STABILIZED CONTROLLED-RELEASE PHARMACEUTICAL COMPOSITION
COMPRISING GLICLAZIDE
Field of the Invention
The present invention relates to a stabilized controUed-release pharmaceutical
composition comprising gliclazide or its pharmaceutically acceptable salts and sodium
citrate as a stabilizing agent.
Background of the Invention
Gliclazide is a weakly acidic drug with a pKa of about 5.8, having a hydrophobic
nature. It belongs to Class II of the biopharmaceutical classification in which dissolution
is the rate-controlling step in drug absorption.
Diamicron® MR is marketed as a modified-release tablet of gliclazide. It is
formulated with using inactive ingredients including calcium hydrogen phosphate
dihydrate, maltodextrin, hypromellose, lactose monohydrate, magnesium stearate, and
anhydrous colloidal silicon dioxide.
U.S. Patent No. 6,733,782 discloses a matrix tablet for the prolonged release of
gliclazide, which provides continuous and consistent release of the active ingredient after
oral administration, wherein the release is insensitive to variations in the pH of the
dissolution medium.
During stability studies, it has been found that Diamicron® MR generates a high
amount of Impurity A, (i.e., p-toluenesulphonamide) originating from the decomposition
of gliclazide in the pharmaceutical composition. This degradation may be attributed to the
presence of certain excipients like calcium hydrogen phosphate dihydrate and/or colloidal
silicon dioxide.
PCT Publication No. WO 2008/062470 is directed to a stabilized controlled-release
dosage form of gliclazide, wherein the dosage form is without a saccharide component and
is optionally free from binder. However, there is a need for an alternate formulation which
further provides improved stability over the solid oral formulations of gliclazide available
in the prior art.
Summary of the Invention
The present invention provides a stabilized controlled-release pharmaceutical
composition comprising gliclazide or its pharmaceutically acceptable salts and sodium
citrate as a stabilizing agent; wherein, the term "stabilized" refers to a pharmaceutical
composition which, when subjected to conditions of 40°C/75% RH for a period of three
months, results in total content of Impurity A originating from the decomposition of
gliclazide in an amount less than 0.25% w/w.
According to one aspect of the present invention, there is provided a stabilized
controlled-release pharmaceutical composition comprising:
a) gliclazide;
b) sodium citrate as a stabilizing agent; and
c) release-controlling polymer(s).
According to another aspect of the present invention, there is provided a stabilized
controlled-release pharmaceutical composition comprising:
a) gliclazide;
b) sodium citrate as a stabilizing agent;
c) release-controlling polymer(s); and
d) other pharmaceutically acceptable excipients; wherein the pharmaceutically
acceptable excipients are free from colloidal silicon dioxide.
According to another aspect, there is provided a stabilized controlled-release
pharmaceutical composition comprising:
a) gliclazide;
b) sodium citrate as a stabilizing agent;
c) two or more release-controlling polymers having different viscosities; and
d) other pharmaceutically acceptable excipients; wherein the pharmaceutically
acceptable excipients are free from colloidal silicon dioxide.
A particular aspect of the present invention provides a stabilized controlled-release
pharmaceutical composition comprising:
a) gliclazide in an amount ranging from 30 mg to 80 mg;
b) sodium citrate as a stabilizing agent in a concentration from 0.5% w/w to
3.0% w/w;
c) two different viscosity grades of hydroxypropyl methylcellulose, a grade
having a viscosity ranging from 100 cps to 750 cps, and a second grade
having a viscosity ranging from 1000 cps to 5000 cps; and
d) other pharmaceutically acceptable excipients; wherein the pharmaceutically
acceptable excipients are free from colloidal silicon dioxide.
According to yet another aspect of the present invention, there is provided a
process for the preparation of a stabilized controlled-release pharmaceutical composition
of gliclazide, the process steps comprising of:
a) blending gliclazide with other pharmaceutically acceptable excipients;
b) mixing sodium citrate with the blend of step a);
c) optionally granulating the blend of step b);
d) lubricating the blend of step b) or granules of step c), and compressing into
suitable size tablets or filling into capsules; wherein the pharmaceutically
acceptable excipients are free from colloidal silicon dioxide.
A further aspect of the present invention provides a process for the preparation of a
stabilized controlled-release pharmaceutical composition of gliclazide, the process steps
comprising of:
a) sifting gliclazide and other pharmaceutically acceptable excipients, and dry
mixing to achieve a uniform blend;
b) dissolving sodium citrate, and optionally a binder, in purified water to form a
solution or dispersion;
c) granulating the blend of step a) using the solution or dispersion of step b);
d) sifting the release-controlling polymer using an appropriate sieve and mixing
with the dried granules of step c);
e) lubricating the blend of step d); and
f) compressing the lubricated granules of step e) into tablets of suitable size, or
optionally filling into capsules; wherein the pharmaceutically acceptable
excipients are free from colloidal silicon dioxide.
Detailed Description of the Invention
The term "stabilized", as used herein, refers to a pharmaceutical composition
which, when subjected to conditions of 40°C/75% RH for a period of three months, results
in total content of Impurity A originating from the decomposition of gliclazide in an
amount less than 0.25% w/w.
"Impurity A", as used herein, refers to p-toluenesulphonamide originating from the
decomposition of gliclazide in the pharmaceutical composition. The relative retention
time (RRT) of Impurity A with respect to the gliclazide peak is at 0.18, as per the
analytical method used herein, and described later.
The term "controUed-release", as used herein, refers to the release of an active
ingredient from a pharmaceutical composition in which the active ingredient is released
according to a desired profile over an extended period of time, and is taken to encompass
sustained-release, modified-release, prolonged-release, delayed-release, and the like.
The term "pharmaceutical composition", as used in this specification, refers to
physically discrete units to be administered in single or multiple dosages, each unit
containing a predetermined quantity of active material in association with the required
pharmaceutically acceptable excipients. The pharmaceutical composition used herein may
be selected from tablets, capsules, sachets, pellets, beads, microspheres, microcapsules, or
granules.
The term "gliclazide", as used herein, includes gliclazide free base and
pharmaceutically acceptable salts, solvates, hydrates, or mixtures thereof The
pharmaceutical composition of the present invention comprises gliclazide in a range of
about 1 mg to about 300 mg. In particular, the compositions may contain about 10 mg to
about 200 mg of gliclazide. Particularly, the pharmaceutical composition may contain
from 30 mg to 80 mg of gliclazide.
The stabilizing agent added to the composition is sodium citrate. In particular,
sodium citrate in a concentration of 0.2% w/w to 5.0% w/w of the composition provides
stability to the pharmaceutical composition. Particularly, the pharmaceutical composition
contains 0.5% w/w to 3.0% w/w of sodium citrate. The effect of sodium citrate in
stabilizing the composition is shown in Table 1, which provides results of stability studies.
The compressed tablets, prior to being packed in blister strips, were subjected to stability
testing at 40°C/75% RH for one month. The samples were analyzed initially, at an
interval of fifteen days, and then at one month. The tablets containing sodium citrate
(Example 1) were found to be more stable as compared to the marketed formulation as
well as to the formulation without sodium citrate (Example 3).
Table 1: Percentage of Impurity A after exposing tablets in open condition (without
blister pack) at 40'>C/75% RH
Formulation
Marketed Tablet - Diamicron® MR 60 mg
Example 1 (containing 1.0% w/w sodium
citrate)
Example 3 (without sodium citrate)
Impurity A (% w/w)
Initial
0.06
0.02
0.02
15 Days
0.19
0.07
0.13
30 days
0.28
0.11
0.20
The controUed-release pharmaceutical composition of the present invention further
comprises release-controlling polymer(s), and optionally, other pharmaceutically
acceptable excipients.
The release-controlling polymer(s), as used herein, is selected from
methylcellulose, ethylcellulose, hydroxyethylcellulose, propylcellulose,
hydroxypropylcellulose, hydroxypropyl methylcellulose (hypromellose),
carboxymethylcellulose, polymethyl methacrylate, polyethyl methacrylate, polybutyl
methacrylate, polyisobutyl methacrylate, polyhexyl methacrylate, polyisodecyl
methacrylate, polylauryl methacrylate, polyphenyl methacrylate, polymethyl acrylate,
polyisopropyl acrylate, polyisobutyl acrylate, polyoctadecyl acrylate, polyethylene,
polypropylene, polyethylene oxide, polyethylene terephthalate, polyvinyl isobutyl ether,
polyvinyl acetate, polyvinyl chloride, polyurethane, or mixtures thereof
In particular, the release-controlling polymer is selected from
hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropyl methylcellulose
(hypromellose, HPMC). The release-controlling polymer may be hydroxypropyl
methylcellulose. The amount of polymer may vary from 10% w/w to 40% w/w of the
total weight of the composition. A particularly used concentration may be from 25% w/w
to 35% w/w.
The release-controlling polymer may be a combination of two or more polymers
having different viscosities. In particular, two or more different viscosity grades of
hydroxypropyl methylcellulose may be used; a grade having a viscosity ranging from 100
cps to 750 cps, and a second grade having a viscosity ranging from 1000 cps to 5000 cps.
Further, the polymer may be added intragranularly and/or extragranularly.
The other pharmaceutically acceptable excipients are selected from diluents,
binders, lubricants, or combinations thereof. The excipients used in the formulation may
be free from colloidal silicon dioxide.
Binders may be selected from pregelatinized starch, copovidone, shellac, zein,
gelatin, polymethacrylates, synthetic resins, Eudragit®, and cellulose polymers.
Diluents may be selected from lactose, calcium hydrogen phosphate dihydrate,
calcium hydrogen phosphate anhydrous, tribasic calcium phosphate, calcium carbonate,
kaolin, magnesium carbonate, and magnesium oxide.
Lubricants may be selected from stearic acid, polyethylene glycol, magnesium
stearate, calcium stearate, zinc stearate, talc, hydrogenated castor oil, and sodium stearyl
fumarate. In particular, the lubricant used herein is magnesium stearate.
The pharmaceutical compositions, as described herein, may be prepared by any of
the known processes such as direct compression, dry granulation, or wet granulation.
According to one of the embodiments, there is provided a method of preparation of
the pharmaceutical composition, the process comprising the steps of:
a) blending gliclazide with other pharmaceutically acceptable excipients;
b) mixing sodium citrate with the blend of step a);
c) optionally granulating the blend of step b); and
d) lubricating the blend of step b) or granules of step c), and compressing into
suitable size tablets or filling into capsules.
In particular, another embodiment provides a process for the preparation of a
stabilized controUed-release pharmaceutical composition of gliclazide, the process
comprising the steps of:
a) sifting gliclazide, diluent, a part of the binder, and release-controlling
polymer, and dry mixing to achieve a uniform blend;
b) dissolving sodium citrate and the remaining part of the binder in purified
water to form a homogenous slurry;
c) granulating the dry powder blend of step a) using the slurry of step b);
d) sifting the controlled-release polymer using an appropriate sieve and mixing
with the dried granules of step c);
e) lubricating the blend of step d);
f) compressing the lubricated granules of step e) into tablets, or optionally
filling into capsules.
The tablets prepared using any of the processes described herein may be further
coated with a film-coating. Suitable coating compositions comprise film-forming
polymer(s), plasticizer(s), opacifier(s), and film smoothener(s). Additionally,
pharmaceutically acceptable colors and lakes may be used.
In particular, film-forming polymers like various grades of hydroxypropyl
methylcellulose; plasticizer such as a glycol, e.g., propylene glycol, or polyethylene
glycol; opacifier such as titanium dioxide; and film smoothener such as talc may be used.
Suitable coating solvents are water or organic solvents selected from ethanol, isopropanol,
acetone, and halogenated hydrocarbons, or mixtures thereof
The invention is fiirther illustrated by the following non-limiting examples.
EXAMPLES
Example 1:
Ingredients
Gliclazide
Pregelatinized starch
Lactose monohydrate
Sodium citrate
Purified water
Hypromellose
Magnesium stearate
Total Weight
Quantity (mg/tablet)
60.00
16.00
144.20
3.20
q.s.
95.00
1.60
320.00
Manufacturing Process:
1. Gliclazide, a part of pregelatinized starch, and lactose monohydrate were
sifted and mixed to obtain a uniform blend;
2. sodium citrate was dissolved in purified water followed by the remaining part
of the pregelatinized starch to form a homogeneous slurry;
3. the blend of step 1 was transferred into a rapid mixer granulator, and
granulated using the slurry of step 2;
8
4. hypromellose was sifted and mixed with the granules of step 3;
5. the blend of step 4 was lubricated using magnesium stearate; and
6. the lubricated granules of step 5 were compressed into tablets of suitable size
using appropriate tooling.
Example 2:
Ingredients
Gliclazide
Pregelatinized starch
Lactose monohydrate
Sodium citrate
Purified water
Hypromellose KlOO LV CR premium
Hypromellose K4M CR
Magnesium stearate
Total Weight
Quantity (mg/tablet)
60.00
16.00
159.20
3.20
q.s.
70.00
10.00
1.60
320.00
Manufacturing Process:
1. Gliclazide, a part of pregelatinized starch, and lactose monohydrate were
sifted and mixed to obtain a uniform blend;
2. sodium citrate was dissolved in purified water followed by the remaining part
of the pregelatinized starch to form a homogeneous slurry;
3. the blend of step 1 was transferred into a rapid mixer granulator and
granulated using the slurry of step 2;
4. hypromellose KlOO LV CR and Hypromellose K4M CR were sifted and
mixed with the granules of step 3;
5. the blend of step 4 was lubricated using magnesium stearate; and
6. the lubricated granules of step 5 were compressed into tablets of suitable size
using appropriate tooling.
Example 3: (Control Example)
Ingredients
Gliclazide
Hypromellose E5 Premium LV
Lactose monohydrate
Purified water
Hypromellose (BeneceFw K750 PH PRM)
Magnesium stearate
Total Weight
Quantity (mg/tablet)
60.00
6.40
157.00
q.s.
95.00
1.60
320.00
Manufacturing Process:
1. Gliclazide, hypromellose E5 Premium LV, and lactose monohydrate were
sifted and mixed to obtain a uniform blend;
2. the blend of step 1 was transferred into a rapid mixer granulator and
granulated using purified water;
3. hypromellose (BeneceF** K750 PH PRM) was sifted, and mixed with the
granules of step 2;
4. the blend of step 3 was lubricated using magnesium stearate; and
5. the lubricated granules of step 4 were compressed into tablets of suitable size
using appropriate tooling.
Stability Testing
The compressed tablets, after being packed in cold-form blisters, were subjected to
stability testing at 40°C/75% RH for three months. The samples were analyzed initially,
and later at intervals of one month and three months for determining the amount of
impurity generated and the extent of degradation. The method for determining related
substances employed high performance liquid chromatography (HPLC) using Lichrospher
RP-8e 5 |am (250 mm * 4 mm) column, and the mobile phase as buffer (pH
2.5):acetonitrile in a ratio of 65:35. The buffer was prepared by adding 2 mL
triethylamine to 1 L water, and adjusting the pH to 2.5 using orthophosphoric acid. The
relative retention time (RRT) of Impurity A with respect to the gliclazide peak was
observed at 0.18.
The marketed tablets (Diamicron® MR), and control tablets (without sodium
citrate. Example 3) were also subjected to similar stability testing protocol, and assessed
for impurities. The comparative results of the stability study are shown in Table 1 (for
10
tablets subjected to stability testing in an open condition), and Table 2 (for tablets packed
in cold-form blister packs), and subjected to stability study protocol.
It was observed that there was more degradation in open conditions than in blister
packs, as the packing further provides protection from the effects of heat and moisture.
As seen from Table 2, the tablets of Example 1 and Example 2 (containing sodium
citrate) have the least amount of Impurity A, thereby being more stable.
Table 2: Percentage of Impurity A after subjecting tablets packed in cold-form
blister packs to 40°C/75% RH
Formulation
Marketed Tablet - Diamicron® MR 60 mg
Example 1
Example 2
Example 3
Impurity A (% w/w)
Initial
0.06
0.02
0.01
0.02
1 month
"
0.09
0.05
0.13
3 months
0.57
0.22
0.15
0.31
Dissolution Study
Table 3 shows the comparison of dissolution profiles of the formulations of
Examples 1, 2, and 3. The dissolution was performed in 900 mL of buffer (pH 7.4) at 100
rpm using the basket (40 mesh) method. The samples were analyzed using HPLC using
Lichrospher RP-8e 5 ^m (250 mm * 4 mm) column, and the mobile phase as buffer (pH
2.5):acetonitrile in a ratio of 60:40. The target dissolution profile at the 6 hour time point
was set as 40% to 65% of drug-release under the given dissolution conditions. As seen
from the results, there is no difference in the dissolution of the formulation from Examples
1,2, and 3; thereby suggesting that sodium citrate does not affect dissolution.
Table 3: Percentage of drug released in dissolution media of pH 7.4 phosphate buffer
Time point (hours)
1
2
4
6
12
Example 1
9
19
39
55
84
Example 2
9
20
39
52
78
Example 3
9
19
40
60
97
11

WE CLAIM:
1. A stabilized controUed-release pharmaceutical composition comprising:
a) gliclazide;
b) sodium citrate as a stabilizing agent; and
c) at least one release-controlling polymer.
2. The stabilized controlled-release pharmaceutical composition of claim 1, wherein
sodium citrate is present in a concentration from 0.5% w/w to 3.0% w/w.
3. The stabilized controlled-release pharmaceutical composition of claim 1, wherein
the at least one release-controlling polymer is selected from methylcellulose,
ethylcellulose, hydroxyethylcellulose, propylcellulose, hydroxypropylcellulose,
hydroxypropyl methylcellulose, carboxymethylcellulose, polymethyl methacrylate,
polyethyl methacrylate, polybutyl methacrylate, polyisobutyl methacrylate, polyhexyl
methacrylate, polyisodecyl methacrylate, polylauryl methacrylate, polyphenyl
methacrylate, polymethyl acrylate, polyisopropyl acrylate, polyisobutyl acrylate,
polyoctadecyl acrylate, polyethylene, polypropylene, polyethylene oxide, polyethylene
terephthalate, polyvinyl isobutyl ether, polyvinyl acetate, polyvinyl chloride, polyurethane,
or mixtures thereof
4. The stabilized controlled-release pharmaceutical composition of claim 3, wherein
the release-controlling polymer is present in a concentration from 25% w/w to 35% w/w.
5. The stabilized controlled-release pharmaceutical composition of claim 3, wherein
the release-controlling polymer may be added intragranularly and/or extragranularly.
6. The stabilized controlled-release pharmaceutical composition of claim 3
comprising two or more release-controlling polymers having different viscosities.
7. The stabilized controlled-release pharmaceutical composition of claim 6, wherein
the release-controlling polymer is a combination of hydroxypropyl methylcellulose having
viscosity ranging from 100 cps to 750 cps, and another grade of hydroxypropyl
methylcellulose having viscosity ranging from 1000 cps to 5000 cps.
8. The stabilized controlled-release pharmaceutical composition of claim 1, further
comprising pharmaceutically acceptable excipients selected from the group consisting of
diluents, binders, lubricants, or mixtures thereof
12
^^w o^^'^'3^7g97®Tl
9. The stabilized controlled-release pharmaceutical composition of claim 8, wherein
the pharmaceutically acceptable excipients are free from colloidal silicon dioxide.
10. The process for the preparation of the stabilized controlled-release pharmaceutical
composition of claim 1, wherein the process steps comprise:
a) blending gliclazide along with other pharmaceutically acceptable excipients;
b) mixing sodium citrate with the blend of step a);
c) optionally granulating the blend of step b); and
d) lubricating the blend of step b) or the granules of step c), and compressing
into suitable size tablets or filling into capsules.
11. The process for the preparation of the stabilized controlled-release pharmaceutical
composition of claim 1, wherein the process steps comprise:
a) sifting gliclazide, diluent, optionally a part of the binder, and optionally a
release-controlling polymer, and dry mixing to achieve a uniform blend;
b) dissolving sodium citrate and optionally the remaining part of the binder in
purified water to form a solution or dispersion;
c) granulating the dry powder blend of step a) using the solution or dispersion
of step b);
d) sifting the controlled-release polymer using the appropriate sieve and mixing
with the dried granules of step c);
e) lubricating the blend of step d); and
f) compressing the lubricated granules of step e) into tablets of suitable size, or
optionally filling into capsules.