Note: Descriptions are shown in the official language in which they were submitted.
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A GLIBENCLAMIDE-METFORMIN COMBINATION FOR THE TREATMENT OF DIABETES
MELLITUS OF TYPE II
The present invention relates to the use of a
combination consisting of glibenclamide and metformin in
one specific ratio as medicament for the treatment of
diabetes mellitus of type II.
Non-insulin dependent diabetes of type II (NID) is
known to be a frequent metabolic disease and the main
cause of hyperglycemia. In recent years, diabetes
mellitus of type II has been proved to be a
heterogeneous disease, with complex, unclarified
metabolic aspects, which disease is cYiaracterized by
three main metabolic abnormalities contributing to
hyperglycemia: the partial or complete decrease in
insulin secretion, the resistance of the peripheral
tissues to insulin and the increased hepatic production
of glucose in fasting conditions.
Diet and physical exertion are unanimously
recognized to be the foundation of the therapy of
diabetes of type II: both of them lead to a reduction in
insulin-resistance and, in the long run, to an
improvement in the pancreas secretive deficit.
However, these provisions are insufficient and a
pharmacological aid with oral hypoglycemic agents is
necessary. At present, the two main families of oral
hypoglycemic agents available are sulfonylureas and
biguanides.
The use of sulfonylureas and biguanides in
monotherapy, in most cases, allows to obtain an
effective glycometabolic control for some years, if an
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appropriate diet and behavioural regimen are kept.
Nevertheless, the efficacy of the therapy with oral
hypoglycemic agents can decrease with time.
After a positive starting response which can last
4-5 years, monotherapy becomes ineffective in a
considerable percentage of patients. These are the so
called "secondary failures" of the therapy with oral
hypoglycemic agents. Such a failure is estimated to
occur each year in 5-10~ of the patients under therapy
with sulfonylureas, therefore after 10 years, only 50~
of the patients still show a satisfactory response.
The secondary failure in patients under treatment
with metformin appears to have an incidence
superimposable to the above mentioned one.
Recent studies show that besides a
qualitative/quantitative deficiency of insulin
secretion, the combined occurrence of insulin-resistance
conditions is at the bottom of NID diabetes.
Since sulfonylureas are capable of stimulating
insulin release, but are not capable of acting on
insulin resistance, and biguanides are able to act on
insulin resistance, whereas they are not able to
stimulate insulin secretion, the therapeutical rationale
of said studies suggested the use of combined
formulations of medicaments capable of finding a remedy
for both the deficiency in insulin secretion and the ,
insulin-resistance condition.
ViQneri et al. (Diabete & Metabolisme, 1991, (17), '
232-234), faced the problem of secondary failure to
sulfonylurea therapy in NID diabetes. The authors
proposed a combination of glibenclamide-metformin in a
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daily dosage of 15 mg and 1500 mg, respectively, in
alternative to insulin therapy in addition to
glibenclamide.
The combined therapy (sulfonylurea + biguanide)
plays therefore a specifically important therapeutical
role, since it allows to obtain an effective metabolic
control in those patients with diabetes of Lype II, in
which the therapy with only sulfonylureas or only
biguanides becomes ineffective with time.
Two biguanides are used in the oral therapy of
diabetes of type II: phenformin and metformin. Although
the former is still widely used, a number of data in
literature clearly show that metformin exerts an
effective normoglycemic action with no risk of lactic
acidosis in the patients, as it can occur in some cases
when using phenformin. Therefore, it is generally
accepted that metformin is the preferred biguanide in
the therapy of diabetes of type II.
The Applicant found, during clinical experiments,
that the sulfonylurea maximum daily dose considered
optimum for the most severe, barely controllable cases
is 15 mg. However, such a dose has to be combined with a
biguanide maximum daily dose of 1500 mg in order to
obtain the maximum therapeutical effect together with
the reduction of untoward effects.
At present 4 combinations are marketed which use a
combination of metformin with glibenclamide (Table 1).
' In the first combination, glibenclamide dose is 2.5 mg
and metformin (expressed as the hydrochloride) dose is
500 mg for each tablet, namely a weight ratio of 1:200.
In the other combinations, doses are respectively: 2.5
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mg of glibenclamide and 400 mg of metformin, namely a
weight ratio of 1:160.
TABLE I
Beady-to-use preparations of sulfonylurea (S) -
Hetformin (1'i) available at present:
llama Manufacturer S (dose/cp) H (dose/cp)
Glucomide Lipha Glibenclamide Metformin
(2.5 mg) (500 mg)
Glibomet Guidotti Glibenclamide Metformin
(2.5 mg) (400 mg)
Suguan M Hoechst Glibenclamide Metformin
(2.5 mg) (400 mg)
Bi-Euglucon M Boehringer M Glibenclamide Metformin
(2.5 mg) (400 mg)
It should be noted, however, that none of these
formulations attain the optimum therapeutical effect due
to the quantitative unbalance of the medicaments in
combination. In fact, using the above mentioned
formulations, in order to obtain the sulfonylurea
maximum dose of 15 mg, which we consider optimum for the
most severe, barely controllable cases, 6 tablets of the
medicament should be taken, thus receiving 2400-3000 mg
of metformin, which is a dose markedly higher than the
maximum one we recommend (1500 mg).
Therefore, the still unsolved problem is to find a '
combination capable of obtaining the maximum increase in
the therapeutical effect with balanced doses of the
single medicaments, thereby decreasing in parallel their
CA 02237571 2006-03-30
untoward effects.
Such a research is of paramount importance, taking
into account that in diabetes of type II it is often
necessary to progressively increase with time the
5 hypoglycemic medicament doses.
The present invention solves the problem to provide
medicament effective for the treatment of diabetes mellitus
of type II in cases of secondary failure to a combination of
glibenclamide-metformin currently used in therapy.
Abstract of the invention
Now it has been found that a combination of
glibenclamide and metformin (expressed as the hydrochloride)
in a 1:100 weight ratio, so as to allow a daily
administration of 15 mg of glibenclamide and 1500 mg of
metformin, is suitable to the preparation of a medicament
useful for the treatment of diabetes mellitus of type II at
any time of the progression of the disease, from its onset
to the most severe cases.
Therefore, it is an object of the present invention
the use of the above mentioned combination in admixture with
conventional carriers and excipients for the preparation of
a medicament for the treatment of diabetes mellitus of
type II, particularly in the cases of "secondary failure" to
a combination of glibenclamide-metformin currently used in
therapy.
In one particular embodiment there is the use of a
combination of glibenclamide-metformin hydrochloride in a
1:100 weight ratio for the preparation of a single-dose
medicament used for the treatment of diabetes mellitus of
type II in cases of secondary failure to a combination of
glibenclamide-metformin hydrochloride in a weight ratio
higher than 1:100.
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5a
In another particular embodiment there is the use of a
combination of glibenclamide-metformin hydrochloride in a
1:100 weight ratio for the preparation of a single-dose
medicament used for the treatment of diabetes mellitus of
type II in cases of secondary failure to a combination of
glibenclamide-metformin hydrochloride in a weight ratio of
1:160 or 1:200.
Detailed disclosure of the invention
According to a first preferred embodiment of the
present invention, the combination of the two active
ingredients is used in a medicament in the form of tablets
with a dosage of 5 mg of glibenclamide and 500
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mg of metformin. This medicament is useful for the
treatment of diabetes mellitus of type II.
The balance of said doses makes the therapeutical
effect optimum at any time of the progression of the
disease, starting from minor cases to the most severe
ones, and particularly, when it is necessary to increase
progressively with time the doses of the two substances.
On the contrary, when combination ratios different
from those of the present invention are used, the
following cases are likely to occur:
- when the ratios are lower than the recommended
ones, the number of metabolically controlled
diabetic patients will definitely be lower;
when the recommended doses are exceeded, there will
be an actual risk of untoward effects.
Therefore, the target area of the patients
responding to the therapy will increase and at the same
time the onset of therapeutical risks will be highly
decreased only when the two medicaments are administered
in combination at the doses present in the tablet, or at
multiple and submultiple doses of the same.
Moreover, it has been proved that a dose increase
beyond the maximum limits herein recommended of 15 mg of
glibenclamide and 1500 mg of metformin daily causes no
further favourable therapeutical effects.
Finally, it should be stressed that the above
mentioned doses can theoretically be attained also using
the two medicaments separately. However, this involves
the need of taking twice as many tablets a day, with
clear compliance problems, especially in the elderly
patients which require concomitant therapies for other
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pathologies which are frequently connected with
diabetes, such as hypertension and vascular diseases.
Said combination of dosages can be used starting
from the onset of the disease in NID diabetics since the
ratio of 5 mg of glibenclamide + 500 mg of metformin
will always be balanced, in both the multiple and
submultiple dosages. In fact, when the tablets are
subdivided, thus obtaining minor and/or fractional daily
dosages, the fixed ratio, which is the balanced one, is
always maintained. Therefore, according to a second
embodiment of the present invention, the medicament is
in the form of a divisible tablet containing the
combination described above.
Alternatively, tablets containing fractions of the
preferred dosage can be prepared, always keeping the
1:100 ratio between the two active principles.
Analogously, in the most severe cases of diabetes
with metabolic decompensation, which cannot be
controlled with the commercially available combination
medicaments, (so that the patients should turn to
insulin therapy), the combination of the invention
allows to treat them, still and for a long time, with
the oral therapy, with obvious benefits for the patients
themselves.
In confirmation of what stated above, the study
profile and the results of the experimentation carried
out are reported in the following.
' Y profile
~amgle size
About 100 diabetics of type II (non insulin-
dependent) have been studied. The sample was calculated
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so that a clinically significant average reduction of
the values of glycated hemoglobin Aic equal to or higher
than 0.6% and an average reduction of glycemia equal to
or higher than 18 mg/dl in the 16 weeks of treatment
could be detected. The standard deviations envisaged for
HbAic and for fasting glycemia are 1.46% and 44 mg/dl.
The analysis makes use of a significance level of 0.05
and a test power of 0.80 (two-tail test).
Description of the studied panel
98 Patients with diabetes mellitus of type II (non
insulin-dependent) were studied. The average age of the
subjects was 57.3 ~ 6.6 years.
The panel consisted of 45 males (46%) and 53
females (54%) of superimposable age.
I5 Starting metabolic ,Srofile
The fasting glycemia measured at examination 1 was
219 ~ 37 mg/dl (95% confidence limits: 211-226 mg/dl;
10-90' percentile: 184-272 mg/dl), 24 hour glycosuria 25
~ 36 g (95% confidence limits: 18-33 g; 10-90 percentile
7-64 g), no acetonuria in all of the patients, glycated
hemoglobin Aic 9.1 ~ 0.9% (95% confidence limits 8.9-
9.2%; 10-90' percentile:8-10.1%).
30
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TABLB A
Metabolic profile of the subjects studied in each
centre.
________________________________________________________
Centre 1 2 3 4 ANOVA
Oneway p=
N 9 31 38 20
fasting
glycemia 21941 21133 22142 22629 ns
(mg/dl)
24 hour
glycosuria 11f14* 2515 37154 * * 0.026
(g/24 hours)
Acetonuria 0 0 0 0 --
Glycated
hemoglobin 8.8f1,1 9.1-X0.7 8.81,0 9.60.4' 0.002
A1c (%)
* p < 0.05 Centre 1 vs Centre 3
** At the Centre 4, glycosuria was doses with a
semiquantitative procedure
p < 0.05 Centre 4 vs Centres 1, 2. 3
t;
l
f the tr
tment
ffi
f th
na
Fva
nn o
e e
cacy o
ea
The parameters the evaluation of the efficacy of
the treatment is based on are:
1. fasting giycemia;
2. post-prandial glycemia;
3. 24 hour glycosuria;
4. presence of acetone in the urines;
5. glycated hemoglobin (HbAlc).
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W~ 97/179?5 PCT/EP96/04860
Other important parameters evaluated during the
study are:
2. body weight
2. total cholesterol plasma levels;
5 3. HDL cholesterol plasma levels;
4. LDL cholesterol plasma levels;
5. arterial pressure values.
Fastinct alvcemia
The average values of the fasting glycemia
10 evidenced during the study are reported in Table B.
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11
I
s t! 1 an a~
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* p < 0.001 vs Examination 1 and Examination 2
p < 0.001 vs Examination 1. p < 0.01 vs
Examination 2
# p < 0.05 vs Examination 1
~ p < 0.01 vs Examination 2
In the whole panel, the fasting glycemia underwent
a significant reduction already after two weeks of
treatment (p < 0.001); said reduction was maintained
subsequently during all the study (16 weeks}. Similar
results were obtained from the analysis carried out at
the single Centres (Centres 2-4). Only in Centre 1, no
reduction in glycemia was detected, partly probably due
to the small number (n. 9) of the studied subjects(Table
B).
Table C reports the results of the glycemia course
in subjects stratified as a function of the Body Mass
Index (BMI; normal weight: BMI < 25 kg/m2- n - 21;
overweight BMI 25-30 kg/m2- n - 52; obeses BMI .~ 30
kg/m2. n = 259).
CA 02237571 1998-05-13
WO 97/17975 PCT/EP96/04860
13
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CA 02237571 1998-OS-13
WO 97!17975 PCT/EP96/04860
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* p < 0.001 vs Examination 1 and Examination 2
~ p < 0.05 vs Examination 2
a
The effects of the treatment are clear (variance
analysis for repeated measurements, p < 0.0001) in the
subjects with normal body weight and in the overweight
subjects (BMI 25-30 kg/m2), which are less sensitive,
but still statistically significant (p < 0.035 in the
obese subgroup (BMI > 30 kg/m2)).
Post-nrandial alvcemia
The mean values of the fasting glycemia evidenced
during the study are reported in Table D. The post
prandial glycemia, measured at the beginning and at the
end of the study, underwent a significant reduction both
in the whole panel (318 to 2b7jmg/dl) and in each of the
25 subgroups defined depending on the Body Mass Index.
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TABL$ D
Post-prandial glycemia: changes during the study.
In the second part of the table the subjects were
.. stratified depending on the BMI (Body Mass Index).
5 ________________________________________________________
$xaminations 2 6 Student's t test for
coupled data weeks (p <)
0 1b
10 Whole 318 267 0.0001
Panel: (64) (79)
BMI: Variance analysis for
measurements (1 factor)
15 <25 kg/m2 317 252 0.0001
25-30 kg/m2 320 263 0.0001
X30 kg/m2 313 287 O.OOI
Anova ns ns
Oneway (p <)
2 Factor analysis
among groups ns
among examinations 0.0001
Adverse events
The untoward effects were infreguent and slight; in
practice, only gastro-intestinal untoward effects such
as nausea, abdomen pains and diarrhoea, more or less
combined together, occurred.
Gonc~usions abonit. the therapeutical efficacy
In the clinical study carried out, the proposed
combination (glibenclamide 5 mg - metformin 500 mg) was
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administered for 16 weeks to patients with diabetes of
type II, in which the combined treatment with
glibenclamide-metformin at the presently available
dosages gave no longer an acceptable metabolic control.
The main result from the evaluation of the efficacy
consists in the significant decrease in the fasting
glycemia (-35 mg/dl), in the glycemia 2 hours after
meals (-51 mg/dI) and in the FIbAlc (-0.9%).
These results are of particular value when
considering that:
1. Whereas the patients with a more severe diabetic
condition (so as to be necessary the use of high
dosages of glibenclamide and metformin), actually
were no longer responsive to the sulfonylurea-
metformin combinations commercially available and
as a consequence it was necessary to start the
subsequent therapeutical option, i.e. the addition
of insulin to the oral therapy or the complete
substitution of the latter with insulin itself.
These cases were treated successfully and the
obtained results prove that the combination
glibenclamide 5 mg + metformin 500 mg is an
important therapeutical tool, which allows to
obtain an effective control of glycid metabolism
still making use of the only hypoglycemizing oral
therapy, thus obtaining a further favourable effect ,
on life-quality of the patients themselves.
2. On the contrary, f or the less severe cases, the '
ratio 5 mg of glibenclamide + 500 mg of metformin,
can be subdivided as desired, thereby having lower
and/or fractional daily dosages thus allowing to
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17
treat the disease from its onset, as the
glibenclamide to metformin ratio, even when
fractioned, will turn out to be very well balanced.
As far as the industrial applicability aspects are
concerned, the medicaments according to the invention
are provided in the form of pharmaceutical composition,
which can be prepared according to conventional
techniques known to those skilled in the art, for
example as described in Remington's Pharmaceutical
Sciences Handbook, Mack. Pub., N.Y., U.S.A. 1995.
Among the pharmaceutical compositions intended for
the treatment of diabetes mellitus of type II, those
which are administered orally are preferred, such as
coated or non-coated tablets, capsules, sugar-coated
pills, granulates, oral suspensions, microgranules,
controlled-release tablets.
Metformin is used preferably in the form of
metformin hydrochloride salt. Of course, it is also
possible to use equivalent amounts of other phosphate,
20, solfite, dithionate, acetate, benzoate, citrate salts
and the like, optionally together with suitable buffers.
On the contrary, glibenclamide is an insoluble
substance.
Since said compound has to be administered in
comparatively high dosages (5 mg of Glibenclamide + 500
mg of Metformin HCl) and for long times in order to
obtain a complete action, the oral route was considered
the simpliest administration method.
In the galenic study carried out to accomplish the
most suitable pharmaceutical form, the following
objectives were taken into account:
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- ready contact of the active ingredient in the
dispersed state with gastroenteral mucosae
- easiness of swallowing
- posology flexibility
- optimization of the technological characteristics
of the granulate for the working up with fast
devices
- choice of the material suitable for the
preservation of the product
- manufacturing process easy to carry out and
economical.
Considering the high unitary dosage required, the
pharmaceutical formulation in lozenge-shaped tablets,
with a central breaking division, has been chosen since
it is considered the most suitable one. Such a tablet
can have the composition as shown in Example 1.
In f act this allows, with comparatively limited
sizes, to carry suitably the active ingredient,. so as to
combine a favourable working-up with optimum bio-
pharmaceutical and technical characteristics besides an
improved swallowability.
The tablets were subjected to wet-granulation; the
excipients reported hereinbelow were selected, after a
number of laboratory tests in order to find the amount
of each excipient to attain the best workability
together with biopharmaceutical and technological
characteristics of the tablets:
- maize starch: diluent and disintegrant;
- precipitated silica: it promotes the cohesion of
the granulates improving their flowability;
- microcristalline cellulose (AvicelTM PH 101): a
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diluent, which favours the formation of compact granules
and therefore of more resistant tablets contributing at
the same time to disaggregation of the pharmaceutical
form, promoting the penetration of liquid inside it by
capillarity;
- gelatin: a binder used in solution to wet the
granular mixture;
- glycerin: it is used in the gelatin solution to
promote wetting and as a plasticizes;
- talc: a lubricant;
- magnesium stearate: a solid lubricant which is
effective in amounts which do not significantly
affect the disaggregation time of the tablets.
In order to improve handling and swallowing, a
coating was moreover applied onto the tablets, which
consists of a methylhydroxypropyl cellulose film as a
film-forming agent, titanium dioxide as an opacifier and
polyethylene glycol 400 as a plasticizes. The
compatibility among the active ingredient and the
selected excipients was ascertained by preliminary
accelerated stability studies.
Finally, for the choice of the container, the
physico-chemical characteristics of the active
ingredient and of the tablet were considered in order to
guarantee a safe preservation; the medicament of the
invention showed a very good stability in an opaque
blister consisting of PVC/PVDC and aluminium.
The manufacturing process was carried out by wet
granulation both by means of kneading in a fast
granulator and drying in air-circulation drier, and in
fluidized bed granulator-drier. In both cases, tablets
CA 02237571 1998-05-13
WO 97/17975 PCT/EP96/04860
with the desired characteristics Were obtained.
The following examples further
illustrate
the
r
invention.
HgB~LP~B.~.
5 A coated tablet contains:
Glibenclamide mg 5.00
Metformin hydrochloride mg 500.00
Maize starch mg 57.50
Precipitate silica mg 20.00
10 Microcrystalline cellulose mg 65.00
Gelatin mg 40.00
Glycerin mg 17.50
Talc mg 17.50
Magnesium stearate mg 7.50
15 Methylhydroxypropylcelluiose mg 12.50
Titanium dioxide mg 6.25
Polyethylene glycol 400 mg 1.25
Unitary theor. average weight mg 750.0
$$bHPLB 2
20 Granulate sachets:
Glibenclamide: mg 5.00
Metformin hydrochloride mg 500.00
Polyvinylpyrrolidone mg 22.00
Saccharose mg 1000.00
Mannitol mg 821.00
Sodium saccharinate mg 10.00 ,
Orange flavour mg 37.00
Lemon flavour mg 10.00 '
Unitary theor. average weight mg 2405.00
CA 02237571 1998-OS-13
WO 97/17975 PCTlEP96/04860
21
~mcoension:
Glibenclamide g 10.100
Metformin hydrochloride g 0.047
Sodium carboxymethylcellulose g 0.079
Microcrystalline cellulose g 0.300
Wild black cherry essence g 0-O89
Anise essence g 0.050
Glycerol g 10.000
Methyl p-hydroxybenzoate g 0.050
Saccharose g 77470
Depurated water q.s. to ml 100
Y
