FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"SUSTAINED RELEASE DOSAGE FORM OF GL1CLAZIDE"
2. APPLICANT:
(a) NAME: INDOCO REMEDIES LIMITED
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: Indoco House, 166 C. S. T. Road, Santacruz (East), Mumbai - 400 098, Maharashtra, India.

3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION:
The present invention relates to a novel sustained release oral dosage form of gliclazide
or its pharmaceutical^ acceptable salts and processes for their preparation.
BACKGROUND OF THE INVENTION:
Diabetes mellitus type 2 or non-insulin dependent diabetes or type 2 diabetes is a disorder thai is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency.
In a person with normal metabolism, insulin is released from the beta (p) cells of the Islets of Langerhans located in the pancreas and after eating ("postprandial), it signals insulin-sensitive tissues in the body (e.g., muscle, adipose) to absorb glucose. This lowers blood glucose levels. The beta cells reduce their insulin output as blood glucose levels fall, with the result that blood glucose is maintained at approximately 5 mmol/L(mM) (90 mg/dL). In an insulin-resistant person, normal levels of insulin do not have the same effect on muscle and adipose cells, with the result that glucose levels stay higher than normal.
Thus, diabetes mellitus type 2 is a chronic, non-progressive disease that has no established cure, but does have well-established treatments which can delay or prevent entirely the formerly inevitable consequences of the condition.
Drugs which are commonly used for the treatment of Diabetes mellitus type 2 belong mainly to the class of sulfonylureas, meglitinides, biguanides, thiazolidinediones, and alpha-glucosidase inhibitors. All these classes of drugs work in different ways to lower blood glucose levels.
Gliclazide belongs to a class of sulfonylureas which are used as hypoglycaemic agent for the management of non-insulin dependent diabetes (type 2) in adults when dietary measures, physical exercise and weight loss alone are not sufficient to control blood glucose. It reduces blood glucose level by stimulating insulin secretion from the (p- cells of the islets of Langerhans and shows high affinity, strong selecting and reversible binding to the B-cell KATP channel with low affinity for the cardiac and vascular KATP,
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It is marketed in most countries of the world as Diamicron® and is available both as conventional oral and sustained release tablet.
Since, in most cases the drug, gliclazide is to be taken for years or throughout the life span of the patient; the sustained release dosage forms are preferred since they are commonly taken only once, compared with counterpart conventional forms that may have to be taken twice or thrice daily to achieve the same therapeutic effect. Typically, these provide an immediate release of drug that promptly produces the desired therapeutic effect, followed by gradual release of additional amounts of drug to maintain this effect over a predetermined period. Further, the sustained plasma drug levels provided by the drug often times eliminate the need for night dosing, which benefits the patients. Because of all theses advantages, alternatives have been proposed by the numerous inventors, of which few noteworthy disclosures arc: US Pat. No. 6,733,782 by Barochez et al provides the controlled release tablet dosage form of Gliclazide using cellulose polymer like hydroxylpropylmethylcellulosc (HP1VIC), glucose syrup (maltodextrin) and hydrous calcium hydrogen phosphate. The inventors claim that the combination of HPMC and maltodextrin in the formulation enables the controlled and complete release of the drug from the formulation. Also, PCT Publication No. WO 2006061697 by Antarkar et al discloses the composition comprising sulfonylurea, polymer, disaccharide and or monosaccharide which provides the drug release profile substantially independent of the pH of the dissolution medium in pH range 4 to 8.
Though, the fore going disclosures provide the controlled and prolonged release of the drugs; however; these inventions are not without their disadvantages as they rely mainly on the use of saccharides which is generally undesirable in formulations for diabetic patients. Many studies and attempts have been made to address the issue of use of saccharides.
Further, Bhagwat et al in US 6,056,977 claims a rate controlling matrix comprising heteropolysaccharides, solubilizing agent along with an alkaline agent to raise the pH of a mixture to 7.0 to 9.0. Also, Gour et al in WO 2008062470 by discloses a controlled release dosage form comprising a controlled release polymer and anhydrous calcium
hydrogen phosphate in order to get a stable formulation. The claimed formulation lacks in
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novelty as only the grade of the excipients is differed from the earlier claimed formulation.
Further, PCX Publication No. WO2006/123213 (now abandoned) by Murpani et al discloses that the composition which is bioequivalent to the innovator's formulation can be obtained by using various controlled release polymers and binders. In addition, Murpani et al mention that the use of specific particle size (D90) of the gliclazide less than about 18 [itn further results in bioavailable formulation.
It would be abundantly evident that the method (s) disclosed therein primarily relate to increasing the bioavailability by using the material of reduced particle size or increased surface area which is a technique widely practiced in pharmaceutical area. However, micronisation or otherwise referred to as milling requires special machines or equipment which calls for not only capital investment but also increases the cost of manufacture. Also, it becomes a critical criterion, which needs to be monitored carefully.
Still further, recent US Publication No. US 2009017116 by Cifter et al mentions that the 'dose dumping is one of the major disadvantage of the controlled release dosage form". They further disclose the composition comprising gliclazide, hydroxypropylmethylcellulose (HPMC), mannitol, and calcium hydrogen phosphate; which they claim does not release more than 25 % amount of active drug in less than 2 hours. However, US 2009017116 fail to provide any disclosure and data about in vitro and in vivo profiles; which substantiates their claim.
WO 2009004654 teaches the use of pH modifier along with release modifier diluent selected from mannitol and microcrystalline cellulose to achieve a controlled release formulation of sulfonylurea.
Few other disclosures have also been made in PCT Publication No. WO 03/063825 by Garg et al, US 6,875,793 by Bhagwat et al and IN 1914218 by Thembalath et al.
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However, most of the previous efforts to develop a stable pharmaceutical composition of gliclazide have not been entirely successful and suffer from one or other aspect of either using the saccharides or using the expensive techniques like micronization.
Thus, there is a continuing need in the art for a novel, stable sustained release formulation of gliclazide which is simple, convenient and economical to manufacture on a commercial scale, exhibits the pH independent profile, and obviates the drawbacks of the compositions and the techniques used for manufacture of the same as disclosed in the prior art.
OBJECTS OF THE INVENTION:
Accordingly, it is an object of the present invention to provide a sustained release pharmaceutical composition for oral administration of gliclazide for treating non-insulin dependent diabetes which is capable of slowly releasing the gliclazide at a predetermined rate for a long time.
Another object of the present invention is to provide a method for the preparation of sustained release pharmaceutical composition.
Another object of the present invention to provide a method for the preparation of sustained release pharmaceutical composition of gliclazide which is simple and convenient to manufacture on a commercial scale
Yet another object of the present invention is to provide a sustained-release, pharmaceutical composition of gliclazide without using saccharides.
A further, object of the present invention is to provide a sustained-release, pharmaceutical composition of gliclazide that resists dose dumping.
A further object of the present invention is to provide a sustained release bioavailable form of gliclazide, by a process which does not take recourse to any micronisation or milling technique and thus is economical.
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Still further object of the present invention is to provide a sustained release pharmaceutical composition of gliclazide which exhibits the pH independent profile over a wide pH range of the gastrointestinal tract.
BRIEF DESCRIPTION OF FIGURES:
The above and other objects and features of the present invention will become apparent from the following description of the invention, when taken in conjunction with the accompanying drawing which respectively shows:
FICi. 1 shows a comparative drug release profile of tablets obtained using Formula A (of example 1) vis a vis Innovator's marketed gliclazide composition (Diamicron®) in USP Apparatus 1 (Basket) at 100 rpm in 7,4 phosphate buffer at 37° C.
FIG, 2 shows a comparative drug release profile of tablets obtained using Formula B (of example 1) vis a vis Innovator's marketed gliclazide composition (Diamicron®) in USP Apparatus 1 (Basket) at 100 rpm in 7.4 phosphate buffer at 37° C.
DESCRIPTION OF THE INVENTION:
The present invention provides a sustained release oral dosage form which has a suitable in-vitro release profile and improved stability. The dosage form comprises of gliclazide or its pharmaceutically acceptable salts and one or more pharmaceutical^ acceptable excipients, water swellable polymer, buffering agent but without a soluble release modifier such as lactose, mannitol and glucose syrup.
One or more of pharmaceutical acceptable is selected from binders, glidants, diluents, disintegrates, and lubricants.
Water-swellable polymer,in the range of 10 to 50 % w/w can be utilized in the formulation of the invention selected from the group including hydroxylpropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose or generally those having average molecular weight of 80 to 1150 kDa. These can be used alone or in combination
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In the present invention preferred water swellable polymer is selected from hydroxylpropylcellulose and hydroxyethylcellulose. However, combination of high and low viscosity of either polymer can also be used to achieve the desired drug release.
One of the important features of this invention is the use of buffering agent in the range of 0,5 to 5 % w/w selected from calcium carbonate, magnesium oxide, magnesium hydroxide, sodium hydrogen carbonate, magnesium carbonate, potassium carbonate. Calcium carbonate is particularly preferred.
The addition of a buffering agent in the said formulation modifies the drug release. Hence, it can be used as a release modifier for a drug having high alkaline solubility and low or negligible acidic solubility. The buffering agent creates a favorable local alkaline microenvironment within and in an immediate vicinity of the gelled tablet. The solubility of gliclazide is pH-dependent which increases with the increase in pH.
One or more of pharmaceutically acceptable excipients are used in the preparation of the sustained release formulation, selected from binders, glidants, diluents, disintegrants, and lubricants.
Binder such as starch, povidone, low viscosity HPMC and others can be used in small amount in a range 0.5 to 10% of the formulation. The preferred binder is povidone. However, KoUidone 30 or 90 or plasdone K-29/30 (ISPP) can also be used as a binder for wet granulation process.
The preferred excipients, bulking agent or filler that is used in the present invention is microcrystalline cellulose. However, other bulking agent or fillers may also be used.
The lubricant and glidant include one or more of talc, colloidal silicon dioxide, magnesium stearate, sodium stearyl tumarate and mixtures thereof.
The particle size of the pharmaceutically active ingredient may be between 1 jam to 250 urn, preferably 1 um to 100 urn.
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The formulation can be prepared by a wet granulation method, dry granulation, slugging method or a direct compression method.
The dosage form of the invention does not comprise any water soluble excipients like sugar, saccharides/polysaccharides, polyols or any such water soluble excipients as a release modifier for the drug from the matrix or gel layer.
The sustained release formulation for oral administration of gliclazide slowly releases the drug into blood at a uniform rate and maintains its constant level and can be effectively used for treating non-insulin dependent diabetes by orally administering once per day in a single dose.
As per the invention, a sustained release oral dosage form of gliclazide or its pharmaceutically acceptable salts, water swellable polymer, buffering agent and one or more pharmaceutically acceptable excipients, without use of any soluble saccharide, sugar or polyol is prepared. The gliclazide is used in the range of 10 to 30% w/w of the total weight of the tablet. The water swellable polymer is selected from hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose or combination thereof The water swellable polymer used is in the range of 10 to 50% w/w, of the total weight of the tablet. The buffering agent is selected from calcium carbonate, magnesium hydroxide and magnesium oxide, sodium hydrogen carbonate, magnesium carbonate, potassium carbonate, calcium carbonate. The range of the buffering agent is 0.5 - 5% w/w of the total weight of the tablet. The pharmaceutically acceptable excipients are selected from microcrystalline cellulose, starch, povidone, talc, colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate or combination thereof. The pll of the dosage form is adjusted to pH 5 to 7. The dosage of gliclazide in the preferred embodiment is in the range of 10 to 60mg. In a typical embodiment, the formulation comprises 10-30 % of gliclazide, 10-20% of hydroxypropylcellulose and 0.5- 5 % w/w of buffering agent such as calcium carbonate, sodium carbonate or magnesium oxide without any soluble saccharides, polysaccharide, sugar or polyols.
In a typical embodiment, a sustained release dosage form was prepared by sieving of
ingredients gliclazide in the range of 10 to 30 % w/w, buffering agent in the range of 0.5
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to 5 % w/w, excipients and mixed in rapid mixer granulator for 10-15 minutes. The mass was wetted with the solution of povidone in water, followed by drying and dried granules were blended with water swellable polymer in a blender, after which lubricant and glidant is added and further blended. The lubricated mass is compressed into tablets
Following examples illustrating the embodiments of the present invention are provided. However, it is exemplary only and should not be regarded as limitations of the present invention.

Example 1:
Sustained Release Tablet of Gliclazide
For Tablet A For Tablets B
Ingredient Quantity
Cms/tab) % aee Quantity (mg/tab) % aee
Gliclazide 30 18.75 30 18.75
Calcium Carbonate 5 3.125 5 3.125
Microcrystalline cellulose 77.5 48.43 77.5 48,43
PVP K-30 (Povidone) 6.7 4.18 6.7 4.18
Purified water q.s q.s „._
HPC (Klucel HXF) 20 12.5 18 11.25
HPC(KlucelEXF) 20 12.5 22 13.75
Magnesium stearate 0.8 0.5 0.8 0.5
Total 160 160
Procedure:
Ingredients gliclazide, calcium carbonate and microcrystalline cellulose were sieved and mixed in rapid mixer granulator for 10-15 minutes. The mass was wetted with the solution of povidone in water. The wet mass was dried to achieve suitable. The dried granules were blended with polymer ingredient Klucel HXF and Klucel HXF in a blende after which magnesium stearate was added and further blended. The lubricated mass was compressed into tablets of 160 mg.

Dissolution characteristics of Tablet formulation
The dissolution was performed in phosphate buffer of pH 7.4 using basket at 37° C and 100 rpm.

Time
hours
4 8
12

in

% drug release of the tablet obtained from formula A
16.7 38.4 59.50
79.2

% drug release of
tablet obtained
from formula B
20,93 40.36 64,12 85.76

% drug release of the marketed Diamicron
11,97 40.40 66.67 89.27

Example 2:

Sustained Release Tablet of Gliclazide
Ingredient Ouantitv
(mg/tab) % aee
1. Gliclazide 30 1875
■i Calcium Carbonate 5 3.125
i. Microcrystalline cellulose 67.5 42.18
4. PVP K-30 (Povidone) 6,7 4,18
S, Purified water q.s
(). NEC (Natrosol HHX) 30 18.75
7. HEC (Natrosol M) 20 12.5
K. Magnesium stearate 0.8 0.5
9. Total 160
Procedure;
Ingredients gliclazide, calcium carbonate and microcrystalline cellulose were sieved and mixed in rapid mixer granulator for 10-15 minutes. The mass was wetted with the solution of povidone in water. The wet mass was dried to achieve suitable. The dried granules were blended with polymer Natrosol HHX and Natrosol M in a blend after which magnesium stearate was added and further blended. The lubricated mass was compressed into tablets of 160 mg.

Dissolution characteristics of Tablet formulation
The dissolution was performed in phosphate buffer of pH 7.4 using basket at 37° C and 100 rpm.
Time in hours % drug release of the tablet % drug release of the
__ obtained from Example 2 marketed Diamieron ®
1 7.78 11.97
4 43.74 40.40
8 75^04 66.67
12 90.21 89.27
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We Claim,
1. A sustained release oral dosage form comprising of gliclazide or its pharmaceutically acceptable salts, water swellable polymer, buffering agent and one or more pharmaceutically acceptable excipients without any soluble saccharide, sugar or polyol.
2. A sustained release oral dosage form of as claimed in claim 1, wherein gliclazide is used in the range of 10 to 30 % w/w.
3. A sustained release oral dosage form as claimed in claim 1, wherein water swellable polymer is selected from hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose or combination thereof.
4. A sustained release oral dosage form as claimed in any of preceding claim, wherein water swellable polymer is in the range of 10 to 50 % w/w.
5. A sustained release oral dosage form as claimed in claim 1, wherein the buffering agent is selected from calcium carbonate, magnesium hydroxide and magnesium oxide, sodium hydrogen carbonate, magnesium carbonate, potassium carbonate, calcium carbonate.
6. A sustained release oral dosage form as claimed in claim 1 and 5, wherein buffering agent is in the range of 0.5 to 5 % w/w.
7. A sustained release oral dosage form as claimed in claim 1, wherein pharmaceutically acceptable excipients is selected from microcrystalline cellulose, starch, povidine, talc, colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarale or combination thereof.
8. A sustained release oral dosage form as claimed in any of preceding claim, wherein dosage form has a pH between 5 to 7.
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9. A sustained release dosage form as claimed in claim 1 to 8, wherein dosage form comprises 10 to 60 mg of gliclazide.
10. A sustained release dosage form of claim 1 comprising 10-30 % of gliclazide, 10-20% of hydroxypropylcellulose and 0.5 - 5% w/w of buffering agent such as calcium carbonate, sodium carbonate or magnesium oxide without any soluble saccharides, polysaccharide, sugar or polyols
Dated this 25th day of May, 2009
Mr. Sundeep V. Bambolkar lndoco Remedies Limited Applicant
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