone),
5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl-
}thiazolidine-2,4-dione (pioglitazone),
5-{[4-((3,4-dihydro-6-hydroxy-2,5,-
7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)-phenyl]-methyl}-thiazolidine-
-2,4-dione (troglitazone),
5-[6-(2-fluoro-benzyloxy)naphthalen-2-ylmethyl]-
-thiazolidine-2,4-dione (MCC555),
5-{[2-(2-naphthyl)-benzoxazol-5-yl]-meth- yl}thiazolidine-2,4-dione
(T-174) and 5-(2,4-dioxothiazolidin-5-ylmethyl)--
2-methoxy-N-(4-trifluoromethyl-benzyl)benzamide (KRP297). Preferred
are pioglitazone, rosiglitazone and troglitazone.
[0029] The structure of the active agents identified by generic or
tradenames may be taken from the actual edition of the standard
compendium "The Merck Index" or from databases, e.g. Patents
International (e.g. IMS World Publications). The corresponding
content thereof is hereby incorporated by reference. Any person
skilled in the art is fully enabled to identify the active agents
and, based on these references, likewise enabled to manufacture and
test the pharmaceutical indications and properties in standard test
models, both in vitro and in vivo.
[0030] Favorable effects can be verified that confirm that
hypoglycemic agents such as insulin enhancers can restore early
phase insulin secretion and reduce post-prandial glucose levels in
subjects with IGM. A multi-center, double-blind, parallel group,
randomized study can be conducted in subjects with IGM in order to
evaluate the incidence of confirmed hypoglycemia and the effects on
prandial glucose associated with the administration of nateglinide
30 mg, 60 mg or 120 mg or placebo before each main meal during 8
weeks of treatment. Subjects are selected on the basis of a 2-hour
plasma glucose value after a 75 g oral glucose tolerance test
(OGTT) and patients essentially meeting the following additional
inclusion criteria are included in the study:
[0031] two-hour glycemia post-OGTT between 7.8 to 11.1 mmol/L (one
OGTT to be performed during the year before entering the study, the
second to be performed within two weeks prior entering the
study);
[0032] FPG<7 mmol/L;
[0033] patients are to have a body mass index (BMI) between 20-32
kg/m2;
[0034] patients are to maintain prior diet during the full course
of study;
[0035] males, non-fertile females, females of child-bearing
potential using a medically approved birth control method are
included;
[0036] the use of other antidiabetics during the trial is not
permitted.
[0037] Corresponding dosages of e.g. nateglinide are administered
with a large glass of water 2 (BID), 3 (TID) or 4 (QID) times daily
depending on the number of main meals (breakfast, lunch, snack,
dinner). The first dose is to be given with the first main meal
(standardized meal i.e. 55% carbohydrates, 25% fat and 20%
protein). Visits are scheduled to be performed at weeks 0, 2, 4 and
8 and the patients are to be fasted for at least 7 hours. All blood
samples for laboratory evaluations are drawn between 07.00 and
10.00 a.m. HbA1c is to be measured at baseline and after 8 weeks of
treatment (fasting glucose and fructosamine). Samples of blood are
to be drawn at 10, 20, 20, 60, 120, and 180 minutes after drug
administration (time 0) and the glucose and insulin levels to be
measured. At weeks 0 and 8 visits, patients complete a standard
meal challenge containing approximately 500 kcal and measurements
of insulin and glucose will be performed.
[0038] The findings from analyses of all obtained data in such a
study clearly revealed that 2 hour prandial glucose levels, HBA1c
and fructosamine levels were surprisingly and significantly
reduced, that early phase insulin secretion was restored, and that
nateglinide could prevent or delay the progression to type 2
diabetes mellitus. With longer treatment and follow-up, conditions
and diseases associated with IGM could be prevented or reduced.
[0039] This type of study in individuals with IGM and particularly
IFG and IGTdiffers from those in diabetics since the subjects have
normal FPG and are nondiabetics or pre-diabetics.
[0040] Surprisingly, hypoglycemic agents as well as a combination
of hypoglycemic agents can be used in subjects with IGM, especially
IFG and/or IGT, for the prevention or delay of progression to overt
diabetes mellitus type 2; for the prevention, reduction or delay in
onset of a condition selected from the group consisting of
increased microvascular complications; increased cardiovascular
morbidity; excess cerebrovascular diseases; increased
cardiovascular mortality and sudden death; higher incidences and
mortality rates of malignant neoplasms; and other metabolic
disturbances that are associated with IGM.
[0041] Furthermore, hypoglycemic agents as well as a combination of
hypoglycemic agents can be used in subjects with IGM, especially
IFG and/or IGT, for the prevention, reduction or delay in onset of
a condition selected from the group e.g. consisting of retinopathy,
other ophthalmic complications of diabetes, nephropathy,
neuropathy, peripheral angiopathy, peripheral angiopathy, gangrene,
myocardial infarctions, coronary heart disease, atherosclerosis,
other acute and subacute forms of coronary ischemia, stroke,
dyslipidemia, hyperuricemia, hypertension, angina pectoris,
microangiopathic changes that result in amputation, cancer, cancer
deaths, obesity, uricemia, insulin resistance, arterial occlusive
disease, and atherosclerosis.
[0042] According to the present invention, hypoglycemic agents can
be used in subjects with IGM, especially with IFG and/or IGT, to
prevent or delay the progression to overt diabetes, to reduce
microvascular complications of diabetes, to reduce vascular,
especially cardiovascular, mortality and morbidity, especially
cardiovascular morbidity and mortality, and to reduce increased
mortality related to cancer in individuals with IGT.
[0043] Accordingly, the present invention relates to a method in
subjects with IGM, especially IFG and/or IGT, for the prevention or
delay of progression to overt diabetes mellitus type 2; for the
prevention, reduction or delay in onset of a condition selected
from the group consisting of increased microvascular complications;
increased cardiovascular morbidity; excess cerebrovascular
diseases; increased cardiovascular mortality and sudden death;
higher incidences and mortality rates of malignant neoplasms; and
other metabolic disturbances that are associated with IGM.
[0044] Especially, the present invention relates to a method used
in subjects with IGM, especially IFG and/or IGT, for the
prevention, reduction or delay in onset of a condition selected
from the group e.g. consisting of retinopathy, other ophthalmic
complications of diabetes, nephropathy, neuropathy, peripheral
angiopathy, peripheral angiopathy gangrene, myocardial infarctions,
coronary heart disease, atherosclerosis, other acute and subacute
forms of coronary ischemia, stroke, dyslipidemia, hyperuricemia,
hypertension, angina pectoris, microangiopathic changes that result
in amputation, cancer, cancer deaths, obesity, uricemia, insulin
resistance, arterial occlusive disease, and atherosclerosis.
[0045] Accordingly, the present invention relates to a method of
prevention or delay of the progression to overt diabetes,
especially type 2 (ICD-9 Code 250.2), prevention or reduction of
microvascular complications like retinopathy (ICD-9 code 250.5),
neurophathy (ICD-9 code 250.6), nephropathy (ICD-9 code 250.4) and
peripheral angiopathy or gangrene (ICD-9 code 250.7), later termed
"microvascular complications" in subjects with IGM, especially IFG
and IGT. Further the present invention relates to a method to
prevent or reduce conditions of excessive cardiovascular morbidity
(ICD-9 codes 410-414), e.g. myocardial infarction (ICD-9 code 410),
arterial occlusive disease, atherosclerosis and other acute and
subacute forms of coronary ischemia (ICD-9 code 411-414), later
termed "cardiovascular morbidity"; to prevent, reduce, or delay the
onset of excess cerebrovascular diseases like stroke (ICD-9 codes
430-438); to reduce increased cardiovascular mortality (ICD-9 codes
390-459) and sudden death (ICD-9 code 798.1); to prevent the
development of cancer (ICD-9 codes 140-208) and to reduce cancer
deaths, in each case, in subjects with IGM, especially IFG and IGT.
The method further relates to a method of prevention or reduction
of other metabolic disturbances that are associated with IGM
including hyperglycemia (including isolated postprandial
hyperglycemia), dyslipidemia (ICD-9 code 272), hyperuricemia (ICD-9
code 790.6) as well as hypertension (ICD-9 codes 401-404) and
angina pectoris (ICD-9 code 413.9), in each case, in subjects with
IGM, especially IFG and IGT.
[0046] The codes identified hereinbefore and herafter according to
the International Classification of Diseases 9.sup.th version and
the corresponding definitions allocated thereto are herewith
incorporated by reference and likewise form part of the present
invention.
[0047] The induction by hypoglycemic agents, in particular of early
phase secretion, is rapidly reversible and the reduction of
postprandial glucose levels is favorable for prevention or
treatment in this indication.
[0048] The method comprises administering to a subject in need
thereof an effective amount of hypoglycemic agents such as an
insulin secretion enhancer or a pharmaceutically acceptable salt
thereof. A subject in need of such method is a warm-blooded animal
including man.
[0049] The present invention also relates to a method to be used in
subjects with IGM, and especially IFG and/or IGT, and associated
diseases and conditions such as isolated prandial hyperglycemia,
prevention or delay of the progression to overt diabetes,
especially type 2, prevention reduction, or delay the onset of
microvascular complications, prevention or reduction of gangrene or
microangiopathic changes that result in amputation, prevention or
reduction of excessive cardiovascular morbidity and cardiovascular
mortality, prevention of cancer and reduction of cancer deaths.
[0050] The present invention likewise relates to a method of
treatment of conditions and diseases associated with IGM and
especially IFG and/or IGT (including isolated prandial
hyperglycemia) including obesity, increased age, diabetes during
pregnancy, dyslipidemia, high blood pressure, uricemia, insulin
resistance, arterial occlusive disease, atherosclerosis,
retinopathy, nephropathy, angina pectoris, myocardial infarction,
and stroke.
[0051] Preferably, said preventions should be effected in
individuals with glucose levels in the ranges that have been proven
in large epidemiologic studies to confer increased cardiovascular,
microvascular and cancer risk. These levels include levels of
plasma glucose .gtoreq.7.8 mmol/L mmol/L after an OGTT or casual
glucose evaluation and/or fasting plasma glucose in the IFG range
(fasting plasma glucose between 6.1 and 7 mmol/l). As new
epidemiologic data become available to lower the glycemic levels
that are incontrovertibly linked to the above-mentioned risks, or
as the international standards for defining the IGT and IFG risk
groups are changed, the use of the invention is also warranted for
treatment of the groups at risk.
[0052] The present invention also relates to a method to be used in
subjects with IFG comprising administering to a subject in need
thereof a therapeutically effective amount of a DPP-IV
inhibitor.
[0053] The present invention relates to the use of a hypoglycemic
agent or a pharmaceutically acceptable salt thereof for the
manufacture of a medicament in subjects with IGM, especially IFG
and/or IGT, for the prevention or delay of progression to overt
diabetes mellitus type 2; for the prevention, reduction or delay in
onset of a condition selected from the group consisting of
increased microvascular complications; increased cardiovascular
morbidity; excess cerebrovascular diseases; increased
cardiovascular mortality and sudden death; higher incidences and
mortality rates of malignant neoplasms; and other metabolic
disturbances that are associated with IGM.
[0054] The present invention relates to the use of an insulin
secretion enhancer or a pharmaceutically acceptable salt thereof
for the manufacture of a medicament for the prevention or delay of
the progression to overt diabetes, especially type 2, prevention or
reduction of microvascular complications, prevention or reduction
of excessive cardiovascular morbidity and cardiovascular mortality,
prevention of cancer and reduction of cancer deaths.
[0055] The present invention relates to the use of an insulin
secretion enhancer or a pharmaceutically acceptable salt for the
manufacture of a medicament in subjects with IGM, and especially
IFG and/or IGT, and associated diseases and conditions such as
isolated prandial hyperglycemia for the following: prevention or
delay of the progression to overt diabetes, especially type 2,
prevention or reduction of microvascular complications, prevention
or reduction of excessive cardiovascular morbidity and
cardiovascular mortality, prevention of cancer and reduction of
cancer deaths.
[0056] The present invention relates to a pharmaceutical
composition in subjects with IGM, especially IFG and/or IGT, for
the prevention or delay of progression to overt diabetes mellitus
type 2; for the prevention, reduction or delay in onset of a
condition selected from the group consisting of increased
microvascular complications; increased cardiovascular morbidity;
excess cerebrovascular diseases; increased cardiovascular mortality
and sudden death; higher incidences and mortality rates of
malignant neoplasms; and other metabolic disturbances that are
associated with IGM; comprising a hypoglycemic agent or a
pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable carrier.
[0057] The present invention relates to a pharmaceutical
composition for the prevention or delay of the progression to overt
diabetes, especially type 2, prevention or reduction of
microvascular complications, prevention or reduction of excessive
cardiovascular morbidity and cardiovascular mortality, prevention
of cancer and reduction of cancer deaths, comprising an insulin
secretion enhancers or a pharmaceutically acceptable salt thereof
and a pharmaceutically acceptable carrier.
[0058] The present invention relates to a pharmaceutical
composition in subjects with IGM, and especially IFG and/or IGT and
associated diseases and conditions such as isolated prandial
hyperglycemia for the following: prevention or delay of the
progression to overt diabetes, especially type 2, prevention or
reduction of microvascular complications, prevention or reduction
of excessive cardiovascular morbidity and cardiovascular mortality,
prevention of cancer and reduction of cancer deaths.
[0059] The corresponding active ingredient or a pharmaceutically
acceptable salt thereof may also be used in form of a hydrate or
include other solvents used for crystallization.
[0060] Furthermore, the present invention relates to the
combination such as a combined preparation or pharmaceutical
composition, respectively, comprising at least one insulin
secretion enhancer and alt least one insulin sensitiser; or at
least two insulin secretion enhancers; or at least two insulin
sensitisers; to be used in subjects with IGM, especially IFG and/or
IGT, for the prevention or delay of progression to overt diabetes
mellitus type 2; for the prevention, reduction or delay in onset of
a condition selected from the group consisting of increased
microvascular complications; increased cardiovascular morbidity;
excess cerebrovascular diseases; increased cardiovascular mortality
and sudden death; higher incidences and mortality rates of
malignant neoplasms; and other metabolic disturbances that are
associated with IGM.
[0061] Further benefits when applying the combination of the
present invention are that lower doses of the individual drugs to
be combined according to the present invention can be used to
reduce the dosage, for example, that the dosages need not only
often be smaller but are also applied less frequently, or can be
used in order to diminish the incidence of side effects. This is in
accordance with the desires and requirements of the patients to be
treated.
[0062] Preferably, the jointly therapeutically effective amounts of
the active agents according to the combination of the present
invention can be administered simultaneously or sequentially in any
order, separately or in a fixed combination.
[0063] The term "therapeutically effective amount" shall mean that
amount of a drug or combination that will elicit the biological or
medical response needed to achieve the therapeutic effect as
specified according to the present invention in the warm-blooded
animal, including man. A "therapeutically effective amount" can be
administered when administering a single hypoglycemic agent and
also in both a fixed or free combination of hypoglycemic agents. A
"jointly effective amount" in a combination according to the
present invention shall also include a non-effective amount of at
least one of the agents to be combined, if the overall effect can
be achieved by the combined administration of the (fixed or free)
combination.
[0064] The pharmaceutical composition according to the present
invention as described hereinbefore and hereinafter may be used for
simultaneous use or sequential use in any order, for separate use
or as a fixed combination.
[0065] Preferred components for a combination according to the
present invention preferably those that are designated as preferred
hypoglycemic agents, that are most preferably selected from
nateglinide, repaglinide, metformin, pioglitazone, rosiglitazone,
troglitazone,
1-{2-[(5-cyanopyridin-2-yl)amino]ethylamino}acetyl-2(S)-cyano-pyrrolidine-
, and
(S)1-[(3-hydroxy-1-adamantyl)amino]-acetyl-2-cyano-pyrrolidine, or,
if appropriate, in each case, a pharmaceutically acceptable salt
thereof.
[0066] In a variation thereof, the present invention likewise
relates to a "kit-of-parts", for example, in the sense that the
components to be combined according to the present invention can be
dosed independently or by use of different fixed combinations with
distinguished amounts of the components, i.e. simultaneously or at
different time points. The parts of the kit of parts can then e.g.
be administered simultaneously or chronologically staggered, that
is at different time points and with equal or different time
intervals for any part of the kit of parts. Preferably, the time
intervals are chosen such that the effect on the treated disease or
condition in the combined use of the parts is larger than the
effect that would be obtained by use of only any one of the
components.
[0067] The invention furthermore relates to a commercial package
comprising the combination according to the present invention
together with instructions for simultaneous, separate or sequential
use.
[0068] The compounds to be combined can be present as
pharmaceutically acceptable salts. If these compounds have, for
example, at least one basic center, they can form acid addition
salts. Corresponding acid addition salts can also be formed having,
if desired, an additionally present basic center. The compounds
having an acid group (for example COOH) can also form salts with
bases.
[0069] Pharmaceutically acceptable salts e.g. of nateglinide are,
for example, salts formed with bases, namely cationic salts such as
alkali and alkaline earth metal salts, as well as ammonium
salts.
[0070] The pharmaceutical compositions according to the invention
can be prepared in a manner known per se and are those suitable for
enteral, such as oral or rectal, and parenteral administration to
mammals (warm-blooded animals), including man, comprising a
therapeutically effective amount of the pharmacologically active
compound, alone or in combination with one or more pharmaceutically
acceptable carries, especially suitable for enteral or parenteral
application.
[0071] The novel pharmaceutical preparations contain, for example,
from about 10% to about 100%, preferably 80%, preferably from about
20% to about 60%, of the active ingredient. Pharmaceutical
preparations according to the invention for enteral or parenteral
administration are, for example, those in unit dose forms, such as
sugar-coated tablets, tablets, capsules or suppositories, and
furthermore ampoules. These are prepared in a manner known per se,
for example by means of conventional mixing, granulating,
sugar-coating, dissolving or lyophilizing processes. Thus,
pharmaceutical preparations for oral use can be obtained by
combining the active ingredient with solid carriers, if desired
granulating a mixture obtained, and processing the mixture or
granules, if desired or necessary, after addition of suitable
excipients to give tablets or sugar-coated tablet cores.
[0072] The doses for hypoglycemic agents for use according to the
present invention may, for example, be those that are being used
for agents that have already been launched. For example, tablets of
repaglinide in doses of 0.5 mg, 1 mg or 2 mg of the active
ingredient or tablets of metformin in doses of 500 mg or 850 mg of
the active ingredient may be taken Likewise these doses may also be
used for the agents to be combined combination according to the
present invention. A person skilled in the art is fully enabled,
based on his knowledge, to determine the specific doses for the
specific hypolipidemic agents whether taken alone or in
combination.
[0073] Nateglinide (I) is preferably administered to the
warm-blooded animal in a dosage in the range of about 5 to 1200,
more preferably 25 to 800, mg/day, when the warm-blooded animal is
a human of about 70 kg body weight. Preferred dosages contain 30
mg, 60 mg or 120 mg of nateglinde to be administered preferably
before the main meals. Depending on the number of main meals the
dose regimen are two times a day (BID) or three times a day (TID)
or four times a day (QID).
[0074] The following Examples illustrate the invention described
above; they are not, however, intended to limit the scope of the
invention in any way.
EXAMPLE 1
Tablets of Nateglinide (I)
[0075] 216,000 tablets, each which contain 120 mg of nateglinide
(I) are prepared as follows:
2 Composition: nateglinide (I) 12.960 kg lactose, NF 30.564 kg
microcrystalline cellulose, NF 15.336 kg povidone, USP 2.592 kg
croscarmellose sodium, NF 3.974 kg colloidal silicon dioxide, NF
1.382 kg magnesium stearate, NF 1.231 kg coating: opadry yellow
1.944 kg purified water, USP* Q.S. *removed during process
[0076] Preparation process: The microcrystalline cellulose,
povidone, part of the croscarmellose sodium, nateglinide (I) and
lactose are mixed in a high shear mixer and afterwards granulated
using purified water. The wet granules are dried in a fluid bed
dryer and passed through a screen. The colloidal silicon dioxide
and the rest of the croscarmellose sodium are mixed, passed through
a screen and blended with the dried granules in a V-blender. The
magnesium stearate is passed through a screen, blended with the
blend from the V-blender and afterwards the total mixture is
compressed to tablets. The opadry yellow is suspended in purified
water and the tablets are coated with the coating suspension.
EXAMPLE 2
Galenic Formulation of Nateglinide (I) No. 1
[0077]
3 intra-granular: nateglinide (I) 120 mg lactose monohydrate 283 mg
microcrystalline cellulose 142 mg povidone 24 mg croscarmellose
sodium 24 mg extra-granular: magnesium stearate 7 mg opadry white
20 mg
EXAMPLE 3
Galenic Formulation of Nateglinide (I) No. 2
[0078]
4 intra-granular: nateglinide (I) 120 mg lactose monohydrate 283 mg
microcrystalline cellulose 142 mg povidone 24 mg croscarmellose
sodium 24 mg extra-granular: croscarmellose sodium 12.8 mg
magnesium stearate 11.4 mg opadry yellow 18.0 mg colloidal silicon
dioxide 12.8 mg
EXAMPLE 4
Tablets of Nateglinide
[0079] 108,000 tablets, each which contain 120 mg of nateglinide
are prepared as follows:
5 Composition: nateglinide 12.960 kg lactose, NF 30.564 kg
microcrystalline cellulose, NF 15.336 kg povidone, USP 2.592 kg
croscarmellose sodium, NF 3.974 kg colloidal silicon dioxide, NF
1.382 kg magnesium stearate, NF 1.231 kg coating: opadry yellow
1.944 kg purified water, USP* Q.S. *removed during process
[0080] Preparation Process: The microcrystalline cellulose,
povidone, a portion of the croscarmellose sodium, nateglinide and
lactose are granulated in a collette gral granulator with the
addition of purified water. The wet granules are dried in a fluid
bed dryer and passed through a screen. The colloidal silicon
dioxide and the rest of the croscarmellose sodium are mixed, passed
through a screen and blended with the dried granules in a
V-blender. The magnesium stearate is passed through a screen,
blended with the blend from the V-blender and afterwards the total
mixture is compressed to tablets. The opadry yellow is suspended in
purified water and the tablets are coated with the coating
suspension. Variants of this process include adding the colloidal
silica and the remaining croscarmellose sodium to the second
granulator load after drying, then screening together; and
combining as many as 3 granulator/drier loads per batch.
EXAMPLE 5
Pharmaceutical Composition of Nateglinide (120 mg)
[0081]
6 nateglinide 120 mg lactose monohydrate 283 mg microcrystalline
cellulose 142 mg Povidone 24 mg croscarmellose sodium 36.8 mg
magnesium stearate 11.4 mg opadry yellow 18.0 mg colloidal silicon
dioxide 12.8 mg
* * * * *