FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
NOVEL CONTROLLED RELEASE DOSAGE FORM OF GLICLAZIDE

Name:
Nationality:
Address:

Applicant
Torrent Pharmaceuticals Limited
Indian
Torrent House, Off Ashram Road, Near
Dinesh Hall, Ahmedabad 380 009, Gujarat,
India

The following specification describes the invention

NOVEL CONTROLLED RELEASE DOSAGE FORM OF
GLICLAZIDE
TECHNICAL FIELD OF THE INVENTION
The present invention relates to controlled release dosage form of Gliclazide exhibiting pH independent release profile over a wide range having one or more release controlling polymer and free from additional saccharide component and process for preparing the same.
BACKGROUND OF THE INVENTION
Gliclazide, having structural formula

is a sulphonylurea compound having an antidiabetic property. Gliclazide is usually administered by oral route in the form of immediate release and modified release tablet. 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, magnesium stearate and anhydrous colloidal silica.
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Gliclazide is a weak 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. The solubility and hence the absorption of gliclazide is pH dependent which ultimately results in the interindividual variation of the bioavailability. Solubility of gliclazide is very less at acidic pH and increases at alkaline pH.
Traditionally, solid oral pharmaceutical dosage forms are comprised of immediate release (IR) dosages in the form of tablets or capsules. These IR dosage forms release the active drug substance into the body of a subject at a rate that is initially very high followed by a rapid decline. One potential result of an IR dosage form is that the subject may have varying degrees of blood level fluctuation, which may result in transient therapeutic overdose, followed by a period of therapeutic under dosing. Another disadvantage with regard to immediate release dosage form is frequent dosing which ultimately results in poor patient compliance.
One of the most frequently utilized methods to extend the drug release and action in the body and/or control blood level fluctuations is modification of the pharmaceutical dosage form. This is usually achieved by any of the systems known to skilled in the art but not limited to Monolithic matrix, Gradient matrix, Membrane controlled system,
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Swelling controlled system, Ion exchange resin system, Osmotically controlled system, Geometrically modified system.
Controlled release drug delivery systems deliver drug to body so as to establish therapeutically effective blood levels of the active ingredient and once these blood levels are achieved they continue to maintain constant blood levels for long duration. By avoiding the blood level fluctuation associated with the conventional dosage forms, controlled release system lower the incidence of adverse effects or side effects. Very importantly controlled release systems reduce the frequency of dosing leading to convenience to the patients in terms of dosing and compliance to the specified dosage regimens.
US6056977 describes once daily controlled release formulation of sulfonylurea comprising a heteropolysaccharide, a homopolysaccharide, and an inert diluent, an alkalizing agent and solubilizing agent. The patent is particularly related to glipizide formulation.
WOOO 18373 discloses the matrix tablet for prolonged release of Gliclazide comprising a combination of cellulose polymer and glucose syrup. The composition contains 2-20% w/w of glucose syrup as an essential ingredient. The publication state that the combination of cellulose compound and glucose syrup (maltodextrin) ensures prolonged,
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continuous and consistent release of gliclazide which is insensitive to the variations in pH of the dissolution medium from pH 6 to 8.
An article published in Medical Science Monitor, International Medical Journal for Experimental and Clinical Research, by Tadeusz W. Hermann et al described their own gliclazide controlled release matrix tablet and compared the dissolution profile with the available market formulation of gliclazide. The controlled release matrix tablet prepared by authors consists of lactose, HPMC, maltodextrin, Kollidon SR.
WO2006061697 discloses sustained release sulfonylurea composition in the form of matrix tablet and comprises sulfonylurea, polymer, disaccharide and / or monosaccharide exhibiting the release of said sulfonylurea substantially independent of the pH over a wide pH range (4-8).
All the prior art described above discloses that to achieve controlled release delivery of gliclazide having pH independent profile essentially require saccharide component in addition to release controlling polymer. Since the gliclazide is an antidiabetic drug used for the control of high blood sugar level, one skilled in the art can appreciate that the dosage form used to control the high blood sugar level should ideally not contain any material which results in the increase in the blood sugar level.
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Applicants of the present invention surprisingly found a simple and easy to manufacture controlled release dosage form of Gliclazide exhibiting pH independent release profile using only one or more release controlling polymer and without using additional saccharide component.
SUMMARY OF THE INVENTION
The present invention relates to controlled release dosage form of Gliclazide exhibiting pH independent release profile over wide range having one or more release controlling polymer and free from additional saccharide component.
The first object of the present invention is to provide controlled release dosage form of Gliclazide exhibiting pH independent release profile over wide pH range of the gastro intestinal tract using one or more release controlling polymer and free from additional saccharide component.
The another object of the present invention is to provide controlled release dosage form of Gliclazide exhibiting pH independent release profile over wide pH range of the gastro intestinal tract using release controlling polymer either singly or in combination.
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It is yet another object of the invention is to provide the process for preparing such pharmaceutical dosage form either by a wet or dry granulation method or by direct compression.
BRIEF DESCRIPTION OF THE DRAWING
Figure-I shows the % cumulative release profile of gliclazide from the matrix tablets of example 1 in dissolution medium of pH 6.2, 6.8 and 7.4.
DETAILED DESCRIPTION OF THE INVENTION
The term "Controlled release" as used herein refers to the release of an active ingredient such as a drug from a composition, formulation or dosage form 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 "dosage form" as used in this specification and the claims refer 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 excipients. The quantity of active material is that calculated to produce the desired therapeutic effect upon administration of one or more of such units. The dosage form used herein
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selected from tablets, capsule, sachets, pellets, beads, microspheres, microcapsules, pills, powders, lozenges, or granules.
The dosage form of the present invention comprises the gliclazide in a range of about 1 mg to about 300 mg. Preferably dosage forms may contain 10 mg to about 200 mg. More preferably dosage forms may contain from 30 to 80 mg.
The term "gliclazide" used herein includes gliclazide free base, pharmaceutically acceptable salts, solvates, or mixtures thereof.
The controlled release pharmaceutical dosage form of the present invention comprises release controlling polymer and optionally other pharmaceutically acceptable excipients but free from any additional saccharide component.
The release controlling polymer used herein is selected from but not limited to methylcellulose, ethylcellulose, hydroxyethylcellulose, propylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, 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,
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polyethylene, polypropylene, polyethylene oxide, polyethylene terephthalate, polyvinyl isobutyl ether, polyvinyl acetate, polyvinyl chloride, polyurethane or a mixture thereof.
Preferably the release controlling polymer used for the present invention is selected form hydroxyethylcellulose, hydroxypropylcellulose and hydroxymethylpropylcellulose. More preferably the release controlling polymer used herein is hydroxypropylmethylcellulose.
Preferably the release controlling polymer used herein is the combination of two polymers having different viscosity. Further the polymer may be added intragranularly and/or extragranularly, preferably polymer is added intragranularly and extragranularly.
The release controlling polymer present in the invention is preferably in a quantity from 5 to 70%w/w, more preferably from 7 to 50% w/w, with respect to the total weight of the pharmaceutical dosage form.
The release controlling polymer when used in the present invention as a combination of two polymers having different viscosity for providing a controlled release of active ingredient from a pharmaceutical dosage form, the required ratio between the low viscosity and high viscosity polymer is from 10: 1 to1: 3, preferably from 6: 1 to 1:2, and more preferably from 3:1 to 1: 1.
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The pharmaceutically acceptable excipients are selected from the following categories but not limited to diluents, binders, fillers, anti-adherents, lubricants, surfactants, alkalizing agents, pH modifiers, buffering agents, stabilizers and other excipients known to the person skilled in the art.
As used herein, the term "binders" is intended to mean inert substance used to form the bridge between the drug particles with other excipients. Binder may be selected from but not limited to polyvinylpyrrolidone, copolyvidone, shellac, zein, gelatin, polymethacrylates, synthetic resins, eudragits, and the like. Preferably the binder used in the present invention is polyvinylpyrrolidone. The binder may be present in an amount ranging from 0.1 % to 25 % by weight of the composition.
As used herein, the term "diluents" or "fillers" is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of dosage form. If desired, more than one diluent or fillers can be used. Such compounds may be selected from calcium hydrogen phosphate, tribasic calcium phosphate, calcium carbonate, kaolin, magnesium carbonate, magnesium oxide and pharmaceutically acceptable excipient known to person skilled in the art. More preferably the diluent or filler used herein is calcium hydrogen phosphate. The "diluent" or "filler" is present in the composition in the range of 40% to 80% by weight of dosage form.
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Anti-adherents agent may be used to prevent the tablet from sticking to the tablet punch and die wall and may be selected from but not limited to talc, kaolin, finely divided silicon dioxide, glyceryl monostearate, and the like. The anti-adherent agent may be present in an amount ranging from 0.1 % to 20 % by weight of the composition.
The Lubricant may be selected from but not limited to group comprising of Stearic acid, Polyethylene glycol, Magnesium stearate, Calcium stearate, Zinc stearate, Talc or Silica, Hydrogenated caster oil, etc. The lubricant may be present in an amount ranging from 0.1 % to 10 % by weight of the composition.
The present invention provides the pH independent, controlled and consistent release of the drug over wide pH range of the gastrointestinal tract.
The instant invention can be prepared using any of the process given below:
Process A:
1. Sifting & Mixing of Gliclazide, with diluent and release controlling polymer.
2. Preparation of binder solution in suitable solvent.
3. Granulation of step 1 with step 2 solution followed by drying & sizing
4. Blending of step 3 with release controlling polymer.
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5. Lubrication of step 4 with lubricant.
6. Optionally compressing the granules from step 5.
Process B:
1. Sifting & Mixing of Gliclazide, with diluent and release controlling polymer.
2. Lubrication of step 1 with lubricant.
3. Optionally compressing the content obtained from step 2.
Process C:
1. Sifting & Mixing of Gliclazide with diluent, release controlling polymer and optionally other pharmaceutically acceptable excipient.
2. Slugging the blend of step 1.
3. Milling and sifting the slugs from step 2.
4. Lubrication of step 3 with lubricant
5. Optionally compressing the content obtained from step 4.
EXAMPLES
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare the various dosage forms and/or perform the various processes of the
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invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever:
Example 1

Sr.No Ingredients Mg/Tablet
1 Gliclazide 30.00
2 HPMCK4M 17.00
3 Calcium hydrogen phosphate dihydrate 86.80
4 PVPK30 8.60
5 Isopropyl alcohol Q.S
6 HPMCE15LV 16.00
7 Magnesium stearate 1.60
Total 160.00
Gliclazide and Calcium hydrogen phosphate dihydrate were mixed in the presence of HPMC K4M and granulated by solution of PVP K30 in isopropyl alcohol to obtain wet mass which was passed through 1.00 mm screen to obtain granules. Granules were dried and blended with HPMC E15LV. Magnesium stearate was sifted through 60# and mixed with the granules. These lubricated granules were compressed to tablets using suitable tablet compressing machine.
The dissolution profiles of the tablets of Gliclazide Modified release Tablet prepared as per examples 1 is given in the table below:
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Dissolution profile
The dissolution of the present invention was determined by following method:
Table 1
Instrument : Apparatus II, USP
RPM : 100
Temperature : 37 °C
Dissolution Medium : 1. 900mL, pH 6.2 phosphate buffer
2. 900mL, pH 6.8 phosphate buffer
3. 900mL, pH 7.4 phosphate buffer
Table 2

TIME (hrs) % Cumulative release profile of gliclazide
pH 7.4 Phosphate Buffer pH 6.8 Phosphate Buffer pH 6.2 Phosphate Buffer
1 10 9 5
2 19 17 14
4 36 36 34
6 50 53 54
8 64 66 73
10 78 77 86
12 86 85 91
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As seen in table 2 above, the release profile of gliclazide fro m the pharmaceutical dosage form is substantially independent of the pH of the dissolution medium over a wide pH range. The pharmaceutical dosage form of the present invention releases gliclazide substantially independent to the variation in a wider pH range. This would also ensure consistent and regular release of drug throughout the gastrointestinal tract independent of pH.
Pharmacokinetics
The relative bioavailability of solid pharmaceutical dosage form of example 1 of the present invention in comparison to the formulation currently on the market (Diamicron® MR) was evaluated. The bioavailability of controlled release Gliclazide Tablets 30 mg was evaluated in fasted state and fed state in a group of 14 healthy subjects. The study was Open Label, Randomised, 2 Period, 2 Treatment, Single dose, Crossover. Blood samples were collected before dose and at predetermined intervals after dose. It was found that the relative bioavailability of the solid pharmaceutical compositions of the present invention is comparable to the formulation currently on the market. The derived Cmax and AUC of the two studies are given in table below:
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Table 3

S.No Study Design Product ID Mean of pharmacokinetic parameters
Cmax(ng/mL) AUCo-t(u.g*h/mL) AUCo-inf(ug*h/mL)
1. Open Label, Randomised, 2 Period, 2 Treatment, Single dose, Crossover Study in Fasted condition Gliclazide Tablet 30 mg, (Torrent Pharmaceuticals) 1316.368 28872.936 31000.749
Diamicron MR® 30 mg Tablet, (Servier Laboratories) 1141.230 26812.935 29664.056
2. Open Label, Randomised, 2 Period, 2 Treatment, Single dose, Crossover Study in Fed condition Gliclazide Tablet 30 mg, (Torrent Pharmaceuticals) 1324.269 27551.766 29583.177
Diamicron MR® 30 mg Tablet, (Servier Laboratories) 1214.313 25529.570 27316.572
Thus from the above data, it can be concluded that the relative bioavailability of the two formulations are comparable.
Dated this 17th day of October, 2006
Praveen Chand Gandhi,
Torrent Pharmaceuticals Limited, Torrent Research Centre P.O. Bhat - 382428, Gandhinagar Gujarat, India
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Figure-I
-pH 7.4 Phosphate Buffer —■—pH 6.8 Phosphate Buffer —*—pH 6.2 Phosphate Buffer
100

12
!

Tim* (hrs)
Figure-I: The % cumulative release profile of gliclazide in dissolution medium of pH 6.2, 6.8 and 7.4.

7th
Dated this 17m day of October, 2006

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Praveen Chand Gandhi,
Torrent Pharmaceuticals Limited, Torrent Research Centre P.O. Bhat- 382428, Gandhinagar Gujarat, India

ABSTRACT
The present invention is directed to controlled release dosage form of Gliclazide, exhibiting pH independent release profile over a wide range, having one or more release controlling polymer and free from additional saccharide component and process for preparing such dosage form.