FIELD OF INVENTION
The present invention relates to a stabilized controlled release pharmaceutical composition comprising Gliclazide or its pharmaceutically acceptable salts and sodium citrate.
BACKGROUND OF INVENTION
Gliclazide is a sulphonylurea compound having antidiabetic property which is usually administered by oral route in the form of immediate release and modified release tablets. Gliclazide is a weakly acidic drug with pKa about 5.8 having hydrophobic nature. It belongs to class II of the biopharmaceutical classification in which dissolution rate is the controlling step in drug absorption.
Diamicron® MR is the modified release tablet of gliclazide available in the market prepared by using inactive ingredients like calcium hydrogen phosphate dihydrate, maltodextrin, hypromellose, lactose monohydrate, magnesium stearate and anhydrous colloidal silicon dioxide.
US6733782 discloses a matrix tablet for the prolonged release of gliclazide which ensures continuous and consistent release of the active ingredient after administration by the oral route, the release being insensitive to variations in the pH of the dissolution medium.
Upon testing for stability, it has been found that the innovator's product Diamicron® MR generates higher amount of an 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 dihydrated calcium hydrogen phosphate and/or colloidal silicon dioxide.
WO2008062470 is directed to a stabilized controlled release dosage form of Gliclazide prepared by avoiding the use of saccharide component and optionally omitting the 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 stabilizing agent; wherein, the term stabilized refers to solid 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 which is less than 0.25%.
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Hence, according to one of the aspects, there is provided a stabilized controlled release pharmaceutical composition comprising:
a) Gliclazide or its pharmaceutically acceptable salts;
b) sodium citrate as a stabilizing agent;
c) one or more release controlling polymers; and
d) optionally other pharmaceutically acceptable excipients;
wherein, the total content of impurity A is less than 0.25% when subjected to conditions of 40°C/75% RH for three months.
According to one of the aspects, there is provided a stabilized controlled release pharmaceutical composition comprising:
a) Gliclazide or its pharmaceutically acceptable salts;
b) sodium citrate as a stabilizing agent;
c) one or more release controlling polymers; and
d) other pharmaceutically acceptable excipients;
wherein, the pharmaceutically acceptable excipients are free from colloidal silicon dioxide and the total content of impurity A is less than 0.25% when said pharmaceutical composition is subjected to conditions of 40°C/75% RH for three months.
According to another aspect is provided a stabilized controlled release pharmaceutical composition comprising:
a) Gliclazide or its pharmaceutically acceptable salts;
b) sodium citrate as a stabilizing agent;
c) a combination of two or more release controlling polymers having different viscosity; and
d) other pharmaceutically acceptable excipients;
wherein, the pharmaceutically acceptable excipients are free from colloidal silicon dioxide and the total content of impurity A is less than 0.25% when said pharmaceutical composition is subjected to conditions of 40°C/75% RH for three months.
A particular aspect of the invention provides a stabilized controlled release pharmaceutical composition comprising:
a) Gliclazide or its pharmaceutically acceptable salts, in an amount being equivalent to 30 mg to 80 mg of Gliclazide base;
b) sodium citrate as a stabilizing agent, in a concentration from 0.5% to 3% w/w;
c) combination of different viscosity grades of hydroxypropyl methylcellulose, a lower viscosity grade ranging from 100-750 cps and a higher viscosity grade ranging from 1000-5000 cps; and
d) other pharmaceutically acceptable excipients;
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wherein, the pharmaceutically acceptable excipients are free from colloidal silicon dioxide and the total content of impurity A is less than 0.25% when said pharmaceutical composition is subjected to conditions of 40°C/75% RH for three months.
According to yet another aspect there is provided a process for the preparation of a stabilized controlled release pharmaceutical composition of gliclazide, the process comprising of steps:
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 and the total content of impurity A is less than 0.25% when said pharmaceutical composition is subjected to conditions of 40X775% RH for three months.
A further aspect provides a process for the preparation of a stabilized controlled release pharmaceutical composition of gliclazide, the process comprising of steps:
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 homogenous slurry;
c) Granulating the blend of step a) using the slurry of step b);
d) Sifting the controlled release polymer using appropriate sieve and mixing with the dried granules;
e) Lubricating the blend of step d);
f) Compressing the lubricated granules into tablets of suitable size or optionally filling into capsules;
wherein the pharmaceutically acceptable excipients are free from colloidal silicon dioxide and the total content of impurity A is less than 0.25% when said pharmaceutical composition is subjected to conditions of 40°C/75% RH for three months.
DETAILED DESCRIPTION OF THE INVENTION
The term "Stabilized" as used herein refers to solid 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 which is less than 0.25%.
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"Impurity A" as used herein refers to p-toluenesulphonamide originating from the decomposition of gliclazide in the pharmaceutical composition. The relative retention time (RTT) of impurity A with respect to Gliclazide peak is at 0.18, as per the analytical method used here and described later.
The term "controlled 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, capsule, sachets, pellets, beads, microspheres, microcapsules, pills or granules.
The term "gliclazide" as used herein includes gliclazide free base, 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, compositions may contain 10 mg to about 200 mg of gliclazide. Particularly, 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% to 5% by weight of the total weight of the composition provides stability to the pharmaceutical composition. Particularly, the pharmaceutical composition contains 1 % to 3% w/w of sodium citrate. The effect of sodium citrate in stabilizing the composition is shown in Table 1 below, which provides results of stability studies conducted at 40''C/75% RH. The tablets containing sodium citrate (Example 1) were found to be more stable as compared to the marketed formulation and the formulation without sodium citrate (Example 3).
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Table 1. Level of Impurity A after exposing tablets in open condition (without blister pack)
to 40X/75% RH
Formulation I Impurity A
Initial 15 Days 30 days
Marketed Tablet - Diamicron® MR 60 mg 006 09 028
Example 1 (containing 1 % w/w sodium citrate) 0.02 0.07 0.11
Example 3 (without sodium citrate) O02 013 O20
The controlled 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, poly isodecyl 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 a mixture thereof.
In particular, the release controlling polymer used is selected form hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropyl methylcellulose (Hypromellose, HPMC). The release controlling polymer may be hydroxypropyl methylcellulose. The amount of polymer may vary from 10% to 40% by weight of the total weight of the composition. Particularly used concentration may be from 25% to 35% w/w.
The release controlling polymer may be a combination of two or more polymers having different viscosity. In particular, two or more different viscosity grades of hydroxypropyl methylcellulose may be used; a lower viscosity grade ranging from 100-750 cps and a higher viscosity grade ranging from 1000-5000 cps.
Further, the polymer may be added intragranularly and/or extragranularly. In particular, the polymer is added both intragranularly and extragranularly.
The other pharmaceutically acceptable excipients are selected from diluents, binders, lubricants, or combinations thereof and other excipients known to the person skilled in the art. The excipients used in the formulation may be free from colloidal silicon dioxide.
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As used herein, the term "binder" is intended to mean inert substance used to form the bridge between the drug particles with other excipients. Binder may be selected from pregelatinized starch, copovidone, shellac, zein, gelatin, polymethacrylates, synthetic resins, eudragits, and cellulose polymers.
As used herein, the term "diluent" is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of the pharmaceutical composition. If desired, more than one diluent can be used. Such compounds as used herein include lactose, calcium hydrogen phosphate (dihydrate), calcium hydrogen phosphate (anhydrous), tribasic calcium phosphate, calcium carbonate, kaolin, magnesium carbonate, and magnesium oxide.
Lubricant may be selected from the group consisting of 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 like direct compression, dry granulation, or wet granulation.
According to one of the embodiment, there is provided a method of preparation of the said pharmaceutical composition, the process steps comprising:
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.
In particular, another embodiment provides a process for the preparation of a stabilized controlled release pharmaceutical composition of gliclazide, the process steps comprising:
a) Sifting Gliclazide, diluent, optionally a part of the binder, and optionally release-controlling polymer and dry mixing to achieve a uniform blend;
b) Dissolving sodium citrate and optionally remaining part of the binder in purified water to form homogenous slurry;
c) Granulating the dry powder blend of step a) using the slurry of step b);
d) Sifting the controlled release polymer using appropriate sieve and mixing with the dried granules;
e) Lubricating the blend of step d);
f) Compressing the lubricated granules into tablets or optionally filling into capsules.
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The tablets prepared using any of the processes described herein may be further provided with a film-coating. Suitable coating compositions comprise a film-forming polymer, a plasticizer, an opacifier and a film smoothner. Additionally pharmaceutically acceptable colours 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 smoothner such as talc may be used. Suitable coating solvents are water as well as organic solvents selected from ethanol, isopropanol, acetone, or halogenated hydrocarbons or mixtures thereof.
The invention is further illustrated by the following non-limiting examples.
Example 1
Ingredients Quantity (mg/tablet)
Gliclazide 60.00
Pregelatinized Starch 16.00
Lactose monohydrate 144.20
Sodium citrate 3^20
Purified water q.s.
Hypromellose 95.00
Magnesium Stearate 1.60
Total weight 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 remaining part of pregelatinized starch to form homogeneous slurry;
3. Blend of step 1 was transferred in a Rapid Mixer Granulator, mixed for homogeneity and granulated using slurry of step 2;
4. Hypromellose was sifted and mixed with granules of step 3;
5. The blend of step 4 was lubricated using magnesium stearate;
6. The lubricated granules of step 5 were compressed into tablets of suitable size using specified tooling.
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Example 2
Ingredients I Quantity (mg/tablet)
GiJclazide 60.00
Pregelatinized Starch 16.00
Lactose monohydrate 159.20
Sodium citrate 3^20
Purified water q.s.
Hypromellose K100 LV CR premium 70.00
Hypromellose K4M CR 10.00
Magnesium Stearate 1.60
Total weight 320.00
Manufacturing Process:
1. Gliclazide, a part of Pregelatinized starcli, and Lactose monohydrate were sifted and mixed to obtain a uniform blend;
2. Sodium citrate was dissolved in purified water followed by remaining part of pregelatinized starch to form homogeneous slurry;
3. Blend of step 1 was transferred in a Rapid Mixer Granulator, mixed for homogeneity and granulated using slurry of step 2;
4. Hypromellose K100 LV CR and Hypromellose K4M CR were sifted and mixed with granules of step 3;
5. The blend of step 4 was lubricated using magnesium stearate;
6. The lubricated granules of step 5 were compressed into tablets of suitable size using specified tooling.
Example 3 (Control example)
Ingredients I Quantity (mg/tablet)
Gliclazide 60.00
Hypromellose 6.40
Lactose monohydrate 157.00
Purified water q.s.
Hypromellose 95.00
Magnesium Stearate 1.60
Total weight 320.00
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Manufacturing Process:
1. Gliclazide, Hypromellose and Lactose monohydrate were sifted and mixed to obtain a uniform blend;
2. Blend of step 1 was transferred in a Rapid Mixer Granulator, mixed for homogeneity and granulated using purified water;
3. Hypromellose was sifted and mixed with granules of step 3;
4. The blend of step 3 was lubricated using magnesium stearate;
5. The lubricated granules of step 4 were compressed into tablets of suitable size using specified tooling.
Stability Testing
The compressed tablets, both prior to packing in blister strips and 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 pm (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 1L water and adjusting the pH to 2.5 using orthophosphoric acid. The relative retention time (RTT) of impurity A with respect to Gliclazide peak is at 0.18.
The marketed tablets (Diamicron® MR) and in-house control tablets (without sodium citrate -example 3) were also subjected to similar stability testing protocol and assessed for amount of impurities. The comparative results of stability study are shown in Table 1 (for tablets subjected to stability testing in open condition) and Table 2 (for tablets packed in cold form blister 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 effect of heat and moisture.
As seen from Table 2, the tablets of example 1 and 2 (containing sodium citrate) have the least amount of impurity A, thereby being stable.
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Table 2. Level of Impurity A after exposing tablets packed in cold-form blister packs to 40 °C/75% RH
Formulation Impurity A
Initial I TM I 3M
Marketed Tablet - Diamicron® MR 60 mg 006 ~ 057
Example 1 002 O09 022
Example 2 001 O05 015
Example 3 O02 OTS 031
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 pH 7.4 buffer at 100 rpm using the basket method. The samples were analyzed using HPLC using Lichrospher RP-8e 5 pm (250 mm * 4 mm) column and the mobile phase as buffer (pH 2.5) : acetonitrile in a ratio of 60:40. 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. Dissolution profile at pH 7.4 phosphate buffer/900 ml/100 rpm/Basket 40 mesh
Time point (hrs) Example 1 Example 2 Example 3
i 9 9 9
2 19 20 19
4 39 39 40
6 55 52 60
12 84 78 97
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WE CLAIM:
1. A stabilized controlled release pharmaceutical composition comprising:
a) Gliclazide or its pharmaceutically acceptable salts;
b) sodium citrate as a stabilizing agent;
c) one or more release controlling polymers; and
d) optionally other pharmaceutically acceptable excipients;
wherein, the total content of impurity A is less than 0.25% when subjected to conditions of 40°C/75% RH for three months.
2. The stabilized controlled release pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable excipients are free from colloidal silicon dioxide.
3. The stabilized controlled release pharmaceutical composition of claim 1, wherein sodium citrate is present in a concentration from 0.5% to 3% w/w.
4. The stabilized controlled release solid pharmaceutical composition of claim 1, wherein the release controlling polymer is selected from methylcellulose, ethylcellulose, hydroxyethylcellulose, propylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, polymethyl methacrylate, polyethyl methacrylate, polybutyl methacrylate, polyisobutyl methacrylate, polyhexyl methacrylate, poly isodecyl methacrylate, polylauryl methacrylate, polyphenyl methacrylate, polymethyl acrylate, polyisopropyl acrylate, polyisobutyl acryiate, polyoctadecyl acrylate, polyethylene, polypropylene, polyethylene oxide, polyethylene terephthalate, polyvinyl isobutyl ether, polyvinyl acetate, polyvinyl chloride, polyurethane or a mixture thereof.
5. The stabilized controlled release pharmaceutical composition of claim 4, wherein the release controlling polymer is present in a concentration from 25% to 35% w/w.
6. The stabilized controlled release pharmaceutical composition of claim 4, wherein the release controlling polymer may be added intragranularly and/or extragranulariy.
7. The stabilized controlled release pharmaceutical composition of claim 4, wherein the release controlling polymer is a combination of two or more release controlling polymers having different viscosity.
8. The stabilized controlled release pharmaceutical composition of claim 7, wherein the release controlling polymer is combination of a lower viscosity grade of hydroxypropyl methylcellulose ranging from 100-750 cps and a higher viscosity grade of hydroxypropyl methylcellulose ranging from 1000-5000 cps.
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9. The stabilized controlled release solid pharmaceutical composition of claim 2, wherein the pharmaceutically acceptable excipients are selected from the group consisting of diluents, binders, lubricants, and combinations thereof.
10. A 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);
d) Lubricating the blend of step b) or 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 release-
controlling polymer and dry mixing to achieve a uniform blend;
b) Dissolving sodium citrate and optionally remaining part of the binder in purified water to form homogenous slurry;
c) Granulating the dry powder blend of step a) using the slurry of step b);
d) Sifting the controlled release polymer using appropriate sieve and mixing with the dried granules;
e) Lubricating the blend of step d);
f) Compressing the lubricated granules into tablets of suitable size or optionally filling into capsules.
12. The stabilized controlled release pharmaceutical composition comprising Gliclazide and
sodium citrate as the stabilizing agent substantially described and exemplified herein.