U.S. patent application number 11/036842 was filed with the patent office on 2005-06-09 for method of treating metabolic disorders, especially diabetes, or a disease or condition associated with diabetes.
Invention is credited to Allison, Malcolm, Ball, Michele Ann, Gatlin, Marjorie Regan, Guitard, Christiane, Karnachi, Anees Abdulquadar, Mannion, Richard Owen.
Application Number | 20050124663 11/036842 |
Document ID | / |
Family ID | 27761597 |
Filed Date | 2005-06-09 |
United States Patent
Application |
20050124663 |
Kind Code |
A1 |
Gatlin, Marjorie Regan ; et
al. |
June 9, 2005 |
Method of treating metabolic disorders, especially diabetes, or a
disease or condition associated with diabetes
Abstract
The invention relates to a combination, such as a combined
preparation or pharmaceutical composition, respectively, which
comprises nateglinide (I) 1 or repaglinide and at least one other
antidiabetic compound selected from the group consisting of
thiazolidinedione derivatives (glitazones), sulfonyl urea
derivatives and metformin for simultaneous, separate or sequential
use in the prevention, delay of progression or treatment of
diseases, especially metabolic disorders and in particular type 2
diabetes and diseases and conditions associated with diabetes; to a
composition, respectively, which comprises nateglinide and a
pharmaceutically acceptable carrier and to a process of making such
composition; the use of such combination or composition for the
preparation of a medicament for the prevention, delay of
progression or treatment of metabolic disorders; a method of
prevention, delay of progression or treatment of diseases in
warm-blooded animals; the use of such combination or composition
for the cosmetic treatment of a mammal in order to effect a
cosmetically beneficial loss of body weight; and to a method of
improving the bodily appearance of a warm-blooded animal.
Inventors: |
Gatlin, Marjorie Regan;
(Hoboken, NJ) ; Ball, Michele Ann; (Morris Plains,
NJ) ; Mannion, Richard Owen; (Mount Arlington,
NJ) ; Karnachi, Anees Abdulquadar; (Hillsborough,
NJ) ; Guitard, Christiane; (Hegenheim, FR) ;
Allison, Malcolm; (Basel, CH) |
Correspondence
Address: |
NOVARTIS
CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 104/3
EAST HANOVER
NJ
07936-1080
US
|
Family ID: |
27761597 |
Appl. No.: |
11/036842 |
Filed: |
January 14, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11036842 |
Jan 14, 2005 |
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10345908 |
Jan 16, 2003 |
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6878749 |
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10345908 |
Jan 16, 2003 |
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09663264 |
Sep 15, 2000 |
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6559188 |
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60304196 |
Apr 7, 2000 |
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60240918 |
Mar 9, 2000 |
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60240911 |
Sep 17, 1999 |
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Current U.S.
Class: |
514/340 ;
514/369; 514/563; 514/592; 514/635 |
Current CPC
Class: |
A61K 9/2054 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 31/195 20130101; A61K 31/44
20130101; A61K 31/64 20130101; A61K 31/425 20130101; A61K 9/2077
20130101; A61K 31/198 20130101; A61K 31/44 20130101; A61K 31/425
20130101; A61K 31/64 20130101; A61K 31/717 20130101; A61P 3/04
20180101; A61K 31/197 20130101; A61P 3/10 20180101; A61K 31/195
20130101 |
Class at
Publication: |
514/340 ;
514/369; 514/563; 514/635; 514/592 |
International
Class: |
A61K 031/4439; A61K
031/426; A61K 031/198; A61K 031/175; A61K 031/155 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 26, 2000 |
GB |
0021055.9 |
Claims
1-41. (canceled)
42. A method for treating diabetes or preventing the outbreak of
diseases and conditions associated with diabetes comprising
administering to a patient in need of such treatment or prevention
a composition comprising nateglinide or a pharmaceutically
acceptable salt thereof, sugar, and microcrystalline cellulose,
wherein the sugar and microcrystalline cellulose are present in an
amount of from 10-90 to 90-10 percent by weight respectively.
43. The method according to claim 51 wherein the diabetes is type 2
diabetes.
44. A method for decreasing the body weight of a mammal comprising
administering to such mammal a composition comprising nateglinide
or a pharmaceutically acceptable salt thereof, sugar, and
microcrystalline cellulose, wherein the sugar and microcrystalline
cellulose are present in an amount of from 10-90 to 90-10 percent
by weight respectively.
Description
[0001] The invention relates to a combination, such as a combined
preparation or pharmaceutical composition, respectively, which
comprises nateglinide or repaglinide and at least one other
antidiabetic compound selected from the group consisting of
thiazolidinedione derivatives (glitazones), sulfonyl urea
derivatives and metformin for simultaneous, separate or sequential
use in the prevention, delay of progression or treatment of
diseases, especially metabolic disorders and in particular type 2
diabetes and diseases and conditions associated with diabetes; the
use of such combination for the preparation of a medicament for the
prevention, delay of progression or treatment of metabolic
disorders; the use of such combination for the cosmetic treatment
of a mammal in order to effect a cosmetically beneficial loss of
body weight; a method of prevention, delay of progression or
treatment of diseases in warm-blooded animals; a method of
improving the bodily appearance of a warm-blooded animal; to a
pharmaceutical composition which comprises nateglinide as the sole
active agent in the composition and a pharmaceutically acceptable
carrier and to a process of making such pharmaceutical
composition.
[0002] The generally accepted aims in the treatment of diabetes are
to provide relief from symptoms, improvement of the quality of life
and prevention of both acute (hyperosmolar coma and ketoacidosis)
and chronic complications (e.g. diabetic neuropathy, diabetic
nephropathy and premature atherosclerosis). Type 2 diabetes is
characterized by both increased peripheral insulin resistance and
abnormal insulin secretion. At least two abnormalities of insulin
secretion are recognized: in the first phase insulin is both
delayed and inadequate in the face of elevated circulating glucose
levels and in the second phase insulin secretion is lost. Several
metabolic, hormonal, and pharmacological entities are known to
stimulate insulin secretion including glucose, amino-acids and
gastrointestinal peptides. The Diabetes Control and Complications
Trial (DCCT) performed in Type I IDDM subjects has established that
lowering of blood glucose is associated with decreases in the onset
and progression of diabetic microvascular complications (Diabetes
Control and Complications Trial Research Group; N. Engl. J. Med.
1993, 329, 977-986). Therefore, one therapeutic focus is on
optimizing and potentially normalizing glycemic control in subjects
with type 2 diabetes. Presently available oral agents fail to meet
this therapeutic challenge in some patient subgroups, result
sometimes in side-effects or are fraught with other problems.
[0003] The present invention relates to a combination, such as a
combined preparation or pharmaceutical composition, respectively,
which comprises nateglinide of formula (I) 2
[0004] or repaglinide and at least one other antidiabetic compound
selected from the group consisting of thiazolidinedione derivatives
(glitazones), sulfonyl urea derivatives and metformin,
[0005] in which the active ingredients are present in each case in
free form or in the form of a pharmaceutically acceptable salt and
optionally at least one pharmaceutically acceptable carrier; for
simultaneous, separate or sequential use, particularly in the
prevention, delay of progression or treatment of diseases,
especially metabolic disorders and in particular type 2 diabetes
mellitus and diseases and conditions associated with diabetes
mellitus. Such a combination is preferably a combined preparation
or a pharmaceutical composition.
[0006] By the term "a combined preparation or pharmaceutical
composition, respectively, which comprises nateglinide or
repaglinide and at least one other antidiabetic compound selected
from the group consisting of glitazones, sulfonyl urea derivatives
and metformin, in which the active ingredients are present in each
case in free form or in the form of a pharmaceutically acceptable
salt and optionally at least one pharmaceutically acceptable
carrier, for simultaneous, separate or sequential use", there is
meant especially a "kit of parts" in the sense that the components
nateglinide or repaglinide and at least one other antidiabetic
compound selected from the group consisting of glitazones, sulfonyl
urea derivatives and metformin 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 which 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 nateglinide or repaglinide and at least one other antidiabetic
compound selected from the group consisting of glitazones, sulfonyl
ureas and metformin, in particular 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 nateglinide or repaglinide and at
least one other antidiabetic compound selected from the group
consisting of glitazones, sulfonyl urea derivatives and metformin,
and especially a strong synergism between nateglinide or
repaglinide and at least one other antidiabetic compound selected
from the group consisting of glitazones, sulfonyl urea derivatives
and metformin.
[0007] In particular, the present invention relates to a method of
treating metabolic disorders, more especially diabetes and in
particular type 2 diabetes mellitus, or a disease or condition
associated with diabetes comprising administering to a warm-blooded
animal in need thereof a jointly therapeutically effective amount
of a combined preparation comprising nateglinide and an
antidiabetic thiazolidinedione derivative, wherein each of the
active ingredients are present in free form or in the form of a
pharmaceutically acceptable salt.
[0008] By the term "a combined preparation or pharmaceutical
composition, respectively, which comprises nateglinide and an
antidiabetic thiazolidinedione derivative, wherein each of the
active ingredients are present in free form or in the form of a
pharmaceutically acceptable salt and optionally at least one
pharmaceutically acceptable carrier, as a combined preparation for
simultaneous, separate or sequential use", there is meant
especially a "kit of parts" in the sense that the components
nateglinide and the antidiabetic thiazolidinedione derivative can
be dosed independently or by use of different fixed combinations
with distinguished amounts of the components at different time
points. Preferably, there is at least one beneficial effect, e.g. a
mutual enhancing of the effect of nateglinide and the antidiabetic
thiazolidinedione derivative, in particular 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 nateglinide and the
antidiabetic thiazolidinedione derivative, especially a strong
synergism between nateglinide and the anti-diabetic
thiazolidinedione derivative.
[0009] "Diseases and conditions associated with diabetes mellitus"
as defined in this application comprise, but are not restricted to
hyperglycemia, hyperinsulinaemia, hyperlipidaemia, insulin
resistance, impaired glucose metabolism, obesity, diabetic
retinopathy, macular degeneration, cataracts, diabetic nephropathy,
glomerulosclerosis, diabetic neuropathy, erectile dysfunction,
premenstrual syndrome, vascular restenosis and ulcerative colitis.
Furthermore, "diseases and conditions associated with diabetes
mellitus" comprise, but are not restricted to: coronary heart
disease, hypertension, angina pectoris, myocardial infarction,
stroke, skin and connective tissue disorders, foot ulcerations,
metabolic acidosis, arthritis, osteoporosis and in particular
conditions of impaired glucose tolerance.
[0010] The term "prevention" means prophylactic administration of
the combination, such as a combined preparation or pharmaceutical
composition, to healthy patients to prevent the outbreak of the
diseases and conditions mentioned herein. Moreover, the term
"prevention" means prophylactic administration of such combination
to patients being in a pre-stage of the disease, especially
diabetes, to be treated. The term "delay of progression" used
herein means administration of the combination, such as a combined
preparation or pharmaceutical composition, to patients being in a
pre-stage of the disease, especially diabetes, to be treated in
which patients a pre-form of the corresponding disease is
diagnosed. The term "method of treating" used herein includes a
method of prevention of a disease, i.e. the prophylactic
administration of the combination, such as a combined preparation
or pharmaceutical composition, to healthy patients to prevent the
outbreak of the diseases and conditions mentioned herein.
[0011] In the present description the meaning of terms "active
agent", "active compound" or in some cases "compound" should be
understood as equivalent.
[0012] Unless stated otherwise, in the present disclosure organic
radicals and compounds designated "lower" contain not more than 7,
preferably not more than 4, carbon atoms.
[0013] Lower alkylene is preferably methylene, ethylene or
propylene. It can be unsubstituted or substituted e.g. by
hydroxy.
[0014] A sulphonyl urea derivative is, for example, glisoxepid,
glyburide, acetohexamide, chloropropamide, glibornuride,
tolbutamide, tolazamide, glipizide, carbutamide, gliquidone,
glyhexamide, phenbutamide or tolcyclamide; and preferably
glimepiride or gliclazide.
[0015] Halogen represents preferably fluoro, chloro or bromo.
[0016] Lower alkyl is, if not stated otherwise, preferably ethyl
or, most preferably, methyl.
[0017] Lower alkoxy is preferably methoxy or ethoxy.
[0018] Cycloalkyl is e.g. C.sub.3-C.sub.8cycloalkyl, preferably
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
cycloheptyl.
[0019] Aryl is e.g. phenyl or naphthyl, each of which can be
substituted e.g. by lower alkyl or halogen, or trifluoromethyl.
[0020] Nateglinide (EP 196222, EP 526171, U.S. Pat. No. 5,463,116
and U.S. Pat. No. 5,488,150),
2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-bu-
tyl}-aminocarbonylmethyl]benzoic acid (repaglinide, U.S. Pat. No.
5,216,167--also known as
(S)-2-ethoxy-4-{2-[[3-methyl-1-[2-(1-piperidinyl-
)phenyl]butyl]-amino]-2-oxoethyl}benzoic acid);
5-{[4-(2-(5-ethyl-2-pyridy-
l)ethoxy)phenyl]-methyl}-thiazolidine-2,4-dione (pioglitazone, EP 0
193 256 A1),
5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazo-
lidine-2,4-dione (rosiglitazone, EP 0 306 228 A1),
5-{[4-((3,4-dihydro-6-h-
ydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)-phenyl]-methyl}-t-
hiazolidine-2,4-dione (troglitazone, EP 0 139 421),
(S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolid-
ine-2,4-dione (englitazone, EP 0 207 605 B1),
5-(2,4-dioxothiazolidin-5-yl-
methyl)-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide (K RP297, J
P 10087641-A), 5-[6-(2-fluoro-benzyloxy)naphthalen-2-yl
methyl]thiazol idine-2,4-dione (MCC555, EP 0 604 983 B1),
5-{[4-(3-(5-methyl-2-phenyl-4--
oxazolyl)-1-oxopropyl)-phenyl]-methyl}-thiazolidine-2,4-dione
(darglitazone, EP 0 332 332),
5-(2-naphthylsulfonyl)-thiazolidine-2,4-dio- ne (AY-31637, U.S.
Pat. No. 4,997,948) and 5-{[4-(1-methyl-cyclohexyl)meth-
oxy)-phenyl]methyl}-thiazolidine-2,4-dione (ciglitazone, U.S. Pat.
No. 4,287,200) are generically and specifically disclosed in the
documents cited in brackets beyond each substance, 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 is hereby incorporated
into the present application by reference to this publications.
Comprised are likewise the corresponding stereoisomers as well as
the corresponding crystal modifications, e.g. solvates and
polymorphs, which are disclosed therein. The term nateglinide as
used herein comprises crystal modifications (polymorphs) such as
those disclosed in EP 0526171 B1 or U.S. Pat. No. 5,488,510,
respectively, the subject matter of which is incorporated by
reference to this application, especially the subject matter of
claims 8 to 10 as well as the corresponding references to the
B-type crystal modification. Preferably, in the present invention
the B- or H-type, more preferably the H-type, is used.
[0021] Any one or more or combinations of these compounds and other
similar compounds or fragments are hereinafter called
"anti-diabetic drugs", in the description of compositions and
methods of treating the disease.
[0022] Furthermore, MCC555 can be formulated as disclosed on page
49, lines 30 to 45, of EP 0 604 983 B1; englitazone as disclosed
from page 6, line 52, to page 7, line 6, or analogous to Examples
27 or 28 on page 24 of EP 0 207 605 B1; and darglitazone and
5-{4-[2-(5-methyl-2-phenyl-4-oxa-
zolyl)-ethoxy)]benzyl}-thiazolidine-2,4-dione (BM-13.1246) can be
formulated as disclosed on page 8, line 42 to line 54 of EP 0 332
332 B1. AY-31637 can be administered as disclosed in column 4,
lines 32 to 51 of U.S. Pat. No. 4,997,948 and rosiglitazone as
disclosed on page 9, lines 32 to 40 of EP 0 306 228 A1, the latter
preferably as its maleate salt.
[0023] Corresponding to the needs of the single patient and under
the proviso that it is intended by a physician to administer the
combinations, e.g. the pharmaceutical compositions, in separate
tablets, it is possible to administer the antidiabetics as
launched, e.g. rosiglitazone in the form as it is launched under
the trademark AVANDIA.TM.. Troglitazone can be administered in the
form as it is launched under the trademarks ReZulin.TM.,
PRELAY.TM., ROMOZIN.TM. (in the United Kingdom) or NOSCAL.TM. (in
Japan). Pioglitazone can be administered as disclosed in Example 2
of EP 0 193 256 A1, preferably in the form of the monohydrochloride
salt or in the form as launched under the trademark ACTOS.TM..
Ciglitazone can, for example, be formulated as disclosed in Example
13 of U.S. Pat. No. 4,287,200. If the drug metformin shall be
administered in a separate pharmaceutical composition, it can be
administered in the form as it is launched e.g. under the trademark
DIABETOSAN.TM.. If the drug metformin shall be administered in a
separate pharmaceutical composition in the form of its
hydrochloride salt, the metformin hydrochloride salt can be
administered in the form as it is launched e.g. under the
trademarks DIABETASE 500.TM., DIABETASE 850.TM. or GLUCOPHAGE
S.TM.. Glyburide can be taken in the form as it is launched under
the trademark AZUGLUCON.TM. or EUGLUCON.TM.. Tolbutamide can be
administered in the form as it is launched under the trademark
ORABET, glimepiride as launched under the trademark AMARYL.TM.,
gliclazide as launched under the trademark DIAMICRON.TM.,
glibomuride as launched under the trademark GLUBORID.TM. and
gliquidone as it is launched under the trademark GLURENORM.TM..
[0024] The compounds to be combined can be present as
pharmaceutically acceptable. 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.
For example the compounds to be combined can be present as a sodium
salt, as a maleate or hydrochloride. The compounds to be combined
can also be present in the form of solvates.
[0025] The recommended dose for rosiglitazone taken as a single
drug is 4 mg or 8 mg administered either as a single dose or in
divided doses twice daily. The best responses with rosiglitazone in
the treatment of diabetes are observed with 4 mg twice daily. The
recommended dose for pioglitazone taken as a single drug is 15 mg,
30 mg or 45 mg taken once daily.
[0026] The nature of diabetes and related diseases or conditions is
multifactorial. Under certain circumstances, drugs with different
mechanisms of action may be combined. However, just considering any
combination of drugs having different mode of action but acting in
the similar field does not necessarily lead to combinations with
advantageous effects.
[0027] All the more surprising is the experimental finding that the
combined administration of nateglinide or repaglinide and at least
one other antidiabetic compound selected from the group consisting
of glitazones, in particular rosiglitazone, troglitazone and
pioglitazone, sulfonyl urea derivatives and metformin results not
only in a beneficial, especially a synergistic, therapeutic effect,
but also in additional benefits resulting from the combined
treatment and further surprising beneficial effects compared to a
monotherapy applying only one of the pharmaceutically active
compounds used in the combinations disclosed herein.
[0028] In particular, all the more surprising is the experimental
finding that the combined administration of nateglinide or a
pharmaceutically acceptable salt thereof and an antidiabetic
thiazolidinedione derivative, results not only in a beneficial,
especially a synergistic, therapeutic effect but also in additional
benefits resulting from combined treatment 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.
[0029] It can be shown by established test models and especially
those test models described herein that the combination of
nateglinide or repaglinide and at least one other antidiabetic
compound selected from the group consisting of glitazones, in
particular rosiglitazone, rosiglitazone and pioglitazone, sulfonyl
urea derivatives and the biguanide metformin, or in each case a
pharmaceutically acceptable salt thereof, results in a more
effective prevention or preferably treatment of diseases,
especially metabolic disorders, and in particular type 2 diabetes
mellitus and diseases and conditions associated with diabetes
mellitus. In particular, it can be shown by established test models
and especially those test models described herein that the
combination of nateglinide and an antidiabetic thiazolidinedione
derivative, or in each case a pharmaceutically acceptable salt
thereof, results in a more effective prevention or preferably
treatment of diseases, especially metabolic disorders, more
especially diabetes and in particular type 2 diabetes mellitus, and
diseases and conditions associated with diabetes.
[0030] If taken simultaneously, this results not only in a further
enhanced beneficial, especially a synergistic, therapeutic effect,
but also in additional benefits resulting from the simultaneous
treatment such as a surprising prolongation of efficacy, a broader
variety of therapeutic treatment and surprising beneficial effects,
e.g. less increase of weight, on diseases and conditions associated
with diabetes mellitus, for a number of combinations as described
herein. Moreover, for a human patient, especially for elderly
people, it is more convenient and easier to remember to take two
tablets at the same time, e.g. before a meal, than staggered in
time, i.e. according to a more complicated treatment schedule. More
preferably, both active ingredients are administered as a fixed
combination, i.e. as a single tablet, in all cases desribed herein.
Taking a single tablet is even easier to handle than taking two
tablets at the same time. Furthermore, the packaging can be
accomplished with less effort.
[0031] 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. The pharmacological activity may, for example, be
demonstrated following essentially an in-vivo test procedure in
mice or in a clinical study as described hereinafter.
[0032] In-Vivo Test in Mice for Blood Glucose Control
[0033] ICR-CDI mice (male, five weeks old, body weight: about 20 g)
are abstained from food for 18 hours, and then used as test
subjects. The combination according to the present invention and
the active ingredients alone are suspended in 0.5% CMC-0.14M sodium
chloride buffer solution (pH 7.4) or suspended in 0.5 percent by
weight. The solution or suspension thus obtained is administered
orally in fixed volume amounts to the test subjects. After
predetermined time, the percentage decrease of the blood glucose
against the control group is determined.
[0034] Clinical Double-Blind, Randomized, Parallel-Group Studies in
Subjects with Type 2 Diabetes Inadequately Controlled on Diet or
Monotherapy and Diet Alone
[0035] These studies prove in particular the synergism of the
claimed combinations, such as the combined preparations or
pharmaceutical compositions, respectively. The beneficial effects
on diseases and conditions associated with diabetes mellitus as
defined in this application can be determined directly through the
results of these studies or by changes in the study design which
are known as such to a person skilled in the art.
[0036] The studies are, in particular, suitable to assess the
effects of monotherapy with nateglinide, repaglinide, a glitazone,
a sulfonyl urea derivative or metformin and a combination of
nateglinideor repaglinide with one or more compounds selected from
the group consisting of a glitazones, a sulfonyl urea derivatives
or metformin on glycemic control. The studies are especially
suitable to assess the effects of monotherapy with metformin or the
corresponding hydrochloride salt or a combination of nateglinide
and metformin or the corresponding hydrochloride salt on glycemic
control. Subjects with a diagnosis of type 2 diabetes who have not
achieved near normoglycemia (HbA.sub.1c<6.8%) on diet only are
chosen for this trial. The effects on glycemic control achieved
with nateglinide monotherapy, monotherapy with a glitazone,
monotherapy with metformin and the combination therapies as given
below are determined in these studies after 16 or 24 weeks with the
control achieved on placebo, all subjects continuing with the same
diet as in the period before treatment. Measures of glycemic
control are validated surrogate endpoints for the treatment of
diabetes. HbA.sub.1c is the single most reliable measurement for
assessing glycemic control (D. Goldstein et al, Tests of Glycemia
in Diabetes; Diabetes Care 1995, 18(6), 896-909) and is the primary
response variable in these studies. Since glycosylation of
hemoglobin is determined by the glucose concentration at the time
each red blood cell is made, HbA.sub.1c provides an estimate of
mean blood glucose for the previous three months.
[0037] Before starting with the double-blind treatment for 16 or 24
weeks, the subjects are administered for four or eight weeks
nateglinide matching placebos before breakfast, lunch and dinner,
and
[0038] (1) a placebo matching with the glitazone troglitazone
administered later on e.g. with breakfast only (study 1--period
I),
[0039] (2) a placebo matching with the glitazone pioglitazone 5 mg
tablet administered later on before breakfast, lunch and dinner
(study 2--period I).
[0040] The subjects are then separated into four treatment groups
for the 16-week or 24-week double-blind studies (period II) as
depicted below. Approximately 150 to 170 subjects are randomized
per treatment group. The total study duration including the run-in
period for each subject is 24 to 28 weeks. Statistical analysis can
be carried out by methods known in the art.
[0041] Study 1: Combination of 120 ma Nateglinide and
Troglitazone
[0042] In a particular embodiment of this study, before starting
with the double-blind treatment for 24 weeks, the subjects are
administered for four weeks nateglinide matching placebos before
breakfast, lunch and dinner, and a placebo matching with the
antidiabetic thiazolidinedione administered later on with breakfast
only (period I). The subjects are then separated into four
treatment groups for the 24-week double-blind study (period II) as
depicted below for the case that troglitazone is chosen as the
antidiabetic thiazolidinedione. Approximately 170 subjects are
randomized per treatment group. The total study duration including
the run-in period for each subject is 28 weeks
1 Treatment Group Treatment 1 120 mg* nateglinide + troglitazone
placebo** 2 600 mg** troglitazone + nateglinide placebo* 3 120 mg*
nateglinide + 600 mg** troglitazone 4 nateglinide placebo* +
troglitazone placebo** *administered before breakfast, lunch, and
dinner; **daily dosage
[0043] Nateglinide tablets contain either 120 mg or matching
placebo. Troglitazone tablets can be purchased commercially and
used to prepare the 600 mg tablets matching the corresponding
placebo capsules.
[0044] Study 2: Combination of 120 mg Nateglinide and
Pioglitazone
2 Treatment Group Treatment 1 120 mg* nateglinide + pioglitazone
placebo* 2 5 mg* pioglitazone + nateglinide placebo* 3 120 mg*
nateglinide + 5 mg* pioglitazone 4 nateglinide placebo* +
pioglitazone placebo* *administered both before breakfast, lunch,
and dinner
[0045] Nateglinide tablets contain either 120 mg or matching
placebo. Pioglitazone tablets can be purchased commercially and
used to prepare the 5 mg tablets matching the corresponding placebo
capsules.
[0046] Study 3: Combination of 60 mg Nateglinide and 250 mg of
Metformin Administered as a Single Pharmaceutical Composition
[0047] In this study in period I the subjects are administered for
four weeks matching placebos before breakfast, lunch and dinner,
before starting with the treatment for 24 weeks. The subjects are
then separated into four treatment groups for the 24-week study
(period II) as depicted below. The total study duration including
the run-in period for each subject is 28 weeks. Both drugs are
combined in a fixed pharmaceutical composition administered before
each main meal comprising as pharmaceutically active
components:
3 Treatment Group Treatment 1 60 mg nateglinide 2 250 mg metformin
3 60 mg nateglinide + 250 mg metformin 4 placebo only
[0048] Study 4: Combination of 60 or 120 mg Nateglinide Before
Meals and 1000 mg of Metformin as a Daily Dosis
[0049] Subjects with HbA.sub.1c values of 6.8-11% receive metformin
for at least 3 months und at least 1500 mg/day during the last 4
weeks before starting period 0. After period 0 extending over 4
weeks in which period 1000 mg/day metformin plus nateglinide
placebo are given to the subjects, the subjects are randomised to
nateglinide placebo, 60 mg nateglinide or 120 mg nateglinide before
main meals for 24 weeks while continuing to receive 1000 mg
metformin daily.
4 Treatment Group Treatment 1 nateglinide placebo* + 1000 mg
metformin ** 2 60 mg nateglinide* + 1000 mg metformin ** 3 120 mg
nateglinide* + 1000 mg metformin ** *administered before main
meals; ** immediately after breakfast and dinner
[0050] For example, the following procedure can be followed in
order to take blood samples: The subject is advised not to take the
morning dose of study medication or eat breakfast on the day of a
scheduled study visit. The morning dose is administered by site
personnel after the collection of all fasting laboratory samples
and completion of all study procedures. Visits are scheduled to be
performed at 2 week intervals during Period I, and 4 to 8 week
intervals during Period II. Subjects have fasted for at least 7
hours at the time of each visit. All blood samples for laboratory
evaluations are drawn between 7:00 AM and 10:00 AM. All tests are
conducted in accordance with GLP (Good Laboratory Practice)
principles following procedures known in the art.
[0051] HbA.sub.1c is measured by High Performance Liquid
Chromatography (HPLC) using the ion-exchange method on a Bio-Rad
Diamat analyzer. A back-up affinity method are used if hemoglobin
variants or hemoglobin degradation peaks are observed.
[0052] Further parameters to be determined are fasting plasma
glucose (FPG), fasting lipids (total, HDL (high density
lipoprotein)- and LDL (low density lipoprotein)-cholesterol, and
triglycerides) and body weight. FPG will be measured using the
hexokinase method and LDL-cholesterol will be calculated using the
Friedewald formula if triglycerides are <400 mg/dL (4.5
mmol/l).
[0053] Hematocrit and hemogloblin, platelet count, erythrocyte
count, total and differential leukocyte count (basophils,
eosinophils, lymphocytes, monocytes, segmented neutrophils and
total neutrophils); albumin, alkaline phosphatase, alanine amino
transferase (serum glutamic pyruvic transaminase), aspartate amino
transferase (serum glutamic oxaloacetic transaminase), blood urea
nitrogen or urea, bicarbonate, calcium, chloride, total creatine
phosphokinase (CPK), creatine phosphokinase muscle-brain fraction
isoenzyme (if CPK is elevated), direct bilirubin, creatinine,
.gamma.-glutamyl transferase, lactate dehydrogenase, potassium,
sodium, total bilirubin, total protein and uric acid in the blood;
and bilirubin, glucose, ketones, pH, protein, and specific gravity
in the subjects urine is determined by laboratory analysis.
Furthermore, body weight, blood pressure (systolic and diastolic,
after 3 minutes sitting) and radial pulse (after 3 minutes sitting)
are determined during the visit.
[0054] The results clearly show that the combinations according to
the present invention can be used for the prevention, delay of
progression and preferably the treatment of metabolic disorders and
in particular diabetes, especially type 2 diabetes mellitus and
diseases and conditions associated with diabetes. The combinations
of the present invention can also be used for the prevention and
preferably the treatment of other diseases.
[0055] The combined administration of nateglinide or repaglinide
and at least one other antidiabetic compound selected from the
group consisting of glitazones, sulfonyl urea derivatives and
metformin results in a beneficial, especially a synergistic,
therapeutic effect, especially on type 2 diabetes, and also in
additional benefits such as a decrease of diabetes-related
mortality, a surprising prolongation of efficacy of the drug (such
delaying the eventual need for insulin), a broader variety of
therapeutic treatment, maintaining the target blood glucose level
in type 2 diabetes patients, providing a good initial blood glucose
control in type 2 diabetes patients, only modest changes in fasting
plasma glucose level, and further surprising beneficial effects,
comprising e.g. less or no gain of body weight, a decrease of
gastrointestinal side effects or an improved safety profile,
compared to a monotherapy applying only one of the pharmaceutically
active compounds used in the combinations disclosed herein. In
particular, the further surprising beneficial effects can also be
observed during the treatment of metabolic disorders other than
type 2 diabetes and during the treatment of diseases and conditions
associated with type 2 diabetes. 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 (e.g. anaemia, oedema, headache).
[0056] Furthermore, in a number of combinations as disclosed herein
the side-effects observed with one of the components surprisingly
do not accumulate on application of the combination.
[0057] The beneficial therapeutic effect, additional benefits and
especially the surprising beneficial effects are observed in
particular with nateglinide. Very good results have been obtained
with the combination of nateglinide and metformin or metformin
hydrochloride.
[0058] The beneficial therapeutic effects, additional benefits and
also the surprising beneficial effects are observed especially in
human subjects suffering from a more severe form of type 2
diabetes, i.e. human subjects having an elevated HbA.sub.1c
(glycosylated haemoglobin) value at baseline of greater 8% and more
particular in human subjects having a HbA.sub.1c value at baseline
of greater than 9.5%, before treatment with the combinations
described herein. If nateglinide is administered to such human
patients, preferably, such human patients obtain a dose of between
90 and 200 mg, more preferably between 100 and 150 mg, for example
120 mg, nateglinide per meal as part of the combination given to
them.
[0059] In one preferred embodiment of the invention, a dose of
between 45 and 85 mg, more preferably 60 mg, of nateglinide per
meal is administered as part of the combination to human subjects
having a HbA.sub.1c value at baseline between 6.8% and 8%, in
particular between 6.8% and 7%. This provides the option to
increase the amount of nateglinide later on, which option is
advantegous especially in a situation when the HbA.sub.1c value at
baseline exceeds values of 7% after starting the treatment of the
human subject for a period of time or constantly or if the
responsible physician determines that the treatment schedule has to
be changed to higher amounts of nateglinide for other reasons. One
preferred combination partner in this embodiment is metformin.
[0060] Furthermore, the beneficial therapeutic effects, additional
benefits and also the surprising beneficial effects are observed
especially in human subjects having a body mass index (BMI) of 20
to 35 kg/m.sup.2, in particular a BMI of 27 to 35 kg/m.sup.2, and
even more enhanced in human subjects with a BMI of 30 to 35
kg/m.sup.2. Human subjects having a BMI greater 30 kg/m.sup.2 are
defined to be clinically obese.
[0061] Additionally, the beneficial therapeutic effects, additional
benefits and also the surprising beneficial effects are observed
especially in patients poorly controlled by monotherapy with one of
the components of the combinations disclosed herein.
[0062] 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 (e.g.
anaemia, oedema, headache). This is in accordance with the desires
and requirements of the patients to be treated.
[0063] In one preferred embodiment of the invention, the
combination is a combined preparation comprising nateglinide and a
glitazone for simultaneous, separate or sequential use in the
prevention or treatment of diseases.
[0064] In particular, the present invention relates to a combined
preparation which comprises nateglinide and a glitazone in which
the active ingredients are present in each case in free form or in
the form of a pharmaceutically acceptable salt and optionally at
least one pharmaceutically acceptable carrier, as a combined
preparation for simultaneous, separate or sequential use in the
prevention or treatment of diseases, especially metabolic
disorders, more especially diabetes and in particular type 2
diabetes mellitus, and diseases and conditions associated with
diabetes.
[0065] In one preferred embodiment of the invention the combination
comprising nateglinide or repaglinide and at least one other
antidiabetic compound selected from the group consisting of
glitazones, sulfonyl urea derivatives and comprises further insulin
or that the combination comprises at least two antidiabetic
compounds selected from the group consisting of glitazones,
sulfonyl urea derivatives and metformin, or a pharmaceutically
acceptable salt thereof.
[0066] Also preferred is a combination in which said other
antidiabetic compound is metformin or metformin hydrochloride or is
selected from the group of glitazones, especially rosiglitazone or
troglitazone, or in particular, pioglitazone.
[0067] Preferred antidiabetic thiazolidinedione derivatives
(glitazones) are those represented by formula (II), 3
[0068] wherein
[0069] A represents
[0070] naphthyl, benzoxazolyl, dihydrobenzopyranyl;
[0071] phenyl or phenylethynyl, both radicals unsubstituted or
substituted by halogen;
[0072] R.sub.1 represents halogen or a radical --XR.sub.4, in
which
[0073] X can be oxygen, methylen, carbonyl or --NH--,
[0074] R.sub.4 is
[0075] (i) naphthyl;
[0076] (ii) phenyl, unsubstituted or substituted by
2,4-dioxo-5-thiazolidinyl; or
[0077] (iii) lower alkyl or hydroxy-lower alkyl, in each case
unsubstituted or substituted by
[0078] a) indole or 2,3-dihydroindole,
[0079] b) pyridyl, lower alkyl-pyridyl, N-lower
alkyl-N-pyridylamino or halogenphenyl,
[0080] c) dihydrobenzopyranyl, which is unsubstituted or
substituted by hydroxy and lower alkyl,
[0081] d) oxazolyl, which is substituted by lower alkyl and
phenyl,
[0082] e) cycloalkyl, which is unsubstituted or substituted by
lower alkyl, or
[0083] f) arylcycloalkylcarbonyl;
[0084] R.sub.2 represents hydrogen or trifluoromethylphenyl-lower
alkyl carbamoyl; and
[0085] R.sub.3 represents hydrogen or arylsulfonyl.
[0086] In one very preferred embodiment of the invention A
represents naphthyl, preferably 2-naphthyl; R.sub.1 preferably is
placed in 6-position of the naphthyl radical and is --XR.sub.4, in
which X is oxygen; R.sub.4 is lower alkyl, most preferably methyl,
which is substituted by halogenphenyl, most preferably
2-fluorophenyl. R.sub.2 and R.sub.3 are both hydrogen.
[0087] In another preferred embodiment of the invention A
represents dihydrobenzopyranyl, preferably
3,4-dihydro-2H-1-benzopyran-2-yl; R.sub.1 preferably is placed in
2-position of the benzopyranyl radical and is preferably
--XR.sub.4, in which X is lower alkylen, preferably methylen; and
R.sub.4 is preferably unsubstituted phenyl. R.sub.2 and R.sub.3 are
both hydrogen.
[0088] In another preferred embodiment of the invention A
represents phenylethynyl; R.sub.1 preferably is placed in
4-position of the phenyl radical and is preferably halogen, most
preferably chloro; R.sub.2 is preferably hydrogen and R.sub.3 is
arylsulfonyl, wherein preferably aryl is phenyl which is
unsubstituted or substituted by halogen, preferably fluorine, lower
alkyl, preferably methyl, or lower alkoxy, preferably methoxy; or
naphthyl. Most preferably R.sub.3 is phenylsulfonyl which is
unsubstituted.
[0089] In a further preferred embodiment the glitazone is
represented by formula (IIa), 4
[0090] in which R.sub.1 is XR.sub.4, X is oxygen and R.sub.4 is
lower alkyl, substituted by indole or 2,3-dihydroindole, most
preferably 2-(indol-1-yl)ethoxy or 2-(2,3-dihydroindol-1-yl)ethoxy.
R.sub.2 and R.sub.3 are hydrogen.
[0091] In another preferred embodiment of the invention the
glitazone is represented by formula (IIa), in which R.sub.1 is
XR.sub.4, X is oxygen and R.sub.4 is hydroxy lower alkyl,
preferably 2-hydroxyethyl, substituted by oxazolyl, preferably
4-oxazolyl, which is substituted by phenyl and lower alkyl,
preferably methyl. R.sub.2 and R.sub.3 are both hydrogen.
[0092] In one very preferred embodiment of the invention the
glitazone is represented by formula (IIa), in which R, is XR.sub.4,
X is oxygen and R.sub.4 is lower alkyl, preferably methyl or ethyl
and most preferably methyl; R.sub.2 is trifluoromethylphenyl-lower
alkyl carbamoyl, preferably trifluoromethylbenzylcarbamoyl; and
R.sub.3 is hydrogen.
[0093] In another preferred embodiment of the invention the
glitazone is represented by formula (IIa), in which R.sub.1 is
XR.sub.4, X is --NH-- and R.sub.4 is aryl-cycloalkylcarbonyl.
Preferably, R.sub.4 is phenylcycloalkylcarbonyl, in which radical
the phenyl residue and the carbonyl residue are bonded at the same
carbon atom of the cycloalkyl ring. Most preferably R.sub.4 is
1-phenyl-1-cyclopropanecarbonyl. R.sub.2 and R.sub.3 are both
hydrogen.
[0094] In one very preferred embodiment of the invention the
glitazone is represented by formula (IIa), in which R.sub.1 is
XR.sub.4, X is oxygen and R.sub.4 is lower alkyl, preferably methyl
or ethyl and most preferably methyl, substituted by pyridyl or
lower alkyl-pyridyl. More preferably lower alkyl is substituted by
lower alkyl-2-pyridyl and most preferably by ethyl-2-pyridyl.
R.sub.2 and R.sub.3 are hydrogen.
[0095] In one very preferred embodiment of the invention the
glitazone is represented by formula (IIa), in which R.sub.1 is
XR.sub.4, X is oxygen and R.sub.4 is lower alkyl, preferably
methyl, which is substituted by dihydrobenzopyranyl, preferably
3,4-dihydro-2H-1-benzopyran-2-yl, which is unsubstituted or,
preferably, substituted by lower alkyl, preferably methyl or ethyl,
and hydroxy. Most preferably X is oxygen, R.sub.4 is methyl, which
is substituted by 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-
-2H-1-benzopyran-2-yl. R.sub.2 and R.sub.3 are hydrogen.
[0096] In another preferred embodiment of the invention the
glitazone is represented by formula (IIa), in which R.sub.1 is
XR.sub.4, X is preferably oxygen and R.sub.4 is lower alkyl
substituted by cycloalkyl, preferably C.sub.5-C.sub.7cycloalkyl,
more preferably cyclohexyl, which is unsubstituted or substituted
by lower alkyl, preferably ethyl or methyl and more preferably
methyl. R.sub.2 and R.sub.3 are hydrogen.
[0097] In one very preferred embodiment of the invention the
glitazone is represented by formula (IIa), in which R.sub.1 is
XR.sub.4, X is oxygen and R.sub.4 is lower alkyl, preferably ethyl,
which is substituted by N-lower alkyl-N-pyridylamino, preferably
N-methyl-N-pyridylamino and most preferably
N-methyl-N-2-pyridylamino. R.sub.2 and R.sub.3 are hydrogen.
[0098] In another preferred embodiment of the invention the
glitazone is represented by formula (IIa), in which R.sub.1 is
XR.sub.4, X is oxygen or carbonyl and R.sub.4 is lower alkyl,
preferably ethyl, which is substituted by oxazolyl substituted by
lower alkyl, preferably methyl, and unsubstituted phenyl. R.sub.2
and R.sub.3 are hydrogen.
[0099] In another preferred embodiment of the invention the
glitazone is represented by formula (IIa), in which R.sub.1 is
XR.sub.4, X is lower alkylen, preferably methylen, R.sub.4 is
phenyl substituted, preferably in 4-position, by
2,4-dioxo-5-thiazolidinyl. R.sub.2 and R.sub.3 are hydrogen.
[0100] In a further preferred embodiment of the invention the
glitazone is 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione.
[0101] In one very preferred embodiment of the invention A
represents benzoxazolyl, preferably 5-benzoxazolyl; R.sub.1
preferably is placed in 2-position of the benzoxazolyl radical and
is --XR.sub.4, in which X is lower alkylene, preferably methylene,
and R.sub.4 is naphthyl, preferably 2-naphthyl. R.sub.2 and R.sub.3
are both hydrogen.
[0102] A very preferred glitazone according to all aspects of the
present invention is selected from the group consisting of
rosiglitazone, MCC555, troglitazone and especially pioglitazone,
and their pharmaceutically acceptable salts. In the case of
pioglitazone the invention relates in particular to the
monohydrochloride salt.
[0103] In a further preferred embodiment of the invention a
glitazone according to all aspects of the present invention is
selected from the group consisting of T-174, KRP297 and their
pharmaceutically acceptable salts.
[0104] Another preferred glitazone according to all aspects of the
present invention is selected from the group consisting of
englitazone, darglitazone, ciglitazone, AY-31637,
5-{[4-(2-(1indolyl)ethoxy)phenyl]met- hyl}-thiazolidine-2,4-dione
(D RF2189), 5-{[4-(2-(2,3-dihydroindol-11-yl)e-
thoxy)phenyl]methyl}-thiazolidine-2,4-dione, BM-13.1246,
bis{4-[(2,4-dioxo-5-thiazolidinyl)methyl]phenyl}methane (YM268),
5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]benzyl}-thiazolidi-
ne-2,4-dione (AD-5075),
5-[3-(4-chlorophenyl])-2-propynyl]-5-phenylsulfony-
l)thiazolidine-2,4-dione,
5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluoroph-
enylsulfonyl)thiazolidine-2,4-dione,
5-[4-(1-phenyl-1-cyclopropanecarbonyl-
amino)-benzyl]-thiazolidine-2,4-dione (DN-108) and their
pharmaceutically acceptable salts.
[0105] In a very preferred embodiment of the invention nateglinide
is administered in combination with metformin, metformin
hydrochloride or a mixture thereof. Nateglinide and metformin,
metformin hydrochloride or a mixture thereof can be administered at
different points in time, e.g. nateglinide before breakfast, lunch
and dinner and metformin, metformin hydrochloride or a mixture
thereof after breakfast, lunch and dinner, or simultaneously.
Preferably, nateglinide and metformin, metformin hydrochloride or a
mixture thereof are administered simultaneously. Very preferably,
nateglinide and metformin, metformin hydrochloride or a mixture
thereof are administered thrice daily before breakfast, lunch and
dinner. It is also very preferred to administer nateglinide and
metformin, metformin hydrochloride or a mixture thereof together in
fixed combination.
[0106] It is one objective of this invention to provide a
pharmaceutical composition comprising an amount, which is jointly
therapeutically effective against metabolic disorders, in
particular type 2 diabetes mellitus or a disease or condition
associated with diabetes mellitus, of (i) nateglinide or
repaglinide or in each case a pharmaceutically acceptable salt
thereof and (ii) and at least one other antidiabetic compound
selected from the group consisting of glitazones, sulfonyl urea
derivatives and metformin or a pharmaceutically acceptable salt
thereof and at least one pharmaceutically acceptable carrier. In
this composition, components (i) and (ii) can be administered
together, one after the other or separately in one combined unit
dosage form or in two separate unit dosage forms. Preferably, the
unit dosage form is a fixed combination. Preferably, a
pharmaceutical composition of the present invention comprising
nateglinide comprises the B- or H-type crystal modification of
nateglinide, more preferably the H-type.
[0107] In particular, the present invention relates to a
pharmaceutical composition comprising jointly therapeutically
effective amounts of nateglinide or a pharmaceutically acceptable
salt thereof, a glitazone or a pharmaceutically acceptable salt
thereof, and at least one pharmaceutically acceptable carrier.
[0108] Furthermore, the invention relates to a combined preparation
or pharmaceutical composition, respectively, which comprises
nateglinide and a glitazone, wherein the combined preparation or
pharmaceutical composition, respectively, comprises at least one
further pharmaceutically active compound e.g. selected from the
group consisting of a sulphonyl urea derivative, a pharmaceutically
acceptable salt thereof, metformin and insulin; or wherein the
combined preparation or pharmaceutical composition, respectively,
comprises at least one further glitazone or a pharmaceutically
acceptable salt therof.
[0109] A further aspect of the present invention is the use of a
pharmaceutical composition comprising nateglinde or repaglinide and
at least one other antidiabetic compound selected from the group
consisting of glitazones, sulfonyl urea derivatives and metformin
in each case in free form or in form of a pharmaceutically
acceptable salt thereof for the preparation of a medicament for the
prevention, delay of progression or treatment of metabolic
disorders, in particular of type 2 diabetes mellitus or a disease
or condition associated with diabetes mellitus. In particular, this
further aspect of the present invention relates to the use of a
pharmaceutical composition comprising nateglinde and a glitazone in
each case in free form or in form of a pharmaceutically acceptable
salt thereof for the preparation of a pharmaceutical preparation
for the prevention or treatment of diseases, especially metabolic
disorders, more especially diabetes and in particular type 2
diabetes mellitus, and diseases and conditions associated with
diabetes.
[0110] Furthermore, the invention relates to a pharmaceutical
composition comprising nateglinde or repaglinide and at least one
other antidiabetic compound selected from the group consisting of
glitazones, sulfonyl urea derivatives and metformin in each case in
free form or in form of a pharmaceutically acceptable salt thereof
for the prevention, delay of progression or treatment of
hyperglycemia, hyperinsulinaemia, hyperlipidaemia, insulin
resistance, impaired glucose metabolism, obesity, diabetic
retinopathy, macular degeneration, cataracts, diabetic nephropathy,
glomerulosclerosis, diabetic neuropathy, erectile dysfunction,
premenstrual syndrome, vascular restenosis, ulcerative colitis,
coronary heart disease, hypertension, angina pectoris, myocardial
infarction, stroke, skin and connective tissue disorders, foot
ulcerations, metabolic acidosis, arthritis, osteoporosis and in
particular conditions of impaired glucose tolerance and especially
type 2 diabetes.
[0111] Further aspects of the present invention are oral dosage
forms and pharmaceutical formulations (compositions) for
administration to mammals suffering from or at risk for diseases
having the characteristics of type 2 diabetes. It will be
understood that any statistically significant attenuation in the
disease symptoms of type 2 diabetes pursuant to the treatment of
the present invention is within the scope of the invention.
[0112] Each oral formulation (composition) according to the present
invention may additionally comprise inert constituents including
pharmaceutically acceptable carriers, diluents, fillers,
solubilizing or emulsifying agents and salts as is well-known in
the art. For example, tablets used for combination therapy may be
formulated in accordance with conventional procedures employing
solid carriers well-known in the art. Capsules employed in for the
combination therapies of the present invention may be made from any
pharmaceutically acceptable material such as gelatin or cellulose
derivatives.
[0113] The term "combination therapy" as used herein means that a
combination which comprises nateglinide or repaglinide and at least
one other antidiabetic compound selected from the group consisting
of glitazones, sulfonyl urea derivatives and metformin, is used for
the treatment, delay of progression or prevention of one of the
diseases, especially metabolic disorders, mentioned herein.
[0114] Examples of solid carriers include bentonite, silica and
other commonly used carriers. Further non-limiting examples of
carriers and diluents that may be used in the combination therapy
formulations of the present invention include saline and any
physiologically buffered saline solution such as phosphate buffered
saline (PBS) and water.
[0115] It will be appreciated that the unit content of active
ingredient or ingredients contained in an individual dose of each
dosage form need not in itself constitute an effective amount since
the necessary effective amount can be reached by administration of
a plurality of dosage units.
[0116] The preferred route of administration of the dosage forms of
the present invention is orally or enterally. Preferred oral or
enteral pharmaceutical formulations or dosage forms may comprise
for example, between about 1 mg and about 1000 mg of nateglinide,
for example.
[0117] In an alternative preferred embodiment of the present
invention the pharmaceutical formulations or dosage forms for the
combination therapies of the present invention can also be
administered to mammals suffering from diseases having the
characteristics of type 2 diabetes in aerosol form. It is expected
that lower amounts of antidiabetic drugs, or disease suppressive
fragments or analogs thereof will be required using aerosol
administration for treating or preventing type 2 diabetes as has
been found in the treatment of other allergic disease states. The
amounts of anti-diabetic drugs or analogs thereof which may be
administered in an aerosol dosage form would be between about 0.1
mg and 10 mg per kg body weight of a mammal per day and may be
administered in single dosage form or multiple dosage forms. The
exact amount to be administered will vary depending on the state
and severity of a patient's disease and the physical condition of
the patient.
[0118] The aerosol pharmaceutical formulations for use in
combination therapies of the present invention may include, as
optional ingredients, pharmaceutically acceptable carriers,
diluents, solubilizing or emulsifying agents, and salts of the type
that are well-known in the art. Examples of such substances include
normal saline solutions, such as physiologically buffered saline
solutions, and water.
[0119] The route of administration of anti-diabetic drugs or
disease suppressive fragments or analogs thereof according to this
alternate embodiment of the present invention is in an aerosol or
inhaled form. The anti-diabetic drugs and related compounds of the
present invention can be administered as a dry powder or in an
aqueous solution. Preferred aerosol pharmaceutical formulations may
comprise for example, a physiologically-acceptable buffered saline
solution containing between about 1 mg and about 1000 mg of
anti-diabetic drugs, disease suppressive fragments or analogs
thereof.
[0120] Dry aerosol in the form of finely divided solid particles of
antidiabetic drugs, disease suppressive fragments or analogs
thereof that are not dissolved or suspended in a liquid are also
useful in the practice of the present invention. The anti-diabetic
drugs may be in the form of dusting powders and comprise finely
divided particles having an average particle size of between about
1 and 5 microns, preferably between 2 and 3 microns. Finely divided
particles may be prepared by pulverization and screen filtration
using techniques well known in the art. The particles may be
administered by inhaling a predetermined quantity of the finely
divided material, which can be in the form of a powder.
[0121] Specific non-limiting examples of the carriers and/or
diluents that are useful in the aerosol pharmaceutical formulations
used for combination therapies of the present invention include
water and physiologically-acceptable buffered saline solutions such
as phosphate buffered saline solutions pH 7.0-8.0.
[0122] The pharmaceutical formulations of the present invention may
be administered in the form of an aerosol spray using for example,
a nebulizer such as those described in U.S. Pat. No. 4,624,251
issued Nov. 25, 1986; U.S. Pat. No. 3,703,173 issued Nov. 21, 1972;
U.S. Pat. No. 3,561,444 issued Feb. 9, 1971 and U.S. Pat. No.
4,635,627 issued Jan. 13, 1971. The aerosol material is inhaled by
the subject to be treated.
[0123] Other systems of aerosol delivery, such as the pressurized
metered dose inhaler (MDI) and the dry powder inhaler as disclosed
in Newman, S. P. in Aerosols and the Lung, Clarke, S. W. and Davia,
D. eds. pp. 197-224, Butterworths, London, England, 1984, can be
used when practicing the present invention.
[0124] Aerosol delivery system of the type disclosed herein are
available from numerous commercial sources including Fisons
Corporation (Bedford, Mass.), Schering Corp. (Kenilworth, N.J.) and
American Pharmoseal Co., (Valencia, Calif.).
[0125] In practical use, the anti-diabetic drugs or combinations
thereof can be combined as the active ingredients in intimate
admixture with a pharmaceutical carrier according to conventional
pharmaceutical compounding techniques. The carrier may take a wide
variety of forms depending on the form of preparation desired for
administration, e.g., oral or parenteral (including intravenous).
In preparing the compositions for oral dosage form, any of the
usual pharmaceutical media may be employed, such as, for example,
water, glycols, oils, alcohols, flavoring agents, preservatives,
coloring agents and the like in the case of oral liquid
preparations, such as, for example, suspensions, elixirs and
solutions; or carriers such as starches, sugars, microcrystalline
cellulose, diluents, granulating agents, lubricants, binders,
disintegrating agents and the like in the case of oral solid
preparations such as, for example, powders, capsules and tablets,
with the solid oral preparations being preferred over the liquid
preparations. Because of their ease of administration, tablets and
capsules represent the most advantageous oral dosage unit form in
which case solid pharmaceutical carriers are obviously employed. If
desired, tablets may be coated by standard aqueous or nonaqueous
techniques.
[0126] In addition to the common dosage forms set out above, the
anti-diabetic drugs or combinations thereof may also be
administered by controlled release means and/or delivery devices
such as those described in U.S. Pat. Nos. 3,845,770; 3,916,899;
3,536,809; 3,598,123; 3,630,200 and 4,008,719, the disclosures of
which are hereby incorporated herein by reference.
[0127] Pharmaceutical compositions of the present invention used
for the combination therapy suitable for oral administration may be
presented as discrete units such as capsules, cachets or tablets
each containing a predetermined amount of the active ingredient, as
a powder or granules or as a solution or a suspension in an aqueous
liquid, a non-aqueous liquid, an oil-in-water emulsion or a
water-in-oil liquid emulsion. Such compositions may be prepared by
any of the methods of pharmacy but all methods include the step of
bringing into association the active ingredient with the carrier
which constitutes one or more necessary ingredients. In general,
the compositions are prepared by uniformly and intimately admixing
the active ingredient with liquid carriers or finely divided solid
carriers or both, and then, if necessary, shaping the product into
the desired presentation. For example, a tablet may be prepared by
compression or molding, optionally with one or more accessory
ingredients. Compressed tablets may be prepared by compressing in a
suitable machine, the active ingredient in a free-flowing form such
as powder or granules, optionally mixed with a binder, lubricant,
inert diluent, surface active or dispersing agent. Molded tablets
may be made by molding in a suitable machine, a mixture of the
powdered compound moistened with an inert liquid diluent.
[0128] The combination of compounds of the present invention is
useful in the treatment of diabetes. For these purposes, the
combinations of the present invention may be administered orally,
parenterally (including subcutaneous injections, intravenous,
intramuscular, intrasternal injection or infusion techniques), by
inhalation spray, or rectally, in dosage unit formulations
containing conventional non-toxic pharmaceutically acceptable
carriers, adjuvants and vehicles. These can be administered in a
fixed combination dosage form or separately.
[0129] Thus, in accordance with the combination therapies of the
present invention there is further provided a method of treating
and a pharmaceutical composition for treating obesity and diabetes.
The treatment involves administering to a patient in need of such
treatment a pharmaceutical composition comprising a pharmaceutical
carrier and a therapeutically effective amount of each compound in
the combination of the present invention.
[0130] These pharmaceutical compositions may be in the form of
orally-administrable suspensions or tablets; nasal sprays; sterile
injectable preparations, for example, as sterile injectable aqueous
or oleaginous suspensions or suppositories.
[0131] In accordance with the methods of the present invention, the
individual components of the combination can be administered
separately at different times during the course of therapy or
concurrently in divided or single combination forms. For example,
in a two-component combination of, e.g., nateglinide or repaglinide
and/or a glitazone as herein defined or metformin, treatment with
nateglinide or repaglinide can commence prior to, subsequent to or
concurrent with commencement of treatment with the glitazone and/or
the metformin. Furthermore, the term administering also encompasses
the use of prodrugs of any of the anti-diabetic drugs that convert
in vivo to the selective anti-diabetic drug. The instant invention
is therefore to be understood as embracing all such regimes of
simultaneous or alternating treatment and the term "administering"
is to be interpreted accordingly.
[0132] When any of the active ingredients are administered in the
combination therapy orally as a suspension, these compositions are
prepared according to techniques well-known in the art of
pharmaceutical formulation and may contain microcrystalline
cellulose for imparting bulk, alginic acid or sodium alginate as a
suspending agent, methylcellulose as a viscosity enhancer, and
sweeteners/flavoring agents known in the art. Furthermore, these
compositions may contain dicalcium phosphate, starch, magnesium
stearate and lactose and/or other excipients, binders, extenders,
disintegrants, diluents and lubricants known in the art.
[0133] When administered by nasal aerosol or inhalation, these
compositions are prepared according to techniques well-known in the
art of pharmaceutical formulation and may be prepared as solutions
in saline, employing benzyl alcohol or other suitable
preservatives, absorption promoters to enhance bioavailability,
fluorocarbons, and/or other solubilizing or dispersing agents known
in the art.
[0134] The compounds utilized in the combination may also be
administered in intravenous (both bolus and infusion),
intraperitoneal, subcutaneous, topical with or without occlusion,
or intramuscular form, all using forms well known to those of
ordinary skill in the pharmaceutical arts. When administered by
injection, the injectable solutions or suspensions may be
formulated according to known art, using suitable non-toxic,
parenterally-acceptable diluents or solvents, such as mannitol,
1,3-butanediol, water, Ringer's solution or isotonic sodium
chloride solution, or suitable dispersing or wetting and suspending
agents, such as sterile, bland, fixed oils, including synthetic
mono- or diglycerides, and fatty acids, including oleic acid.
[0135] When rectally administered in the form of suppositories,
these compositions may be prepared by mixing the drug with a
suitable non-irritating excipient, such as cocoa butter, synthetic
glyceride esters or polyethylene glycols, which are solid at
ordinary temperatures, but liquidity and/or dissolve in the rectal
cavity to release the drug.
[0136] The active ingredients of the combination of the present
invention may be administered as a pharmaceutical composition, for
example, with an inert diluent, or with an assimilable edible
carrier, or they may be enclosed in hard or soft shell capsules, or
they may be compressed into tablets, or they may be incorporated
directly with the food of the diet. For oral therapeutic
administration, which includes sublingual administration, these
active compounds may be incorporated with excipients and used in
the form of tablets, pills, capsules, ampules, sachets, elixirs,
suspensions, syrups, and the like. Such compositions and
preparations should contain at least 0.1 percent of the active
ingredients. The percentage of active ingredients in these
compositions may, of course, be varied and may conveniently be
between about 2 percent to about 60 percent of the weight of the
unit. The amount of active ingredients in such therapeutically
useful compositions is such that an effective dosage will be
obtained. The active compounds can also be administered
intranasally as, for example, liquid drops or spray.
[0137] The effective dosage of each of the active ingredients
employed in the combination therapy may vary depending on the
particular compound employed, the mode of administration, the
condition being treated and the severity of the condition being
treated. Thus, the dosage regimen utilizing the compounds of the
present invention is selected in accordance with a variety of
factors including type, species, age, weight, sex and medical
condition of the patient; the severity of the condition to be
treated; the route of administration; the renal and hepatic
function of the patient; and the particular compound thereof
employed. A physician, clinician or veterinarian of ordinary skill
can readily determine and prescribe the effective amount of the
drug required to prevent, counter or arrest the progress of the
condition. Optimal precision in achieving concentration of drug
within the range that yields efficacy without toxicity requires a
regimen based on the kinetics of the drug's availability to target
sites. This involves a consideration of the distribution,
equilibrium, and elimination of a drug.
[0138] The amount of nateglinide or repaglinide in compositions of
the invention will of course vary, e.g. depending on the intended
route of administration and to what extent other components, as
hereinbefore described, are present. In general however the
nateglinide or repaglinide will be present in an amount within the
range of from 0.05 especially about 0.1 to about 35% by weight
based on the total weight of the composition.
[0139] Nateglinide or repaglinide will suitably be present in the
compositions of the invention in an amount of from about 0.5 to
about 90% by weight based on the total weight of the composition.
In the case of compositions in accordance with the invention
comprising an additional component metformin, this will generally
be present in an amount of from about 1 to about 90% by weight,
more commonly from about 5 or 10 to about 70% by weight based on
the total weight of the composition. In the case of compositions in
accordance with the invention comprising an additional component
thiazolidinone derivative, this will generally be present in an
amount of from about 2 to about 50% by weight based on the total
weight of the composition.
[0140] The tablets, pills, capsules, and the like may also contain
a binder such as gum tragacanth, acacia, corn starch or gelatin;
excipients such as dicalcium phosphate; a disintegrating agent such
as corn starch, potato starch, alginic acid; a lubricant such as
magnesium stearate; and a sweetening agent such as sucrose, lactose
or saccharin. When a dosage unit form is a capsule, it may contain,
in addition to materials of the above type, a liquid carrier such
as a fatty oil.
[0141] Various other materials may be present as coatings or to
modify the physical form of the dosage unit. For instance, tablets
may be coated with shellac, sugar or both. A syrup or elixir may
contain, in addition to the active ingredient, sucrose as a
sweetening agent, methyl and propylparabens as preservatives, a dye
and a flavoring such as cherry or orange flavor.
[0142] These active compounds may also be administered parenterally
for combination therapies of the present invention. Solutions or
suspensions of these active compounds can be prepared in water
suitably mixed with a surfactant such as hydroxypropylcellulose.
Dispersions can also be prepared in glycerol, liquid polyethylene
glycols and mixtures thereof in oils. Under ordinary conditions of
storage and use, these preparations contain a preservative to
prevent the growth of microorganisms.
[0143] Especially, the present invention relates to a
pharmaceutical composition for combination therapy comprising
nateglinide and metformin in a pharmaceutical carrier, which is
preferably in the form of a tablet, a capsule, a suspension or a
liquid. Such pharmaceutical composition contains most preferably
from about 100 mg to about 130 mg of nateglinide and from about 320
mg to about 1500 mg, more preferably 330 mg to 350 mg, metformin
per dose unit.
[0144] The pharmaceutical forms suitable for injectable use include
sterile aqueous solutions or dispersions and sterile powders for
the extemporaneous preparation of sterile injectable solutions or
dispersions. In all cases, the form must be sterile and must be
fluid to the extent that easy syringability exists. It must be
stable under the conditions of manufacture and storage and must be
preserved against the contaminating action of microorganisms such
as bacteria and fungi. The carrier can be a solvent or dispersion
medium containing, for example, water, ethanol, polyol (e.g.
glycerol, propylene glycol and liquid polyethylene glycol),
suitable mixtures thereof, and vegetable oils.
[0145] When combinations of the anti-diabetic drugs described in
this invention are formulated, the relative proportion of
ingredients in the compositions of the invention will, of course,
vary considerably depending on the particular type of composition
concerned, e.g. whether it is a tablet, troche, liquid, such as an
emulsion or microemulsion, or suspension and so forth. The relative
proportions will also vary depending on the particular ingredients
employed and the desired physical characteristics of the product
composition. Determination of workable proportions in any
particular instance will generally be within the capability of the
worker skilled on the art. All indicated proportions and relative
weight ranges described below are accordingly to be understood as
being indicative of preferred or individually inventive teachings
only and not as not limiting the invention in its broadest
aspect.
[0146] It will be understood that in the discussion of methods
which follows, references to the compounds of formula I are meant
to also include the pharmaceutically acceptable salts.
[0147] A further aspect of the present invention is a method of
treating a warm-blooded animal, especially a human, having
metabolic disorders, in particular type 2 diabetes mellitus or a
disease or condition associated with diabetes mellitus, comprising
administering to the animal a combination of nateglinide or
repaglinide and at least one other antidiabetic compound selected
from the group consisting of glitazones, sulfonyl urea derivatives
and metformin in an amount which is jointly therapeutically
effective against metabolic disorders in which both compounds can
also be present in the form of their pharmaceutically acceptable
salts. Preferably, such a method of treating is carried out with
nateglinide and at least one other antidiabetic compound selected
from the group consisting of glitazones, sulfonyl urea derivatives
and metformin contained in the same dosage unit form. The
combination is preferably administered simultaneously.
[0148] In particular, the present invention relates to a method of
treating diabetes or a disease or condition associated with
diabetes comprising administering to a warm-blooded animal in need
thereof jointly therapeutically effective amounts of nateglinide in
free or pharmaceutically acceptable salt form, and a glitazone, in
free or pharmaceutically acceptable salt form, simultaneously or
sequentially in any order, separately or in a fixed combination.
Preferably, in this method nateglinide and the glitazone are
provided as a combined preparation. In one preferred embodiment,
this method further comprises administration of a therapeutically
effective amount of at least one further pharmaceutically active
compound selected from the group consisting of sulphonyl urea
derivatives, a pharmaceutically acceptable salt thereof, metformin
and insulin; or at least one further glitazone, or a
pharmaceutically acceptable salt thereof. Preferably, in this
method the glitazone is a compound of formula (II), wherein A
represents naphthyl, benzoxazolyl, dihydrobenzopyranyl, indole,
phenyl (optionally substituted by halogen) or phenylethynyl
(optionally substituted by halogen); R.sub.1 represents halogen or
a radical --XR.sub.4, in which X can be oxygen, lower alkylen,
carbonyl or --NH--, R.sub.4 is naphthyl; phenyl, unsubstituted or
substituted by 2,4-dioxo-5-thiazolidinyl; or lower alkyl or hydroxy
lower alkyl, unsubstituted or substituted by a) indole or
2,3-dihydroindole, b) pyridyl, lower alkyl-pyridyl, N-lower
alkyl-N-pyridylamino or halogenphenyl, c) dihydrobenzopyranyl,
which is unsubstituted or substituted by hydroxy and lower alkyl,
d) oxazolyl, which is substituted by lower alkyl and phenyl, e)
cycloalkyl, which is unsubstituted or substituted by lower alkyl,
or f) arylcycloalkylcarbonyl; R.sub.2 represents hydrogen or
trifluoromethylphenyl-lower alkyl carbamoyl; and R.sub.3 represents
hydrogen or arylsulfonyl. In a first more preferrred embodiment of
this method, the glitazone is selected from the group consisting of
englitazone, darglitazone, ciglitazone, DRF2189, BM-13.1246,
AY-31637, YM268, AD-5075, DN-108,
5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenyl]met-
hyl}-thiazolidine-2,4-dione,
5-[3-(4-chloro-phenyl])-2-propynyl]-5-phenyls-
ulfonyl)thiazolidine-2,4-dione, and
5-[3-(4-chlorophenyl])-2-propynyl]-5-(-
4-fluorophenylsulfonyl)thiazolidine-2,4-dione or a pharmaceutically
acceptable salt therof. In a second more preferred embodiment of
this method, the glitazone is selected from the group consisting of
rosiglitazone, pioglitazone, troglitazone, and MCC555 or a
pharmceutically acceptable salt thereof. In a second more preferred
embodiment of this method, the glitazone is selected from the group
consisting of T-174 and KRP297 or a pharmaceutically acceptable
salt thereof.
[0149] Especially, the present invention relates to a method of
treating diabetes or a disease or condition associated with
diabetes comprising administering to a warm-blooded animal in need
thereof jointly therapeutically effective amounts of nateglinide in
free or pharmaceutically acceptable salt form, and a glitazone, in
free or pharmaceutically acceptable salt form, simultaneously or
sequentially in any order, separately or in a fixed combination,
which method further comprises administration of a therapeutically
effective amount of at least one further pharmaceutically active
compound selected from the group consisting of sulphonyl urea
derivatives, a pharmaceutically acceptable salt thereof, metformin
and insulin; or at least one further glitazone or a
pharmaceutically acceptable salt thereof. This particular
embodiment of the invention relates especially to a method of
treating type 2 diabetes patients by using an effective amount of a
combination of at least one short-acting hypoglycemic agent with at
least one other longer-acting hypoglycemic agent, in an amount
sufficient to treat post-prandial hyperglycemia. Preferably, the
short acting hypoglycemic agent is nateglinide. Also preferably,
the long acting hypoglycemic agent is metformin. In an alternate
preferred embodiment, the long acting hypoglycemic agent is a
glitazone, most preferably
5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione; rosiglitazone,
pioglitazone, troglitazone, MCC555; T-174; KRP297; englitazone,
darglitazone, ciglitazone, AY-31637,
5-{[4-(2-(1-indolyl)ethoxy)phenyl]me- thyl}-thiazolidine-2,4-dione
(DRF2189), 5-{[4-(2-(2,3-dihydroindol-1-yl)et-
hoxy)phenyl]methyl}-thiazolidine-2,4-dione, BM-13.1246,
bis{4-[(2,4-dioxo-5-thiazolidinyl)methyl]phenyl}methane (YM268),
5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]benzyl}-thiazolidi-
ne-2,4-dione (AD-5075),
5-[3-(4-chlorophenyl])-2-propynyl]-5-phenylsulfony-
l)thiazolidine-2,4-dione,
5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluoroph-
enylsulfonyl)thiazolidine-2,4-dione; or
5-[4-(1-phenyl-1-cyclopropanecarbo-
nylamino)-benzyl]-thiazolidine-2,4-dione (DN-108); or a
pharmaceutically acceptable salt thereof. In the present
embodiment, the short acting hypoglycemic and the long acting
hypoglycemic agent are contained in the same dosage unit.
[0150] The invention relates also to a combination as disclosed
herein for use in the prevention, delay of progression or treatment
of diseases, the use of such combination for the preparation of a
medicament for the prevention, delay of progression or treatment of
metabolic disorders, and the use of such combination for the
cosmetic treatment of a mammal in order to effect a cosmetically
beneficial loss of body weight.
[0151] The ratio of the daily doses of nateglinde or repaglinide or
a pharmaceutically acceptable salt thereof to the glitazone,
sulfonyl urea derivative or metformin or in each case a
pharmaceutically acceptable salt thereof may vary within wide
limits especially depending of the nature of the compounds
selected. In order to obtain a synergistic effect of the
components, preferably the ratio of nateglinde or a
pharmaceutically acceptable salt thereof to the glitazone is
between 12000:1 and 1:2800, more preferably between 500:1 and
1:100, for example between 1.5:1, and between 400:1 and 2:1 in case
of rosiglitazone; and between 50:1 and 1:3 in case of pioglitazone.
The ratio of nateglinde to rosiglitazone is preferably between 50:1
and 20:1, e.g. 22.5:1 or 45:1. The ratio of nateglinde to
pioglitazone is preferably between 30:1 and 3:1, e.g. 24:1, 12:1 or
8:1.
[0152] In one preferred embodiment of the invention the ratio of
the daily doses of nateglinde to metformin is between 1:3.5 and
1:40, preferably 1:4 and 1:7.1, and very preferably between 1:4.1
and 1:4.5, for example 1:4.2. In a further preferred embodiment of
the invention the ratio of the daily doses of nateglinde to
metformin is between 1:2 and 1:3.
[0153] In one preferred embodiment of the invention the ratio of
the daily doses of nateglinde to metformin hydrochloride is between
1:1.25 and 1:9, more preferably between 1:2.5 and 1:5, e.g. 1:4.2.
In a further preferred embodiment of the invention the ratio of the
daily doses of nateglinde to metformin hydrochloride is between 4:1
and 1:1, more preferably between 2.5:1 and 1.5:1, e.g. 2:1. In
another preferred embodiment of the invention the ratio of the
daily doses of nateglinde to metformin hydrochloride is between
25:1 and 4.5:1, more preferably between 20:1 and 8:1, in particular
18:1, 16:1, 14:1, 10:1 and especially 12:1.
[0154] A therapeutically effective amount of each of the components
of the combination of the present invention may be administered
simultaneously or sequentially and in any order.
[0155] 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.
[0156] In particular, a therapeutically effective amount of each of
the components of the combination of the present invention may be
administered simultaneously or sequentially and in any order, and
the components may be administered separately or as a fixed
combination. For example, the method of treatment of the invention
may comprise (i) administration of the nateglinide in free or
pharmaceutically acceptable salt form and (ii) adminstration of the
glitazone in free or pharmaceutically acceptable salt form,
simultaneously or sequentially in any order, in jointly
therapeutically effective amounts, preferably in synergistically
effective amounts, e.g. in daily dosages corresponding to the
ratios described herein.
[0157] If not indicated otherwise, 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.
[0158] If not indicated otherwise, 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 for the combination
therapy that may be used 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. If not indicated otherwise, 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.
[0159] The dosage regimen of any of the individual components of
the combinations disclosed herein may be adjusted to provide the
optimal therapeutic response. The exact amount of the
pharmaceutically active compounds mentioned below, the specific
dose level and frequency of dosage for any particular patient may
vary depending upon factors known to the person skilled in the art
including species of the warm-blooded animal, body weight, sex,
diet and age, the nature and severity of the condition to be
treated, the mode of administration and the particular combination
to be employed. In particular, the dosage range of the combination
of nateglinide and an antidiabetic thiazolidinedione derivative of
formula (II) to be employed depends upon factors known to the
person skilled in the art including species of the warm-blooded
animal, body weight and age, the nature and severity of the
condition to be treated, the mode of administration and the
particular substance to be employed. Unless stated otherwise
herein, nateglinide and a glitazone of formula (II) are preferably
divided and administered from one to four times per day, preferably
the combination is taken together with or, preferably, before every
meal.
[0160] Nateglinide is preferably administered to the warm-blooded
animal in a dosage in the range of about 5 to 1200, more preferably
10 to 1000 and most preferably 25 to 800 mg/day, especially when
the warm-blooded animal is a human of about 70 kg body weight. In
one preferred embodiment of the invention 60 mg or 120 mg
nateglinide (I) are applied thrice daily. Repaglinide is
administered in a dosage of preferably 0.01 to 8 mg per meal, more
preferably about 0.2 to 5 mg per meal, and most preferably 0.5 mg
to 4 mg per meal.
[0161] If the the warm-blooded animal is a human the dosage of
MCC555 is preferably in the range of about 0.1 to 2000, more
preferably about 0.25 to 500, and most preferably 0.5 to 100,
mg/day, per adult patient. The dosage of englitazone or
darglitazone is preferably in the range of about 0.05 to 50, more
preferably about 0.05 to 5, mg/kg body weight of the patient per
day, if the warm-blooded animal is a human. The dosage of AY-31637
is in the range of about 0.5 to 200, more preferably about 2.5 to
100, mg/kg body weight of the patient per day, if the warm-blooded
animal is a human. The dosage of ciglitazone is in the range of
about 0.25 to 200, more preferably about 0.5 to 50, mg/kg body
weight of the patient per day, if the warm-blooded animal is a
human. The dosage of DN-108 is in the range of about 0.25 to 200,
more preferably about 5 to 100, mg/kg body weight of the
warm-blooded animal. If the antidiabetic thiazolidinedione is
T-174, KRP297, AD-5075, 5-[3-(4-chlorophenyl])-2-pro-
pynyl]-5-phenylsulfonyl)-thiazolidine-2,4-dione or
5-[3-(4-chlorophenyl])--
2-propynyl]-5-(4-fluoro-phenylsulfonyl)thiazolidine-2,4-dione, the
dosage of said compound is preferably in the range of about 0.1 to
2500, more preferably about 0.5 to 2000, and most preferably 1 to
1000, mg/day. If the antidiabetic thiazolidinedione is
rosiglitazone, the dosage of said compound is in case of the
warm-blooded animal being a human of about 70 kg body weight
preferably in the range of about 0.1 to 500, more usually about 0.5
to 100, and most preferably 1 to 20, for example 1, 2, 4 or 8,
mg/day, per adult patient. If the warm-blooded animal being is a
human of about 70 kg body weight, the dosage of pioglitazone is
preferably in the range of about 0.1 to 1000, more usually about 1
to 500, and most preferably 10 to 150, for example 15, 30, 45 or
90, mg/day, per adult patient.
[0162] In one preferred embodiment, the active ingredient is
metformin, the warm-blooded animal being is a human of about 70 kg
body weight and the dosage of said compound is preferably in the
range of about 750 to 2000, and most preferably 1000 to 1500,
mg/day, per adult patient. In one preferred embodiment of the
invention, 180 mg of nateglinide and 750 mg of metformin are given
as a daily dose to a human patient of about 70 kg body weight. In a
further preferred embodiment of the invention, the active
ingredient metformin shall be applied in the form of metformin
hydrochloride in a dosage between 1500 and 3000, especially 1500,
1700 or 2550 mg/day to a warm-blooded animal of about 70 kg body
weight. In another preferred embodiment, the active ingredient
metformin shall be applied in the form of metformin hydrochloride
in a dosage between 700 and 1250, especially between 750 and 1100,
e.g. 1000, mg/day to a warm-blooded animal of about 70 kg body
weight.
[0163] If the sulfonyl urea derivative glyburide is chosen as
active ingredient and the warm-blooded animal being is a human of
about 70 kg body weight, the dosage of said compound is preferably
in the range of about 0.5 to 20, more preferably 1.75 to 15, for
example 3.5, 7.0 or 10.5, mg/day. If the sulfonyl urea derivative
tolbutamide is chosen as active ingredient and the warm-blooded
animal being is a human of about 70 kg body weight, the dosage of
said compound is preferably in the range of about 100 to 3500, more
preferably 250 to 3000, for example 500, 1000, 1500, 2000, 2500,
mg/day. If the sulfonyl urea derivative glimepiride is chosen as
active ingredient and the warm-blooded animal being is a human of
about 70 kg body weight, the dosage of said compound is preferably
in the range of about 0.25 to 12, more preferably 0.5 to 10 and
most preferably between 1 and 3, mg/day. If the sulfonyl urea
derivative gliclazide is chosen as active ingredient and the
warm-blooded animal being is a human of about 70 kg body weight,
the dosage of said compound is preferably in the range of about 5
to 500, more preferably 15 to 300 and most preferably between 40
and 120, mg/day. If the sulfonyl urea derivative glubornuride is
chosen as active ingredient and the warm-blooded animal being is a
human of about 70 kg body weight, the dosage of said compound is
preferably in the range of about 5 to 250, more preferably 12.5 to
75 and most preferably between 12.5 and 50, mg/day. If the sulfonyl
urea derivative gliquidone is chosen as active ingredient and the
warm-blooded animal being is a human of about 70 kg body weight,
the dosage of said compound is preferably in the range of about 5
to 500, more preferably 30 to 120 and most preferably between 30
and 45, mg/day.
[0164] The preparation of metformin (dimethyldiguanide) and its
hydrochloride salt is state of the art and was disclosed first by
Emil A. Werner and James Bell, J. Chem. Soc. 121, 1922, 1790-1794.
The preparation of DRF2189 and of
5-{[4-(2-(2,3-dihydroindol-1-yl)-ethoxy)phe-
nyl]methyl}-thiazolidine-2,4-dione is described in B. B. Lohray et
al., J. Med. Chem. 1998, 41, 1619-1630; Examples 2d and 3g on pages
1627 and 1628. The preparation of
5-[3-(4-chlorophenyl])-2-propynyl]-5-phenylsulfo-
nyl)-thiazolidine-2,4-dione and the other compounds in which A is
phenylethynyl mentioned herein can be carried out according to the
methods described in J. Wrobel et al., J. Med. Chem. 1998, 41,
1084-1091.
[0165] A further object of the invention is to provide a
pharmaceutical composition that is effective for the treatment or
prevention of metabolic disorders, more especially diabetes and in
particular type 2 diabetes mellitus, or a disease or condition
associated with diabetes.
[0166] Another object of the invention is to provide a composition,
in particular a pharmaceutical composition, e.g., of nateglinide,
that is easily manufactured.
[0167] The compositions as disclosed hereinafter preferably
comprise nateglinide as the sole active, in particular
pharmacologically active, agent.
[0168] Under these aspects and as disclosed hereinafter, the
present invention relates to a composition, in particular a
pharmaceutical composition, containing nateglinide in free or
pharmaceutically acceptable salt form, and a pharmaceutically
acceptable carrier, wherein the composition is capable of being
granulated in the presence of water without the need for a
subsequent pulverization step prior to tabletting; and to a
composition, in particular a pharmaceutical composition, comprising
nateglinide in free or pharmaceutically acceptable salt form, and a
pharmaceutically acceptable carrier, wherein upon administration
about 90 percent by weight of nateglinide is released within a ten
minute period.
[0169] The present invention also relates to a process of making a
composition, in particular a pharmaceutical composition, that
contains nateglinide in free or pharmaceutically acceptable salt
form, and a pharmaceutically acceptable carrier, wherein the
process includes granulating the drug substance and one or more
pharmaceutically acceptable carriers in the presence of water,
without a subsequent pulverization step.
[0170] The present invention also relates to a method for the
treatment or prophylaxis of diabetes or a disease or condition
associated with diabetes by administering to a warm-blooded animal
in need thereof a pharmaceutical composition that contains a
therapeutically effective amount of nateglinide in free or
pharmaceutically acceptable salt form, wherein the composition is
capable of being granulated in the presence of water without the
need for a subsequent pulverization step prior to tabletting.
[0171] As the active agent, in particular drug substance, for the
composition, in particular pharmaceutical composition, nateglinide
is described in EP 196222 and EP 526171, the entire contents of
each being expressly incorporated herein by reference.
[0172] The active drug substance can be present as its
pharmaceutically acceptable salts as defined herein-above, such as
acid addition salts, for example, as a sodium salt or as a
maleate.
[0173] Each oral composition according to the present invention may
additionally comprise inert constituents including pharmaceutically
acceptable carriers. As used herein, the term "pharmaceutically
acceptable carrier" refers to the ingredients of the composition,
in particular pharmaceutical composition, excluding the active drug
substance. Examples of pharmaceutically acceptable carriers include
binders, disintegrants, diluents, fillers, glidants,
anti-adherents, lubricants, solubilizing or emulsifying agents and
salts. For example, tablets may be formulated in accordance with
conventional procedures employing solid carriers well known in the
art. Tabletting aids, commonly used in tablet composition can be
used and reference is made to the extensive literature on the
subject, see in particular Fiedler's "Lexicon der Hilfstoffe", 4th
Edition, ECV Aulendorf 1996 which is incorporated herein by
reference.
[0174] Disintegrants that may be used include CMC-Ca, CMC-Na,
crosslinked polyvinyl pyrrolidone (Crospovidone, Polyplasdone of
Kollidon XL), alginic acid, sodium alginate and guar gum. Preferred
disintegrants include cross-linked polyvinyl pyrrolidone
(Crospovidone), croscarmellose sodium (Ac-Di-Sol). Other
disintegrants include hydroxypropyl ether cellulose with a low
degree of substitution, in which a very small portion of hydroxyl
groups owned by a pyranose ring of the cellulose is etherified with
propylene oxide. Such hydroxypropyl celluloses contain from 5.0 to
about 16.0% by weight of a hydroxypropyl in the quantitative
determination of a dried hydroxypropyl cellulose with a low degree
of substitution (see Japanese Pharmacopoeia, 13.sup.th Edition,
D885 to D-888; United States Pharmacopoeia, 23.sup.rd Edition, pp.
2253-2254; each of which we expressly incorporated herein by
reference). Examples of such hydroxypropyl ethers of cellulose
include L-HPC manufactured by Shin-Etsu Chemical Co., Ltd. (LH-11,
LH-20, LH-21, LH-22, LH-30, LH-31, LH-32 and the like. The presence
of hydroxypropyl ether cellulose in the pharmaceutical composition
is optional. Thus, in a preferred embodiment, the composition, in
particular pharmaceutical composition, does not contain the
above-described hydroxypropyl ether celluloses.
[0175] Particularly preferred disintegrants are croscarmellose
sodium and cross-linked polyvinyl pyrrolidone.
[0176] The amount of disintegrant employed can be from about 2 to
about 20, or up to about 30 percent by weight, although the highest
level might cause blistering of the tablet during storage. A
particularly preferred range is from 2-15 percent by weight, and
even more preferred is 2-10 percent by weight; 4-10 percent by
weight is also a preferred range of disintegrant.
[0177] Binders for the composition, in particular pharmaceutical
composition, include starches, e.g. potato starch, wheat starch,
corn starch, gums such as gum tragacanth, acacia gum or gelatin,
microcrystalline cellulose, e.g. products known under the
registered trade marks Avicel, Filtrak, Heweten or Pharmacel,
hydroxypropyl cellulose, hydroxyethyl cellulose (HEC) and
hydroxypropylmethyl cellulose (HPMC), e.g. hydroxypropyl cellulose
having a hydroxypropyl content of 5 to 16% by weight and a
molecular weight of from 80,000 to 1,150,000, more particularly
140,000 to 850,000, or a polyvinyl pyrrolidone such as Povidone.
Polyvinyl pyrrolidone is particularly preferred.
[0178] The amount of binder employed can be from about 0.1 to about
5 percent by weight. A particularly preferred range is from 1-5
percent by weight, and even more preferred is 2-4 percent by
weight.
[0179] Glidants that may be used include silica, magnesium
trisilicate, powdered cellulose, starch, talc and tribasic calcium
phosphate. Colloidal silica (e.g., Aerosil) is particularly
preferred.
[0180] The amount of anti-adherent employed can be up to about 5
percent by weight or from 0 to about 5 percent by weight. A
particularly preferred range is from 0.5-2 percent by weight, and
even more preferred is 0.5-1 percent by weight.
[0181] Fillers or diluents that can be used include confectioner's
sugar, compressible sugar, dextrates, dextrin, dextrose, lactose,
mannitol, microcrystalline cellulose, in particular having a
density of about 0.45 g/cm.sup.3, e.g. Avicel, powdered cellulose,
sorbitol, sucrose and talc. Lactose and microcrystalline cellulose
are particularly preferred, separately or in a mixture of 10-90 to
90-10, especially 25-75 to 75-25, e.g., 67-33, percent by weight
respectively. Lubricants for the composition, in particular
pharmaceutical composition, include stearic acids and its salts
such as Mg, Al or Ca stearate, polyethylene glycol 4000-8000, e.g.,
6000, and talc. Magnesium stearate is particularly preferred.
[0182] The amount of lubricant employed can be from about 0.75 to
about 3 percent by weight. A particularly preferred range is from
about 1.5 to about 3 percent by weight, and even more preferred is
about 1.8 to about 2.5 percent by weight.
[0183] Thus, a particularly preferred embodiment for this
embodiment of the invention includes a galenical formulation for
nateglinide or repaglinide in the form of a tablet comprising in
the core lactose monohydrate, microcrystalline cellulose, povidone,
croscarmellose sodium, and in the coating magnesium stearate,
opadry white, croscarmellose sodium and colloidal silicon
dioxide.
[0184] The total amount of pharmaceutically acceptable carriers in
the composition, in particular pharmaceutical composition, may
range from about 30 to about 75 weight percent. A particularly
preferred range is from 50-70 weight percent, and even more
preferred is about 53 to about 67 weight percent.
[0185] One or more of these additives can be selected and used by
the skilled artisan having regard to the particular desired
properties of the solid oral dosage form by routine experimentation
and without any undue burden.
[0186] Within the above preferred ranges of ingredients, the
absolute amounts of each additive and the amounts relative to other
additives is dependent on the desired properties of the solid oral
dosage form and may also be chosen by the skilled artisan by
routine experimentation without undue burden.
[0187] Where accelerated or immediate release is desired, e.g.,
about 60% to 95%, e.g., 75%, e.g., 85%, e.g. about 90 percent by
weight release within a thirty minute, e.g., a twenty minute, e.g.,
a ten minute, more particularly a five minute period, e.g., in
water or artificial stomach juices (e.g., HCl 0.1 N), e.g., in a
tablet form, one may use a disintegrant such as crosslinked
polyvinyl pyrrolidone, for example those products known under the
registered trade marks Polyplasdone.RTM.XL or Kollidon.RTM.CL.
[0188] In particular, the disintegrant may have a molecular weight
in excess of 1,000,000, more particularly having a particle size
distribution of less than 400 microns or less than 74 microns, or
reactive additives (effervescent mixtures) that effect rapid
disintegration of the tablet in the presence of water, for example
so-called effervescent tablets that contain an acid in solid form,
typically citric acid, which acts in water on a base containing
chemically combined carbon dioxide, for example sodium hydrogen
carbonate or sodium carbonate, and releases carbon dioxide.
[0189] Hence, the present invention relates to a composition, in
particular a pharmaceutical composition, comprising (a) nateglinide
in free or pharmaceutically acceptable salt form, and (b) a
pharmaceutically acceptable carrier, wherein upon administration
about 90 percent by weight of nateglinide is released within a ten
minute period. Preferably, such composition comprises a
disintegrant having, in particular, a molecular weight in excess of
1,000,000. Furthermore, the disintegrant has preferably a particle
size distribution of less than 400 microns or, more preferably,
less than 74 microns. In a very preferred embodiment of this aspect
of the invention, the disintegrant is a crosslinked polyvinyl
pyrrolidone.
[0190] In a solid oral dosage form wherein the active agent is
nateglinide or a pharmaceutically acceptable salt thereof,
preferred additives are microcrystalline cellulose,
hydroxypropylcellulose, carboxymethylcellulose (CMC) or CMC-Na, Mg,
Ca or Al stearate, polyvinyl pyrrolidone, anhydrous colloidal
silica, lactose, and any combination thereof. The amounts of
additive employed will depend in part upon how much active agent is
to be used. The stearate, e.g., magnesium stearate, is preferably
employed in amounts of 1.0 to 5.0% by weight, e.g. 1.5 to 3.0
percent by weight by weight. The silica is preferably employed in
an amount of from 0.5 to 10%, especially 1 to 5%, by weight.
[0191] The composition, in particular pharmaceutical composition,
of the present invention suitable for oral administration may be
presented as discrete units such as capsules, cachets or tablets
each containing a predetermined amount of the active ingredient, as
a powder or granules. Such compositions may be prepared by any of
the methods of pharmacy but all methods include the step of
bringing into association the active ingredient with the carrier,
which constitutes one or more necessary ingredients. In general,
the compositions are prepared by uniformly and intimately admixing
the active ingredient with liquid carriers or finely divided solid
carriers or both, and then, if necessary, shaping the product into
the desired presentation. For example, a tablet may be prepared by
corn pression or molding, optionally with one or more accessory
ingredients. Compressed tablets may be prepared by compressing in a
suitable machine, the active ingredient in a free-flowing form such
as powder or granules, optionally mixed with a binder, lubricant,
inert diluent, surface active or dispersing agent. Molded tablets
may be made by molding in a suitable machine, a mixture of the
powdered compound moistened with an inert liquid diluent.
Desirably, each tablet contains from about 2.5 mg to about 500 mg
of the active ingredient, preferably about 60 mg to about 200 mg,
and most preferably about 120 mg to about 180 mg of the active
ingredient.
[0192] When a dosage unit form is a capsule, it may contain, in
addition to materials of the above type, a liquid carrier such as a
fatty oil. Capsules employed in the present invention may be made
from any pharmaceutically acceptable material such as gelatin or
cellulose derivatives.
[0193] Various other materials may be present as coatings or to
modify the physical form of the dosage unit. For instance, tablets
may be coated with shellac, sugar or both.
[0194] The composition, in particular pharmaceutical composition,
may be used for enteral, such as oral or rectal, 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 carriers, especially suitable for enteral or parenteral
application.
[0195] The composition, in particular pharmaceutical composition,
contains, for example, from about 10 to about 100 percent by
weight, preferably 80 percent by weight, preferably from about 20
to about 60 percent by weight, of the active ingredient. The most
preferable commercial levels range from 18 to 29% active
ingredients. Compositions according to the invention for enteral
administration are, for example, those in unit dose forms, such as
sugarcoated tablets, tablets, capsules or suppositories.
[0196] These are prepared in a manner known per se, for example by
means of conventional mixing, granulating, sugar-coating,
dissolving or lyophilizing processes. Thus, the pharmaceutical
composition can be obtained by corn bining 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.
[0197] The granulation step may be performed by a high shear wet
granulator, of the type conventional in the art. Either a top or
bottom driven granulator may be used, with a collette gral
granulator being an example of a preferred embodiment. One skilled
in the art can readily determine the optimal granulation time. A
preferred granulation time ranges from about 1 to about 4 minutes,
and is most preferably about 2 minutes.
[0198] After granulation, the granules may be dried by conventional
steps, including for example a drying step performed by a fluid bed
drier. The dried granules may then be passed to a wire mesh screen
apparatus to break up any fraction of granules having an
undesirable size. Examples of preferred screening devices include a
Frewitt MG 400 and a Frewitt MG 624.
[0199] After granulation, the granules may be further blended with
additional composition ingredients, or even additional quantities
of ingredients previously granulated. Diffusion mixers of various
mixing container geometries may be used for the blending step.
Typical mixers used for blending include, for example, a V-blender
or a bin blender such as a Stocklin mixer.
[0200] In a preferred embodiment of the invention, the composition,
in particular pharmaceutical composition, is produced by a process
that comprises granulating in the presence of water to form
granules, drying the granules, and optionally screening the
granules, for example, through a wire mesh screen. All of the
ingredients of the composition may be added prior to or during the
granulation. Alternatively, all or a portion of one or more of the
ingredients may be added after the granulation step is complete.
For example, all or a portion of anti-adherent (e.g., silica), all
or a portion of lubricant (e.g., magnesium stearate) and/or all or
a portion of disintegrant (e.g., croscarmellose or any salt
thereof) may be added after the granulation. In a preferred aspect
of the invention, all ingredients except the magnesium stearate and
the colloidal silica are loaded into the granulator, then they are
added later. In one aspect of the invention, the process of
producing the composition, in particular pharmaceutical
composition, may be performed without the need for a pulverization
step. As used herein, the terms "pulverization" and "pulverize"
refer to any process that involves the grinding or smashing cutting
of particles to reduce the particles' size. In a preferred aspect
of the invention, the composition, in particular pharmaceutical
composition, is capable of being produced without pulverizing the
granules between the granulation step and the drying and/or
compression step used to form the granules into a tablet.
[0201] The composition, in particular pharmaceutical composition,
described herein is further capable of being granulated without the
need for pulverization before or after the granulation step. As
used herein, the term "capable of being granulated without the need
for pulverization" defines a property of the composition as opposed
to a requirement that the composition is actually produced without
a pulverization step. Thus, the term "capable of . . . " when used
to describe a composition, specifically does not impose any process
or product-by-process limitation on the composition. The
composition is further capable of being successfully formed, by
compression for example, into tablets ready for administration to
the patient.
[0202] It has been observed that after granulation, a granular
composition having an acceptable granule size was obtained even
though water was added during the granulation. More specifically,
the composition, in particular pharmaceutical composition, is
capable of being grnulated (and successfully tabletted after
granulation) in the presence of about 25 to about 80% percent by
weight of water without the need for the above-mentioned
pulverization. Preferably, the granulation may be performed with
the addition of about 25 to about 40 percent by weight water. More
preferably, the granulation may be performed with the addition of
about 22 to about 37 percent by weight water, and even more
preferably 27 percent by weight water, when producing tablets
containing 120 mg, 90 mg, 60 mg, and 30 mg of nateglinide. When
producing 180 mg nateglinide tablets, preferably about 33 to about
40, and more preferable, 33 to about 37 percent by weight of water
is added to the granulation. Because the granules may be screened,
after a drying step, without the loss of substantial quantities of
material, a pulverization step may be successfully avoided.
[0203] A further aspect of the present invention is a composition,
in particular a pharmaceutical composition, for nateglinide in the
form of a pharmaceutically acceptable composition such as a tablet
comprising pharmaceutically acceptable binders, excipients, and the
like as well as an acceptable coating. Such composition further
comprises preferably lubricants, most preferably stearic acid, or
Mg, Al, or Ca stearate, anti adherents, or colorants.
[0204] It can be shown by established test models and especially
those test models described herein that the nateglinide or its
pharmaceutically acceptable salt results in a more effective
prevention, delay of progression or preferably treatment of
diseases, especially metabolic disorders, more especially diabetes
and in particular type 2 diabetes mellitus, and diseases and
conditions associated with diabetes.
[0205] 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. The pharmacological activity may, for example, be
demonstrated following essentially an in-vivo test procedure in
mice or in a clinical study as described above.
[0206] Furthermore, the invention relates to a preparation or a
composition, in particular a pharmaceutical composition,
respectively, which comprises nateglinide or a pharmaceutically
acceptable salt thereof.
[0207] A further aspect of the present invention is a composition,
in particular a pharmaceutical composition, for nateglinide in the
form of a pharmaceutically acceptable composition such as a tablet
comprising pharmaceutically acceptable binders, excipients, and the
like as well as an acceptable coating.
[0208] Preferably, the composition comprises the B- or H-type
crystal modification of nateglinide, more preferably the H-type.
The active ingredient or a pharmaceutically acceptable salt thereof
may also be used in form of a hydrate or include other solvents
used for crystallization.
[0209] The dosage range of the nateglinide depends upon factors
known to the person skilled in the art including species of the
warm-blooded animal, body weight and age, the nature and severity
of the condition to be treated, and the mode of administration to
be employed. Unless stated otherwise herein, nateglinide is
preferably divided and administered from one to four times per
day.
[0210] Nateglinide is preferably administered to the warm-blooded
animal in a dosage in the range of about 5 to 1200, more preferably
10 to 1000 and most preferably 25 to 800 mg/day, especially when
the warm-blooded animal is a human of about 70 kg body weight.
[0211] A further aspect of the present invention is a
pharmaceutical composition for nateglinide in the form of a tablet
comprising in the core lactose monohydrate, microcrystalline
cellulose, polyvinyl pyrrolidone, croscarmellose sodium, colloidal
silicon dioxide, and magnesium stearate, and optionally a coating
such as opadry yellow.
[0212] Furthermore, the invention relates to a pharmaceutical
composition comprising (a) nateglinide in free or pharmaceutically
acceptable salt form, and (b) a pharmaceutically acceptable
carrier, wherein the composition is capable of being granulated in
the presence of water without the need for a subsequent
pulverization step prior to tabletting for the prevention, delay of
progression or treatment of hyperglycemia, hyperinsulinaemia,
hyperlipidaemia, insulin resistance, impaired glucose metabolism,
obesity, diabetic retinopathy, macular degeneration, cataracts,
diabetic nephropathy, glomerulosclerosis, diabetic neuropathy,
erectile dysfunction, premenstrual syndrome, vascular restenosis,
ulcerative colitis, coronary heart disease, hypertension, angina
pectoris, myocardial infarction, stroke, skin and connective tissue
disorders, foot ulcerations, metabolic acidosis, arthritis,
osteoporosis and in particular conditions of impaired glucose
tolerance and especially type 2 diabetes.
[0213] Further aspects of the present invention are a
pharmaceutical composition comprising (a) nateglinide in free or
pharmaceutically acceptable salt form, and (b) a pharmaceutically
acceptable carrier, wherein the composition is capable of being
granulated in the presence of water without the need for a
subsequent pulverization step prior to tableting (i) for use in the
prevention, delay of progression or treatment of metabolic
disorders and (ii) the use of such composition for the preparation
of a medicament for the prevention, delay of progression or
treatment of metabolic disorders.
[0214] Furthermore, the invention relates to a method of improving
the bodily appearance of a mammal, including man, especially man
suffering from a metabolic disorder, in particular type 2 diabetes,
which comprises orally administering to said mammal
[0215] (i) a combination, e.g. as a combined preparation or as a
composition, as described herein or
[0216] (ii) a composition comprising (a) nateglinide in free or
pharmaceutically acceptable salt form, and (b) a pharmaceutically
acceptable carrier, wherein the composition is capable of being
granulated in the presence of water without the need for a
subsequent pulverization step prior to tabletting,
[0217] in a dosage effective to influence, e.g. to increase or
decrease, the glucose metabolism, or to influence the body weight
by other mechanisms, and repeating said dosage until a cosmetically
beneficial loss of body weight has occurred. Such combinations and
compositions described herein independently of each other can also
be used to prevent, for cosmetic reasons, a further increase in
body weight in humans experiencing such an increase. Moreover, the
invention relates to the combinations and compositions described
herein useful for improving the bodily appearance of a mammal,
especially a human being, and the use of such combinations and
compositions in order to improve the bodily appearance of a mammal,
especially a human being. Overweight is one of the risk factors for
developing a metabolic disorder, in particular type 2 diabetes, and
at the same time often the result of such a metabolic disorder,
especially type 2 diabetes. Furthermore, a number of antidiabetics
are known to cause weight gain. Hence, humans suffering from
metabolic disorders, especially type 2 diabetes, are often faced
with overweight. Therefore, the cosmetically beneficial loss of
body weight can be effected especially in humans suffering from a
metabolic disorder, such as type 2 diabetes. The combinations, e.g.
a combined preparation or a composition, and compositions described
herein independently of each other can also be used to replace or
complement an antidiabetic drug taken by a human suffering from
type 2 diabetes in order to prevent, for cosmetic reasons, a
further increase of the body weight.
[0218] In particular, the present invention relates to a method of
improving the bodily appearance of a mammal which comprises orally
administering to said mammal nateglinide in free or
pharmaceutically acceptable salt form, and a glitazone in free or
pharmaceutically acceptable salt form in a dosage effective to
influence the glucose metabolism, and repeating said dosage until a
cosmetically beneficial loss of body weight has occurred, wherein
the active ingredients are administered simultaneously or
sequentially in any order, separately or in a fixed combination.
Also in particular, the present invention relates to a method of
improving the bodily appearance of a mammal which comprises orally
administering to said mammal a composition comprising (a)
nateglinide in free or pharmaceutically acceptable salt form, and
(b) a pharmaceutically acceptable carrier, wherein the composition
is capable of being granulated in the presence of water without the
need for a subsequent pulverization step prior to tabletting.
Moreover, the the present invention relates to a method of
improving the bodily appearance of a mammal which comprises orally
administering to said mammal a composition comprising (a)
nateglinide in free or pharmaceutically acceptable salt form, and
(b) a pharmaceutically acceptable carrier, wherein upon
administration about 90 percent by weight of nateglinide is
released within a ten minute period.
[0219] 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
[0220] 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
[0221] Preparation process--variante (a): 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.
EXAMPLE 2
Galenic Formulation of Nateglinide No. 1
[0222]
6 intra-granular: nateglinide 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 No. 2
[0223]
7 intra-granular: nateglinide 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
[0224] The following Examples illustrate the manufacture of
monotherapy compositions wherein nateglinide is the sole active
agent and no subsequent pulverization step is performed after
granulation; they are not, however, intended to limit the scope of
the invention in any way.
EXAMPLE 4
Tablets of Nateglinide
[0225] 108,000 tablets, each which contain 120 mg of nateglinide
are prepared as follows:
8 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
[0226] 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 (60 mg)
[0227]
9 nateglinide 60 mg lactose monohydrate 141.5 mg microcrystalline
cellulose 71 mg Povidone 12 mg croscarmellose sodium 18.4 mg
magnesium stearate 5.7 mg colloidal silicon dioxide 6.4 mg opadry
pink 9 mg
EXAMPLE 6
Pharmaceutical Composition of Nateglinide (120 mg)
[0228]
10 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
EXAMPLE 7
Pharmaceutical Composition of Nateglinide (180 mg)
[0229]
11 nateglinide 180 mg lactose monohydrate 214 mg microcrystalline
cellulose 107 mg povidone 23 mg croscarmellose sodium 58.5 mg
magnesium stearate 15.2 mg opadry red 18.0 mg colloidal silicon
dioxide 12.3 mg
EXAMPLE 8
Composition, in Particular Pharmaceutical Composition of
Nateglinide
[0230] 5.112 kg microcrystalline cellulose, 0.864 kg polyvinyl
pyrrolidone, 0.864 kg croscarmellose sodium, 4.320 kg nateglinide,
and 10.118 kg lactose were granulated in a collette gral granulator
while adding {fraction (5/7)} L of purified water. The resulting
granules were dried in a Glatt CGP30 fluid bed drier. The particle
size distribution of a sample was determined by sieve as shown in
Table 1.
12 TABLE 1 Cumulative Weight Percentage Retained 25# 35# 45# 60#
80# 120# 170# 325# Batch 710 .mu.m 500 .mu.m 355 .mu.m 250 .mu.m
180 .mu.m 125 .mu.m 90 .mu.m 45 .mu.m 60 mg 1.0 4.1 8.2 14.7 17.9
20.7 38.2 85.3 nateglinide 120 mg 0.6 2.8 7.0 10.5 13.4 16.0 28.3
89.8 nateglinide 30 mg 1.1 4.9 11.6 18.5 22.0 25.3 37.1 88.3
nateglinide
[0231] Thus, as can be seen in Table 1, the composition is capable
of being granulated in the presence of water to provide, without a
pulverization step, a granular composition containing less than
about 1 weight percent of granules having a size of 710 .mu.m (25#)
or more, less than about 5 weight percent of granules having a size
of 500 .mu.m (35#) or more, less than about 12 weight percent of
granules having a size of 355 .mu.m or more, less than about 20
weight percent of granules having a size of 250 .mu.m or more, less
than about 25 weight percent of granules having a size of 180 .mu.m
or more, less than about 40 weight percent of granules having a
size of 125 .mu.m or more, less than about 70 weight percent of
granules having a size of 90 .mu.m or more, and/or less than about
99 weight percent of granules having a size of 45 .mu.m or
more.
[0232] More preferably, the composition is capable of being
granulated in the presence of water to provide, without a
pulverization step, a granular composition containing less than
about 1 weight percent of granules having a size of 710 .mu.m (25#)
or more, less than about 5 weight percent of granules having a size
of 500 .mu.m (35 #) or more, less than about 2 weight percent of
granules having a size of 355 .mu.m or more, less than about 20
weight percent of granules having a size of 250 .mu.m or more, less
than about 25 weight percent of granules having a size of 180 .mu.m
or more, less than about 25 weight percent of granules having a
size of 125 .mu.m or more, less than about 40-50 weight percent of
granules having a size of 90-95 .mu.m or more, and/or less than
about 90 weight percent of granules having a size of 45 .mu.m or
more.
[0233] Other embodiments of the invention will be apparent to those
skilled in the art from consideration of the specification and
practice of the invention disclosed herein. It is intended that the
specification and examples be considered as exemplary only, with a
true scope and spirit of the invention being indicated by the
following claims.
* * * * *