U.S. patent application number 11/295928 was filed with the patent office on 2006-04-27 for combination.
Invention is credited to Malcolm Allison, Marjorie Regan Gatlin.
Application Number | 20060089389 11/295928 |
Document ID | / |
Family ID | 36206938 |
Filed Date | 2006-04-27 |
United States Patent
Application |
20060089389 |
Kind Code |
A1 |
Allison; Malcolm ; et
al. |
April 27, 2006 |
Combination
Abstract
The present invention relates to a combination, especially a
pharmaceutical composition, comprising as active ingredients (i) an
AT.sub.1-receptor antagonist or a pharmaceutically acceptable salt
thereof; (ii) (a) an insulin secretion enhancer or a
pharmaceutically acceptable salt thereof or (b) an insulin
sensitizer or a pharmaceutically acceptable salt thereof; and, in
case of a pharmaceutical composition, a pharmaceutically acceptable
carrier.
Inventors: |
Allison; Malcolm; (Basel,
CH) ; Gatlin; Marjorie Regan; (Hoboken, NJ) |
Correspondence
Address: |
NOVARTIS;CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 104/3
EAST HANOVER
NJ
07936-1080
US
|
Family ID: |
36206938 |
Appl. No.: |
11/295928 |
Filed: |
December 7, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10362340 |
Jun 16, 2003 |
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PCT/EP01/09587 |
Aug 20, 2001 |
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11295928 |
Dec 7, 2005 |
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60327553 |
Aug 22, 2000 |
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Current U.S.
Class: |
514/342 ;
514/369; 514/381; 514/563; 514/592 |
Current CPC
Class: |
A61P 3/10 20180101; A61K
31/41 20130101; A61K 31/426 20130101; A61K 31/155 20130101; A61K
31/155 20130101; A61K 31/195 20130101; A61K 31/426 20130101; A61K
31/4439 20130101; A61K 31/4439 20130101; A61K 31/41 20130101; A61K
31/175 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 45/06 20130101; A61K 31/198 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 31/175 20130101; A61K 31/195 20130101;
A61K 31/198 20130101 |
Class at
Publication: |
514/342 ;
514/369; 514/381; 514/563; 514/592 |
International
Class: |
A61K 31/4439 20060101
A61K031/4439; A61K 31/426 20060101 A61K031/426; A61K 31/41 20060101
A61K031/41; A61K 31/195 20060101 A61K031/195; A61K 31/175 20060101
A61K031/175 |
Claims
1. A pharmaceutical composition, wherein the active ingredients
consist of (i) an AT.sub.1-receptor antagonist or a
pharmaceutically acceptable salt thereof; (ii) (a) an insulin
secretion enhancer or a pharmaceutically acceptable salt thereof or
(b) an insulin sensitizer or a pharmaceutically acceptable salt
thereof; and (iii) a pharmaceutically acceptable carrier.
2. A compostion acording to claim 1 wherein the AT.sub.1 receptor
antagonist is selected from the group consisting of valsartan,
losartan, candesartan, eprosartan, irbesartan, olmesartan,
tasosartan, and telmisartan, and, in each case, a pharmaceutically
acceptable salt thereof.
3. A composition according to claim 2 wherein the AT.sub.1 receptor
antagonist is valsartan or a pharmaceutically acceptable salt
thereof.
4. A composition according to claim 1 wherein the insulin secretion
enhancer is selected from tolbutamide; chlorpropamide; tolazamide;
acetohexamide; glycopyramide; glibenclamide; gliclazide;
1-butyl-3-metanilylurea; carbutamide; glibonuride; glipizide;
gliquidone; glisoxepid; glybuthiazole; glibuzole; glyhexamide;
glymidine; glypinamide; phenbutamide; tolylcyclamide, nateglinide
repaglinide; mitiglinide; glimepiride; and, in each case, a
pharmaceutically acceptable salt thereof.
5. A composition according to claim 4 wherein the insulin secretion
enhancer is nateglinide or a pharmaceutically acceptable salt
thereof.
6. A composition according to claim 1 wherein the insulin
sensitizer is metformin or a pharmaceutically acceptable salt
thereof.
7. A composition according to claim 1 for the prevention, delay of
progression or treatment of a of disease or disorder selected from
the group consisting of hypertension, congestive heart failure,
diabetes, especially type 2 diabetes mellitus, diabetic
retinopathy, macular degeneration, diabetic nephropathy,
glomerulosclerosis, chronic renal failure, diabetic neuropathy,
syndrome X, premenstrual syndrome, coronary heart disease, angina
pectoris, myocardial infarction, stroke, vascular restenosis,
hyperglycemia, hyperinsulinaemia, hyperlipidaemia,
hypertryglyceridemia, insulin resistance, impaired glucose
metabolism, conditions of impaired glucose tolerance (IGT),
conditions of impaired fasting plasma glucose, obesity, diabetic
retinopathy, macular degeneration, cataracts, diabetic nephropathy,
glomerulosclerosis, diabetic neuropathy, erectile dysfunction, skin
and connective tissue disorders, foot ulcerations and ulcerative
colitis, endothelial dysfunction and impaired vascular
compliance.
8. A composition according to claim 1 for the prevention, delay of
progression or treatment of a of disease or disorder selected from
the group consisting of hypertension, especially ISH, congestive
heart failure, endothelial dysfunction, impaired vascular
compliance, IGT and type II diabetes mellitus.
9. A method for the prevention, delay of progression or treatment
of a disease or disorder which may be inhibited by the inhibition
of AT.sub.1 receptor and/or by the enhancement of insulin secretion
comprising administering to a warm-blooded animal, including man,
in need thereof jointly therapeutically effective amounts of (i) an
AT.sub.1-receptor antagonist or a pharmaceutically acceptable salt
thereof; (ii) (a) an insulin secretion enhancer or a
pharmaceutically acceptable salt thereof or (b) an insulin
sensitizer or a pharmaceutically acceptable salt thereof.
10. Use of a combination comprising as active ingredients (i) an
AT.sub.1-receptor antagonist or a pharmaceutically acceptable salt
thereof; (ii) (a) an insulin secretion enhancer or a
pharmaceutically acceptable salt thereof or (b) an insulin
sensitizer or a pharmaceutically acceptable salt thereof; for the
manufacture of a medicament for the prevention, delay of
progression or treatment of a disease or disorder which may be
inhibited by the inhibition of AT.sub.1 receptor and by the
enhancement of insulin secretion.
11. The composition according to claim 2 for the prevention, delay
of progression or treatment of a of disease or disorder selected
from the group consisting of hypertension, congestive heart
failure, diabetes, especially type 2 diabetes mellitus, diabetic
retinopathy, macular degeneration, diabetic nephropathy,
glomerulosclerosis, chronic renal failure, diabetic neuropathy,
syndrome X, premenstrual syndrome, coronary heart disease, angina
pectoris, myocardial infarction, stroke, vascular restenosis,
hyperglycemia, hyperinsulinaemia, hyperlipidaemia,
hypertryglyceridemia, insulin resistance, impaired glucose
metabolism, conditions of impaired glucose tolerance (IGT),
conditions of impaired fasting plasma glucose, obesity, diabetic
retinopathy, macular degeneration, cataracts, diabetic nephropathy,
glomerulosclerosis, diabetic neuropathy, erectile dysfunction, skin
and connective tissue disorders, foot ulcerations and ulcerative
colitis, endothelial dysfunction and impaired vascular
compliance.
12. The composition according to claim 3 for the prevention, delay
of progression or treatment of a of disease or disorder selected
from the group consisting of hypertension, congestive heart
failure, diabetes, especially type 2 diabetes mellitus, diabetic
retinopathy, macular degeneration, diabetic nephropathy,
glomerulosclerosis, chronic renal failure, diabetic neuropathy,
syndrome X, premenstrual syndrome, coronary heart disease, angina
pectoris, myocardial infarction, stroke, vascular restenosis,
hyperglycemia, hyperinsulinaemia, hyperlipidaemia,
hypertryglyceridemia, insulin resistance, impaired glucose
metabolism, conditions of impaired glucose tolerance (IGT),
conditions of impaired fasting plasma glucose, obesity, diabetic
retinopathy, macular degeneration, cataracts, diabetic nephropathy,
glomerulosclerosis, diabetic neuropathy, erectile dysfunction, skin
and connective tissue disorders, foot ulcerations and ulcerative
colitis, endothelial dysfunction and impaired vascular
compliance.
13. The composition according to claim 4 for the prevention, delay
of progression or treatment of a of disease or disorder selected
from the group consisting of hypertension, congestive heart
failure, diabetes, especially type 2 diabetes mellitus, diabetic
retinopathy, macular degeneration, diabetic nephropathy,
glomerulosclerosis, chronic renal failure, diabetic neuropathy,
syndrome X, premenstrual syndrome, coronary heart disease, angina
pectoris, myocardial infarction, stroke, vascular restenosis,
hyperglycemia, hyperinsulinaemia, hyperlipidaemia,
hypertryglyceridemia, insulin resistance, impaired glucose
metabolism, conditions of impaired glucose tolerance (IGT),
conditions of impaired fasting plasma glucose, obesity, diabetic
retinopathy, macular degeneration, cataracts, diabetic nephropathy,
glomerulosclerosis, diabetic neuropathy, erectile dysfunction, skin
and connective tissue disorders, foot ulcerations and ulcerative
colitis, endothelial dysfunction and impaired vascular
compliance.
14. The composition according to claim 5 for the prevention, delay
of progression or treatment of a of disease or disorder selected
from the group consisting of hypertension, congestive heart
failure, diabetes, especially type 2 diabetes mellitus, diabetic
retinopathy, macular degeneration, diabetic nephropathy,
glomerulosclerosis, chronic renal failure, diabetic neuropathy,
syndrome X, premenstrual syndrome, coronary heart disease, angina
pectoris, myocardial infarction, stroke, vascular restenosis,
hyperglycemia, hyperinsulinaemia, hyperlipidaemia,
hypertryglyceridemia, insulin resistance, impaired glucose
metabolism, conditions of impaired glucose tolerance (IGT),
conditions of impaired fasting plasma glucose, obesity, diabetic
retinopathy, macular degeneration, cataracts, diabetic nephropathy,
glomerulosclerosis, diabetic neuropathy, erectile dysfunction, skin
and connective tissue disorders, foot ulcerations and ulcerative
colitis, endothelial dysfunction and impaired vascular
compliance.
15. The composition according to claim 6 for the prevention, delay
of progression or treatment of a of disease or disorder selected
from the group consisting of hypertension, congestive heart
failure, diabetes, especially type 2 diabetes mellitus, diabetic
retinopathy, macular degeneration, diabetic nephropathy,
glomerulosclerosis, chronic renal failure, diabetic neuropathy,
syndrome X, premenstrual syndrome, coronary heart disease, angina
pectoris, myocardial infarction, stroke, vascular restenosis,
hyperglycemia, hyperinsulinaemia, hyperlipidaemia,
hypertryglyceridemia, insulin resistance, impaired glucose
metabolism, conditions of impaired glucose tolerance (IGT),
conditions of impaired fasting plasma glucose, obesity, diabetic
retinopathy, macular degeneration, cataracts, diabetic nephropathy,
glomerulosclerosis, diabetic neuropathy, erectile dysfunction, skin
and connective tissue disorders, foot ulcerations and ulcerative
colitis, endothelial dysfunction and impaired vascular
compliance.
16. The composition according to claim 2 for the prevention, delay
of progression or treatment of a of disease or disorder selected
from the group consisting of hypertension, especially ISH,
congestive heart failure, endothelial dysfunction, impaired
vascular compliance, IGT and type II diabetes mellitus.
17. The composition according to claim 3 for the prevention, delay
of progression or treatment of a of disease or disorder selected
from the group consisting of hypertension, especially ISH,
congestive heart failure, endothelial dysfunction, impaired
vascular compliance, IGT and type II diabetes mellitus.
18. The composition according to claim 4 for the prevention, delay
of progression or treatment of a of or disorder selected from the
group consisting of hypertension, especially ISH, congestive heart
failure, endothelial dysfunction, impaired vascular compliance, IGT
and type II diabetes mellitus.
19. The composition according to claim 5 for the prevention, delay
of progression or treatment of a of or disorder selected from the
group consisting of hypertension, especially ISH, congestive heart
failure, endothelial dysfunction, impaired vascular compliance, IGT
and type II diabetes mellitus.
20. The composition according to claim 6 for the prevention, delay
of progression or treatment of a of disease or disorder selected
from the group consisting of hypertension, especially ISH,
congestive heart failure, endothelial dysfunction, impaired
vascular compliance, IGT and type II diabetes mellitus.
21. The composition according to claim 7 for the prevention, delay
of progression or treatment of a of disease or disorder selected
from the group consisting of hypertension, especially ISH,
congestive heart failure, endothelial dysfunction, impaired
vascular compliance, IGT and type II diabetes mellitus.
Description
[0001] The present invention relates to a combination, especially a
pharmaceutical composition, comprising as active ingredients [0002]
(i) an AT.sub.1-receptor antagonist or a pharmaceutically
acceptable salt thereof; [0003] (ii) (a) an insulin secretion
enhancer or a pharmaceutically acceptable salt thereof or [0004]
(b) an insulin sensitizer or a pharmaceutically acceptable salt
thereof; and, [0005] in case of a pharmaceutical composition, a
pharmaceutically acceptable carrier.
[0006] AT.sub.1-receptor antagonists (also called angiotensin II
receptor antagonists or blockers) are understood to be those active
ingredients that bind to the AT.sub.1-receptor subtype of
angiotensin II receptor but do not result in activation of the
receptor. As a consequence of the blockade of the AT.sub.1
receptor, these antagonists can, for example, be employed as
antihypertensives or for treating congestive heart failure.
[0007] The class of AT.sub.1 receptor antagonists comprises
compounds having differing structural features, essentially
preferred are the non-peptidic ones. For example, mention may be
made of the compounds that are selected from the group consisting
of valsartan (cf. EP 443983), losartan (cf. EP 253310), candesartan
(cf. EP 459136), eprosartan (cf. EP403159), irbesartan (cf. EP
454511), olmesartan (cf. U.S. Pat. No. 5,616,599), tasosartan (cf.
EP 539086), and telmisartan (cf. EP 502314), or, in each case, a
pharmaceutically acceptable salt thereof.
[0008] Preferred AT.sub.1-receptor antagonist are those agents that
have been marketed, most preferred is valsartan or a
pharmaceutically acceptable salt thereof.
[0009] Insulin secretion enhancers are active ingredients that have
the property to promote the secretion of insulin from pancreatic
.beta.-cells. Examples of insulin secretion enhancers are
sulfonylureas (SU), 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]-benzensulfonamide
(glycopyramide); glibenclamide (glyburide); gliclazide;
1-butyl-3-metanilylurea; carbutamide; glibonuride; glipizide;
gliquidone; glisoxepid; glybuthiazole; glibuzole; glyhexamide;
glymidine; glypinamide; phenbutamide; and tolylcyclamide, or a
pharmaceutically acceptable salt thereof.
[0010] Insulin secretion enhancers furthermore include short-acting
insulin secretion enhancers, such as the new phenylalanine
derivative nateglinide
[N-(trans-4-isopropylcyclohexyl-carbonyl)-D-phenylalanine] (cf. EP
196222 and EP 526171) of the formula ##STR1## repaglinide
[(S)-2-ethoxy-4-{2-[[3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-o-
xoethyl}benzoic acid--cf. EP 589874]; calcium
(2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinlycarbonyl)-propionate
dihydrate (mitiglinide--cf. EP 507534); furthermore representatives
of the new generation of SUs such as glimepiride (cf. EP 31058);
and in free or pharmaceutically acceptable salt form.
[0011] Insulin secretion enhancers likewise include the long-acting
insulin secretion enhancer DPP-IV inhibitors, GLP1 and GLP1
agonists.
[0012] DPP-IV is responsible for inactivating GLP-1. More
particularly, DPP-IV generates a GLP-1 receptor antagonist and
thereby shortens the physiological response to GLP-1. GLP-1 is a
major stimulator of pancreatic insulin secretion and has direct
beneficial effects on glucose disposal.
[0013] The DPP-IV inhibitor can be peptidic or, preferably,
non-peptidic. DPP-IV inhibitors are in each case generically and
specifically disclosed e.g. in WO 98/19998, DE 196 16 486 A1, WO
00/34241 and WO 95/15309, in each case in particular in the
compound claims and the final products of the working examples, the
subject-matter of the final products, the pharmaceutical
preparations and the claims are hereby incorporated into the
present application by reference to these publications. Preferred
are those compounds that are specifically disclosed in Example 3 of
WO 98/19998 and Example 1 of WO 00/34241, respectively.
[0014] GLP-1 is a insulinotropic proteine which was described,
e.g., by W. E. Schmidt et al. in Diabetologia 28, 1985, 704-707 and
in U.S. Pat. No. 5,705,483.
[0015] The term "GLP-1 agonists" used herein means variants and
analogs of GLP-1(7-36)NH.sub.2 which are disclosed in particular in
U.S. Pat No. 5,120,712, U.S. Pat. No. 5,118666, U.S. Pat. No.
5,512,549, WO 91/11457 and by C. Orskov et al in J. Biol. Chem. 264
(1989) 12826. The term "GLP-1 agonists" comprises especially
compounds like GLP-1(7-37), in which compound the carboxy-terminal
amide functionality of Arg.sup.36 is displaced with Gly at the 37th
position of the GLP-1(7-36)NH.sub.2 molecule and variants and
analogs thereof including GLN.sup.9-GLP-1(7-37),
D-GLN.sup.9-GLP-1(7-37), acetyl LYS.sup.9-GLP-1(7-37),
LYS.sup.18-GLP-1(7-37) and, in particular, GLP-1(7-37)OH,
VAL.sup.8-GLP-1(7-37), GLY.sup.8-GLP-1 (7-37),
THR.sup.8-GLP-1(7-37), MET.sup.8-GLP-1(7-37) and
4-imidazopropionyl-GLP-1. Special preference is also given to the
GLP agonist analog exendin-4, described by Greig et al in
Diabetologia 1999, 42, 45-50.
[0016] A preferred insulin secretion enhancer is repaglinide, most
preferred is nateglinide.
[0017] 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 (being directed to the H-form crystal modification)
as well as the corresponding references to the B-form crystal
modification.
[0018] 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.
[0019] The term short-acting insulin secretion enhancer" comprises
corresponding agents with a maximum secretion of insulin that is
attained within one hour, preferably within 30 minutes, after the
administration of the agent, most preferably within 20 minutes
having a biological half-life, T 1/2, of less than two hours,
preferably, 1.5 hours. The term long-acting insulin secretion
enhancer" comprises corresponding agents with a maximum secretion
of insulin that is attained more than one hour after administration
of the agent.
[0020] A preferred insulin sensitizer is metformin or a
pharmaceutically acceptable salt thereof such as the
mono-hydrochloride.
[0021] Especially preferred is a combination of valsartan or a
pharmaceutically acceptable salt thereof and nateglinide or a
pharmaceutically acceptable salt thereof.
[0022] The corresponding active ingredients or a pharmaceutically
acceptable salts thereof may also be used in form of a solvate,
such as a hydrate or including other solvents, used for
crystallization.
[0023] 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.
[0024] The pharmaceutical activities as effected by administration
of representatives of the class of AT.sub.1-receptor antagonists or
insulin secretion enhancers, respectively, or of the combination of
active agents used according to the present invention can be
demonstrated e.g. by using corresponding pharmacological models
known in the pertinent art. The person skilled in the pertinent art
is fully enabled to select a relevant animal test model to prove
the hereinbefore and hereinafter indicated therapeutic indications
and beneficial effects.
[0025] To evaluate the antihypertensive activity of the combination
according to the invention, for example, the methodology as
described by Lovenberg W: Animal models for hypertension research.
Prog. Clin. Biol. Res. 1987, 229, 225-240 may be applied. For the
evaluation that the combination according to the present invention
may be used for the treatment of congestive heart failure, for
example, the methods as disclosed by Smith H J, Nuttall A:
Experimental models of heart failure. Cardiovasc Res 1985, 19,
181-186 may be applied. Molecular approaches such as transgenic
methods are also described, for example by Luft et al.:
Hypertension-induced end-organ damage. "A new transgenic approach
for an old problem." Hypertension 1999, 33, 212-218.
[0026] The insulin secretion enhancing properties of the
combination according to the present invention may be determined by
following the methodology as disclosed, for example, in the
publication of T.Ikenoue et al. Biol.Pharm.Bull. 29(4), 354-359
(1997).
[0027] The corresponding subject matter of these four references is
herewith incorporated by reference in this specification.
[0028] Accordingly, the combination according to the present
invention may be used, e.g., for the prevention, delay of
progression or treatment of diseases and disorders that may be
inhibited by the inhibition of AT.sub.1 receptor, that may be
inhibited by the enhancement of insulin secretion and that may be
inhibited by insulin sensitization. Especially, the combination
according to the present invention may be used, e.g., for the
prevention, delay of progression or treatment of diseases and
disorders selected from the group consisting of hypertension,
congestive heart failure, diabetes, especially type 2 diabetes
mellitus, diabetic retinopathy, macular degeneration, diabetic
nephropathy, glomerulosclerosis, chronic renal failure, diabetic
neuropathy, syndrome X, premenstrual syndrome, coronary heart
disease, angina pectoris, myocardial infarction, stroke, vascular
restenosis, hyperglycemia, hyperinsulinaemia, hyperlipidaemia,
hypertryglyceridemia, insulin resistance, impaired glucose
metabolism, conditions of impaired glucose tolerance (IGT),
conditions of impaired fasting plasma glucose, obesity, diabetic
retinopathy, macular degeneration, cataracts, diabetic nephropathy,
glomerulosclerosis, diabetic neuropathy, erectile dysfunction,
premenstrual syndrome, skin and connective tissue disorders, foot
ulcerations and ulcerative colitis, endothelial dysfunction and
impaired vascular compliance. Preferably, said combination may be
used for the treatment of hypertension, especially ISH, congestive
heart failure, endothelial dysfunction, impaired vascular
compliance, IGT and type II diabetes mellitus.
[0029] A "disease or condition which may be inhibited by the
Inhibition of AT.sub.1 receptor" as defined in this application
comprises, but is not limited to hypertension, congestive heart
failure, diabetes, especially type 2 diabetes mellitus, diabetic
retinopathy, macular degeneration, diabetic nephropathy,
glomerulosclerosis, chronic renal failure, diabetic neuropathy,
syndrome X, premenstrual syndrome, coronary heart disease, angina
pectoris, myocardial infarction, stroke, vascular restenosis,
endothelial dysfunction and the like. A "disease or condition which
may be inhibited by the enhancement of insulin secretion" as
defined in this application comprises, but is not limited to
hyperglycemia, hyperinsulinaemia, hyperlipidaemia,
hypertryglyceridemia, insulin resistance, impaired glucose
metabolism, conditions of impaired glucose tolerance (IGT),
conditions of impaired fasting plasma glucose, obesity, diabetic
retinopathy, macular degeneration, cataracts, diabetic nephropathy,
glomerulosclerosis, diabetic neuropathy, erectile dysfunction,
premenstrual syndrome, coronary heart disease, hypertension, angina
pectoris, myocardial infarction, stroke, vascular restenosis, skin
and connective tissue disorders, foot ulcerations and ulcerative
colitis, endothelial dysfunction and impaired vascular
compliance.
[0030] A "disease or condition that may be inhibited by insulin
sensitization" as defined in this application comprises, but is not
limited to hyperglycemia, hyperinsulinaemia, hyperlipidaemia,
hypertryglyceridemia, insulin resistance, impaired glucose
metabolism, conditions of impaired glucose tolerance (IGT),
conditions of impaired fasting plasma glucose, obesity, diabetic
retinopathy, macular degeneration, cataracts, diabetic nephropathy,
glomerulosclerosis, diabetic neuropathy, erectile dysfunction,
premenstrual syndrome, coronary heart disease, hypertension, angina
pectoris, myocardial infarction, stroke, vascular restenosis, skin
and connective tissue disorders, foot ulcerations and ulcerative
colitis, endothelial dysfunction and impaired vascular
compliance.
[0031] Hypertension, in connection with a "disease or condition
which may be inhibited by the inhibition of AT.sub.1 receptor", a
"disease or condition which may be inhibited by the enhancement of
insulin secretion", a "disease or condition that may be inhibited
by insulin sensitization" includes and is not limited to mild,
moderate and severe hypertension as defined in Journal of
Hypertension 1999, 17:151-183, especially on page 162. Especially
preferred is "isolated systolic hypertension" (ISH).
[0032] 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, e.g. separately or in a fixed combination.
[0033] Under certain circumstances, drugs with different mechanisms
of action may be combined. However, just considering any
combination of drugs having different modes of action but acting in
the similar field does not necessarily lead to combinations with
advantageous effects.
[0034] All the more surprising is the experimental finding that the
combined administration of an AT.sub.1 receptor antagonist and
insulin secretion enhancer and/or an insulin sensitizer, or, in
each case, a pharmaceutically acceptable form thereof, results not
only in a beneficial, especially a potentiating or a synergistic,
therapeutic effect. Independent thereof, additional benefits
resulting from combined treatment can be achieved such as a
surprising prolongation of efficacy, a broader variety of
therapeutic treatment and surprising beneficial effects on diseases
and conditions associated with diabetes, e.g. less gain of weight.
An additional and preferred aspect of the persent invenion is the
prevention, delay of progression or treatment of the condition of
isolated systolic hypertension and impaired vascular compliance
which means decreased vascular elasticity.
[0035] The term "potentiation" shall mean an increase of a
corresponding pharmacological activity or therapeutical effect,
respectively. Potentiation of one component of the combination
according to the present invention by co-administration of an other
component according to the present invention means that an effect
is being achieved that is greater than that achieved with one
component alone.
[0036] The term "synergistic" shall mean that the drugs, when taken
together, produce a total joint effect that is greater than the sum
of the effects of each drug when taken alone.
[0037] ISH is the most common form of hypertension in people over
50 years. It is defined as elevated systolic blood pressure (above
140 mm Hg) in conjunction with normal diastolic blood pressure
(below 90 mm Hg). Elevated systolic blood pressure is an
independent risk factor for cardiovascular diseases and may lead
e.g. to myocardial hypertrophy and heart failure. ISH is
furthermore characterized by an increased pulse pressure, defined
as the difference between systolic and diastolic blood pressures.
Elevated pulse pressure is being recognized as the type of
hypertension the least likely to be well controlled. A reduction of
elevated systolic blood perssure and correspondingly of pulse
pressure is associated with a significant risk reduction in
cardiovascular death. It has surprisingly been found that the
combination of an AT.sub.1 receptor antagonist and an insulin
secretion enhancer or an insulin sensitizer leads to a decrease of
ISH and pulse rate, both in hypertensive patients having type 2
diabetes mellitus and in hypertensive patient that do not have type
2 diabetes mellitus.
[0038] Furthermore, it has been found that the chronic
co-administration of either an insulin sensitizer or an insulin
secretion enhancer imparts the beneficial effect on blood vessel
morphology and function and results in a decrease of vascular
stiffness and correspondingly in a maintenance and in an
improvement of vascular compliance. Accordingly, it has been found
that the addition of an insulin sensitizer and/or an insulin
secretion enhancer to that of an AT.sub.1 receptor antagonist would
potentiate the effect on systolic blood pressure and further
improve vascular stiffness/compliance. Conversely, the proven
antihypertensive effects of an AT.sub.1 receptor antagonist on
systolic and diastolic blood pressure may be potentiated by the
addition of an insulin sensitizer and/or an insulin secretion
enhancer. The benefit of these combinations may also extend to an
additional or potentiated effect on endothelial function, and
improve vascular function and structure in various organs/tissues
including the kidney, heart, eye and brain. Through the reduction
in glucose levels, an anti-thrombotic and anti-atherosclerotic
effect can also be demonstrated. Reduction of glucose would prevent
or minimize the glycosylation of any structural or functional
protein within the cardio-renal system. This effect proves to be
highly beneficial by evoking an additive or synergistic effect on
vascular function/structure when administered with an AT.sub.1
receptor antagonist which alone improves cardiovascular function
and structure through a distinct mechanism.
[0039] Further benefits 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.
[0040] For example, it has turned out that the combination
according to the present invention provides benefit especially in
the treatment of modest hypertension or isolated systolic
hypertension that is beneficial to all diabetic patients regardless
of their hypertensive status, e.g. reducing the risk of negative
cardiovascular events by two different modes of action.
[0041] The AT.sub.1 receptor antagonists, especially valsartan,
have proven to be also useful in the treatment of type 2 diabetes
mellitus beyond the reduction of blood pressure in for example
improving microalbuminuria. At sub-therapeutic doses, with respect
to the treatment of hypertension, the combination according to the
invention may be merely used for the treatment of diabetes,
especially type 2 diabetes mellitus. In view of the reduced dose of
the AT.sub.1 receptor antagonist, there is a considerable safety
profile of the combination making it suitable for first line
therapy.
[0042] The present invention relates to the use of a combination
comprising as active ingredients [0043] (i) an AT.sub.1-receptor
antagonist or a pharmaceutically acceptable salt thereof; [0044]
(ii) (a) an insulin secretion enhancer or a pharmaceutically
acceptable salt thereof or [0045] (b) an insulin sensitizer or a
pharmaceutically acceptable salt thereof; [0046] for the
manufacture of, a medicament for the prevention, delay of
progression or treatment of a disease and disorder which may be
inhibited by the inhibition of AT.sub.1 receptor and by the
enhancement of insulin secretion, for example, for the prevention,
delay of progression or treatment of hypertension, especially
modest hypertension, ISH, congestive heart failure, endothelial
dysfunction, impaired vascular compliance, IGT and type II diabetes
mellitus.
[0047] The present invention also relates to a method for the
prevention, delay of progression or treatment of a disease and
disorder which may be inhibited by the inhibition of AT.sub.1
receptor and/or by the enhancement of insulin secretion comprising
administering to a warm-blooded animal, including man, in need
thereof jointly therapeutically effective amounts of [0048] (i) an
AT.sub.1-receptor antagonist or a pharmaceutically acceptable salt
thereof; [0049] (ii) (a) an insulin secretion enhancer or a
pharmaceutically acceptable salt thereof or [0050] (b) an insulin
sensitizer or a pharmaceutically acceptable salt thereof.
[0051] 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.
[0052] The pharmaceutical composition according to the present
invention comprises a "kit of parts" in the sense that the
components can be dosed independently or by use of different fixed
combinations with distinguished amounts of the components at
different time points. The parts of the "kit of parts" can then
e.g. be administered simultaneously or chrono-logically 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. Preferably, there is at least one beneficial effect,
e.g. a mutual enhancing of the effect of [0053] (i) an
AT.sub.1-receptor antagonist or a pharmaceutically acceptable salt
thereof; [0054] (ii) (a) an insulin secretion enhancer or a
pharmaceutically acceptable salt thereof or [0055] (b) an insulin
sensitizer or a pharmaceutically acceptable salt thereof; [0056] in
particular a potentiation or a synergism, e.g. a more than additive
effect, additional advantageous effects, less side effects, a
combined therapeutical effect in a non-effective dosage of one or
each of the components, especially a potentiation or a strong
synergism.
[0057] 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.
[0058] These pharmaceutical preparations are for enteral, such as
oral, and also rectal or parenteral, administration to homeotherms,
with the preparations comprising the pharmacological active
compound either alone or together with customary pharmaceutical
auxiliary substances. For example, the pharmaceutical preparations
consist of from about 0.1% to 90%, preferably of from about 1% to
about 80%, of the active compound. Pharmaceutical preparations for
enteral or parenteral, and also for ocular, administration are, for
example, in unit dose forms, such as coated tablets, tablets,
capsules or suppositories and also ampoules. These are prepared in
a manner that is known per se, for example using conventional
mixing, granulation, coating, solubulizing or lyophilizing
processes. Thus, pharmaceutical preparations for oral use can be
obtained by combining the active compound with solid excipients, if
desired granulating a mixture which has been obtained, and, if
required or necessary, processing the mixture or granulate into
tablets or coated tablet cores after having added suitable
auxiliary substances.
[0059] The dosage of the active compound can depend on a variety of
factors, such as mode of administration, homeothermic species, age
and/or individual condition.
[0060] Preferred dosages for the active ingredients of the
pharmaceutical combination according to the present invention are
therapeutically effective dosages, especially those which are
commerically available.
[0061] Normally, in the case of oral administration, an approximate
daily dose of from about 1 mg to about 360 mg is to be estimated
e.g. for a patient of approximately 75 kg in weight.
[0062] The dosage of the active compound can depend on a variety of
factors, such as mode of administration, homeothermic species, age
and/or individual condition.
[0063] Valsartan, as a representative of the class of
AT.sub.1-receptor antagonists, will be supplied in the form of
suitable dosage unit form, for example, a capsule or tablet, and
comprising a therapeutically effective amount, e.g. from about 20
to about 320 mg, of valsartan which may be applied to patients. The
application of the active ingredient may occur up to three times a
day, starting e.g. with a daily dose of 20 mg or 40 mg of
valsartan, increasing via 80 mg daily and further to 160 mg daily
up to 320 mg daily. Preferably, valsartan is applied twice a day
with a dose of 80 mg or 160 mg, respectively, each. In a low-does
formulation, valsartan with a dose of 20 mg or 40 mg may be used.
Corresponding doses may be taken, for example, in the morning, at
mid-day or in the evening. Preferred is b.i.d. administration.
[0064] The insulin secretion enhancer 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, 120 mg or 180 mg of
nateglinde to be administered preferably before the main meals. In
a low dose combination, the dosage of nateglinide to be
administered preferably is 30 mg, 40 mg or furthermore 60 mg.
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).
[0065] The insulin secretion enhancer repaglinde is preferably
administered in a dosage range of about 0.01 mg to about 8 mg, more
preferred from about 0.5 to about 6 mg.
[0066] The insulin sensitizer metformin is preferably administered
in a dosage range of about 100 mg to about 1200 mg per dose unit,
especially 500 mg, 850 mg or 1000 mg. In a low dose combination,
metformin is preferably administered in a dosage of 125 mg, 250 mg
or 500 mg.
FORMULATION EXAMPLE 1
[0067] Film-Coated Tablets: TABLE-US-00001 Composition Components
Per Unit (mg) Standards Granulation Valsartan [=active ingredient]
80.00 Microcrystalline cellulose/ 54.00 NF, Ph. Eur Avicel PH 102
Crospovidone 20.00 NF, Ph. Eur Colloidal anhydrous silica/ 0.75 Ph.
Eur/ colloidal silicon dioxide/Aerosil 200 NF Magnesium stearate
2.5 NF, Ph. Eur Blending Colloidal anhydrous silica/ 0.75 Ph. Eur/
colloidal silicon dioxide/Aerosil 200 NF Magnesium stearate 2.00
NF, Ph. Eur Coating Purified water*.sup.) -- DIOLACK pale red
00F34899 7.00 Total tablet mass 167.00 *.sup.)Removed during
processing.
[0068] The film-coated tablet is manufactured e.g. as follows:
[0069] A mixture of valsartan, microcrystalline cellulose,
crospovidone, part of the colloidal anhydrous silica/colloidal
silicon dioxide/Aerosile 200, silicon dioxide and magnesium
stearate is premixed in a diffusion mixer and then sieve through a
screnning mill. The resulting mixture is again pre-mixed in a
diffusion mixer, compacted in a roller compacter and then sieve
through a screening mill. To the resulting mixture, the rest of the
colloidal anhydrous silica/colloidal silicon dioxide/Aerosile 200
are added and the final blend is made in a diffusion mixer. The
whole mixture is compressed in a rotary tabletting machine and the
tabletts are coated with a film by using Diolack pale red in a
perforated pan.
FORMULATION EXAMPLE 2
[0070] Film-Coated Tablets: TABLE-US-00002 Composition Components
Per Unit (mg) Standards Granulation Valsartan [=active ingredient]
160.00 Microcrystalline cellulose/ 108.00 NF, Ph. Eur Avicel PH 102
Crospovidone 40.00 NF, Ph. Eur Colloidal anhydrous silica/ 1.50 Ph.
Eur/ colloidal silicon dioxide/Aerosil 200 NF Magnesium stearate
5.00 NF, Ph. Eur Blending Colloidal anhydrous silica/ 1.50 Ph. Eur/
colloidal silicon dioxide/Aerosil 200 NF Magnesium stearate 4.00
NF, Ph. Eur Coating Opadry Light Brown 00F33172 10.00 Total tablet
mass 330.00
[0071] The film-coated tablet is manufactured e.g. as described in
Formulation Example 1.
FORMULATION EXAMPLE 3
[0072] Film-Coated Tablets: TABLE-US-00003 Compostion Components
Per Unit (mg) Standards Core: Internal phase Valsartan 40.00
[=active ingredient] Silica, colloidal anhydrous 1.00 Ph. Eur,
USP/NF (Colloidal silicon dioxide) [=Glidant] Magnesium stearate
2.00 USP/NF [=Lubricant] Crospovidone 20.00 Ph. Eur [Disintegrant]
Microcrystalline cellulose 124.00 USP/NF [=Binding agent] External
phase Silica, colloidal anhydrous, 1.00 Ph. Eur, USP/NF (Colloidal
silicon dioxide) [=Glidant] Magnesium stearate 2.00 USP/NF
[Lubricant] Film coating Opadry .RTM. brown OOF 16711*.sup.) 9.40
Purified Water**.sup.) -- Total tablet mass 199.44 *.sup.)The
composition of the Opadry .RTM. brown OOF16711 coloring agent is
tabulated below. **.sup.)Removed during processing
[0073] Opadry.RTM. Composition: TABLE-US-00004 Approximate
Ingredient % Composition Iron oxide, black (C.I. No. 77499, E 172)
0.50 Iron oxide, brown (C.I. No. 77499, E 172 0.50 Iron oxide, red
(C.I. No. 77491, E 172) 0.50 Iron oxide, yellow (C.I. No. 77492, E
172) 0.50 Macrogolum (Ph. Eur) 4.00 Titanium dioxide (C.I. No.
77891, E 171) 14.00 Hypromellose (Ph. Eur) 80.00
[0074] The film-coated tablet is manufactured e.g. as described in
Formulation Example 1.
FORMULATION EXAMPLE 4
[0075] Capsules: TABLE-US-00005 Components Compostion Per Unit (mg)
Valsartan [=active ingredient] 80.00 Microcrystalline cellulose
25.10 Crospovidone 13.00 Povidone 12.50 Magnesium stearate 1.30
Sodium lauryl sulphate 0.60 Shell Iron oxide, red 0.123 (C.I. No.
77491, EC No. E 172) Iron oxide, yellow 0.123 (C.I. No. 77492, EC
No. E 172) Iron oxide, black 0.245 (C.I. No. 77499, EC No. E 172)
Titanium dioxide 1.540 Gelatin 74.969 Total tablet mass 209.50
[0076] The tablet is manufactured e.g. as follows:
[0077] Granulation/Drying
[0078] Valsartan and microcrystallin cellulose are spray-granulated
in a fluidised bed granulator with a granulating solution
consisting of povidone and sodium lauryl sulphate dissolved in
purified water. The granulate obtained is dried in a fluidiesd bed
dryer.
[0079] Milling/Blending
[0080] The dried granulate is milled together with crospovidone and
magnesium stearate. The mass is then blended in a conical srew type
mixer for approximately 10 minutes.
[0081] Encapsulation
[0082] Teh empty hard gelatin capsules are filled with the blended
bulk granules under controlled temperature and humidity conditions.
The filed capsules are dedustee, visually inspected, weightchecked
and quarantied until by Quality assurance department.
FORMULATION EXAMPLE 5
[0083] Capsules: TABLE-US-00006 Components Composition Per Unit
(mg) Valsartan [=active ingredient] 160.00 Microcrystalline
cellulose 50.20 Crospovidone 26.00 Povidone 25.00 Magnesium
stearate 2.60 Sodium lauryl sulphate 1.20 Shell Iron oxide, red
0.123 (C.I. No. 77491, EC No. E 172) Iron oxide, yellow 0.123 (C.I.
No. 77492, EC No. E 172) Iron oxide, black 0.245 (C.I. No. 77499,
EC No. E 172) Titanium dioxide 1.540 Gelatin 74.969 Total tablet
mass 342.00
[0084] The formulation is manufactured e.g. as described in
Formulation Example 4.
FORMULATION EXAMPLE 6
[0085] Hard Gelatine Capsule: TABLE-US-00007 Components Compostion
Per Unit (mg) Valsartan [=active ingredient] 80.00 Sodium
laurylsulphate 0.60 Magnesium stearate 1.30 Povidone 12.50
Crospovidone 13.00 Microcrystalline cellulose 21.10 Total tablet
mass 130.00
EXAMPLES 7 to 11
[0086] TABLE-US-00008 Example 7 8 9 10 11 Composition Composition
Composition Composition Composition per per per per per Components
unit (mg) unit (mg) unit (mg) unit (mg) unit (mg) Granulation
Valsartan 80.000 160.000 40.000 320.000 320.000 Drug Substance (DS)
Microcrystalline 54.000 108.000 27.000 216.000 216.000 Cellulose
(NF, Ph.Eur.)/ Avicel PH 102 Crospovidone (NF, 15.000 30.000 7.500
80.000 60.000 Ph.Eur.) Colloidal Anhydrous 1.500 3.000 0.750 3.000
6.000 Silica (Ph. Eur.)/Colloidal Silicon Dioxide (NF)/Aerosil 200
Magnesium Stearate 3.000 6.000 1.500 10.000 12.000 (NF, Ph.Eur.)
Blending Colloidal Anhydrous -- -- -- 3.000 -- Silica (Ph.
Eur.)/Colloidal Silicon Dioxide (NF)/Aerosil 200 Magnesium
Stearate, 1.500 3.000 0.750 8.000 6.000 NF, Ph.Eur. Core Weight/mg
155.000 310.000 77.500 640.000 620.000 Coating -- -- 3.800 15.000
16.000
EXAMPLE 12
[0087] 108,000 tablets, each which contain 120 mg of nateglinide
are prepared as follows: TABLE-US-00009 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
[0088] Preparation process: The microcrystalline cellulose,
povidone, part of the croscarmellose sodium, nateglinide and
lactose are mixed in a high shear mixer and afterwards granulated
using purified water. Alternatively, 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.
EXAMPLES 13-15
[0089] TABLE-US-00010 Component 60 mg 120 mg 180 mg Starlix DS
(H-form crystal modification) 60 120 180 Lactose Monohydrate 141.5
283 214 MicrocrystallineCellulose 71 142 107 Povidone K30 12 24 23
Croscarmellose Sodium 12 24 34 Sub-Total (Granulation) 296.5 593
558 Croscarmellose Sodium 6.4 12.8 24.5 Colloidal Silicone Dioxide
6.4 12.8 12.3 Magnesium Stearate 5.7 11.4 15.2 Sub-Total (Core)
(315) (630) (610) Opadry 9 18 18 Total 324 648 628
* * * * *