WO2008062470A2

WO2008062470A2 - Stabilized controlled release dosage form of gliclazide

Info

Publication number: WO2008062470A2
Application number: PCT/IN2007/000496
Authority: WO
Inventors: Gour Samanta; Rajneesh Shrivastava; Bhavesh Shah; Jaya Abraham
Original assignee: Torrent Pharmaceuticals Limited
Priority date: 2006-10-19
Filing date: 2007-10-18
Publication date: 2008-05-29
Also published as: WO2008062470A3

Abstract

The present invention is directed to stabilized 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 saccharide component and optionally free from binder and process for preparing such dosage form.

Description

STABILIZED CONTROLLED RELEASE DOSAGE FORM OF GLICLAZIDE

TECHNICAL FIELD OF THE INVENTION

The present invention relates to stabilized 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 saccharide component and optionally free from binder 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. 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, 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.

WOOOl 8373 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, continuous and consistent release of gliclazide which is insensitive to the variations in pH of the dissolution medium from pH 6 to 8. IN 194218 discloses process for preparation of controlled release antidiabetic composition of gliclazide using approximately 25.8% of gliclazide and other pharmaceutically acceptable excipients like controlled release polymers, binders, lubricants and glidants. 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 Al 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). WO 2006 123213 Al discloses modified release composition of gliclazide using one or more controlled release polymers, one or more binders and optionally one or more pharmaceutically acceptable excipients.

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. In the entire prior art use of diluents like Lactose, which is made of glucose and galactose or Starch, which is made of amylose and amylopectin is disclosed. Moreover, starch is a polymer of α-D-glucose. Hence these excipients contain glucose in some form or other. According to US 6733782 Bl, use of combination of cellulose polymer compound and glucose syrup is required for prolonged release of gliclazide. In another perspective, gliclazide, which is an antidiabetic drug and used for the control of high blood sugar level, one skilled in the art can appreciate that the dosage¹ 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.

Applicants of the present invention surprisingly found a simple and easy to manufacture stabilized controlled release dosage form of Gliclazide exhibiting pH independent release profile using one or more release controlling polymer, without using saccharide component and optionally without using binder. SUMMARY OF THE INVENTION

The present invention relates to stabilized controlled release dosage form of Gliclazide exhibiting pH independent release profile over wide range having one or more release controlling polymer and free from saccharide component and optionally free from binder.

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 without using 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 without using binder.

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 without using binder and 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 by using magnesium stearate in an amount of less than 1.1% and more preferably less than 0.6% of the total weight of the composition.

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 without using Povidone.

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. The present invention relates to controlled release dosage form of Gliclazide, wherein use of anhydrous Calcium Hydrogen Phosphate provides stability to the composition.

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 selected from tablets, capsule, sachets, pellets, beads, microspheres, microcapsules, pills, powders, lozenges, or granules.

The term "saccharide component" as used herein includes excipients such as glucose syrup, lactose, maltodextrin, starch, modified starch, microcrystalline cellulose, dextrose, mannitol, lactitol, xylitol, cyclodextrin, Sucrose, Glucose, Galactose, Fructose, Sorbitol, Maltose, Maltitol, Isomalt, Xanthan gum and the like, Carrageenan, Starch, Polydextrose, Trehalose, Cellobiose etc.

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 saccharide component and optionally free from binder. The release controlling polymer used herein is selected from but not limited to 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. Preferably the release controlling polymer used for the present invention is selected form hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropyl methylcellulose (Hypromellose, HPMC). More preferably the release controlling polymer used herein is hydroxypropyl methylcellulose.

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 to 1: 3, preferably from 6: 1 to 1:2, and more preferably from 3: 1 to 1 : 1. Hypromellose is available in various grades having viscosity in the range of 3 cps to 100,000 cps when measured at 25°C at the 2 % concentration in water.

The other 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 copolyvidone, shellac, zein, gelatin, polymethacrylates, synthetic resins, eudragits, cellulose polymers and the like. The binder may be present in an amount ranging from 0.0 % to 25 % by weight of the composition. It was surprisingly found that the impurity levels in formulation increases by the use of binders such as povidone.

As used herein, the term "diluents" or "fillers" is intended to mean inert substances x 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 as used herein include calcium hydrogen phosphate (dihydrate), calcium hydrogen phosphate (anhydrous), tribasic calcium phosphate, calcium carbonate, kaolin, magnesium carbonate, magnesium oxide and the like. More preferably the diluent or filler used herein is calcium hydrogen phosphate (anhydrous). The "diluent" or "filler" is present in the composition in the range of 40% to 80% by weight of dosage form. It was observed that composition devoid of glucose syrup and containing calcium hydrogen phosphate

(dihydrate) were found to be unstable at higher temperature.

It was surprisingly found that use of calcium hydrogen phosphate (dihydrate) resulted in higher impurity levels while it was not so with the use of its anhydrous grade.

Table 1

CHP: Calcium Hydrogen Phosphate ^v

Impurity A: p-Tolunesulphonamide

The similar degradation behavior was observed in presence of povidone.

Anti-adherents agent may be used to prevent the tablet from sticking to the tablet punch and die wall and may be selected from talc, kaolin, finely divided silicon dioxide, colloidal 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.

A used herein, the term "lubricants" is intended to mean Lubricant can be selected from the group comprising of stearic acid, Polyethylene glycol, Magnesium stearate, Calcium stearate, Zinc stearate, Talc or Silica, Hydrogenated caster oil and Sodium stearyl fumarate.

The lubricant may be present in an amount ranging from 0.1 % to 10 % by weight of the composition. Preferably the lubricant used herein is magnesium stearate in an amount of less than 1.1% and more preferably less than 0.6% of the total weight of the composition. The composition can be stabilized by using pharmaceutically acceptable excipients known to the person skilled in the art.

As used herein, the term "solvent" comprises without limitation water, isopropyl alcohol, dichloromethane, etc and mixtures thereof.

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 other pharmaceutically acceptable excipients.

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 granules with lubricant and optionally with other pharmaceutically acceptable excipients.

5. Optionally compressing the granules from step 4. Process B: 1. Sifting & Mixing of Gliclazide, with diluent and other pharmaceutically acceptable excipients.

2. Addition of solvents to step 1 followed by drying & sizing.

3. Blending of step 2 granules with lubricant and optionally with other pharmaceutically acceptable excipients. 4. Optionally compressing the granules from step 3. Process C:

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 D:

1. Sifting & Mixing of Gliclazide with diluent and optionally other pharmaceutically acceptable excipient.

2. Slugging the blend of step 1. 3. Milling and sifting the slugs from step 2.

4. Blending of step 3 granules with lubricant and optionally other pharmaceutically acceptable excipient.

5. Optionally compressing the content obtained from step 4.

As per instant invention gliclazide may have particle size distribution as below: 1. D₉₀ less than 70 microns preferably less than 60 microns but greater than 20 microns.

2. D₅₀ less than 30 microns preferably less than 20 microns but greater than 7 microns.

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 invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever:

Example 1

Table 2

Manufacturing Procedure: 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 El 5LV. 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: Dissolution profile

The dissolution of the present invention was determined by following method:

Table 3

Instrument Apparatus II, USP RPM 100

Temperature 37.5 °C Dissolution Medium 1. 90OmL, pH 6.2 phosphate buffer

2. 90OmL, pH 6.8 phosphate buffer

3. 90OmL, pH 7.4 phosphate buffer Table 4

As seen in table 2 above, the release profile of gliclazide from 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: Table 5

Thus from the above data, it can be concluded that the relative bioavailability of the two formulations are comparable.

Stability Data: Example 1

Table 6

Impurity A: p-Toluenesulphonamide ND: Not Done Example 2

Table 7

Manufacturing Procedure: Gliclazide and Calcium hydrogen phosphate (anhydrous) were mixed in the presence of hypromellose and again in presence of solution isopropyl alcohol and dichloromethane to obtain wet mass which was passed through 1.00 mm screen to obtain granules. Granules were dried. Magnesium stearate was sifted through 60# and mixed with the granules. These lubricated granules were compressed to tablets using suitable tablet compressing machine. Example 3

The composition was prepared according to the process and formula as described in example- 1 with following changes:

1. Calcium Hydrogen Phosphate (Anhydrous) in place of Calcium Hydrogen Phosphate (Dihydrate).

2. Without using PVP K30.

This composition was also found to be bio-equivalent with formulation of Gliclazide MR Tablets 30 mg currently on the market (Diamicron^® MR). Stability Data: Example 3 Pack: PVC/Alu Blisters Storage Condition: 40°C/75%RH

Table 9

*: p-toluenesulphonamide

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

Claims

1. A stable solid oral controlled release pharmaceutical dosage form of Gliclazide characterized in that dosage form comprises of one or more release controlling , polymer, anhydrous calcium hydrogen phosphate and without saccharide component.

2. A stable solid oral controlled release pharmaceutical dosage form of Gliclazide characterized in that dosage form comprises release controlling polymer and without saccharide component and optionally free from binder.

3. A stable solid oral controlled release pharmaceutical dosage form according to claim 1, wherein the release controlling polymer is cellulose polymer.

4. A stable solid oral controlled release pharmaceutical dosage form according to claim 1 to 3, wherein the release controlling polymer comprise methylcellulose, ethylcellulose, hydroxyethylcellulose, propylcellulose, hydroxypropylcellulose, hydroxypropyl methyl cellulose, carboxymethylcellulose.

5. A stable solid oral controlled release pharmaceutical dosage form according to claim 1, wherein the release controlling polymer is present in an amount 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.

6. A stable solid oral controlled release pharmaceutical dosage form according to claim 3, wherein the cellulose polymer comprises hydroxypropylmethylcellulose.

7. A stable solid oral controlled release pharmaceutical dosage form according to claim 1, wherein the said dosage form further comprises of diluents, anti-adherents, lubricants, surfactants, alkalizing agents, pH modifiers, buffering agents, stabilizers and optionally binders.

8. A process for preparing the stable solid oral controlled release pharmaceutical dosage form according to any previous claims, characterized in that the process steps comprise of following steps:

A) Sifting & Mixing of Gliclazide, with diluent and other pharmaceutically acceptable excipients.

B) Preparation of binder solution in suitable solvent. C) Granulation of step A with step B solution followed by drying & sizing.

D) Blending of step C granules with lubricant and optionally with other pharmaceutically acceptable excipients. >

E) Optionally compressing the granules from step D.

9. A process for preparing the stable solid oral controlled release pharmaceutical dosage form according to any previous claims, characterized in that the process steps comprise of following steps:

A) Sifting & Mixing of Gliclazide, with diluent and other pharmaceutically acceptable excipients. B) Addition of solvents to step-A followed by drying & sizing. '

C) Blending of step-B granules with lubricant and optionally with other pharmaceutically acceptable excipients. \

D) Optionally compressing the granules from step -C.

10. A process for preparing the stable solid oral controlled release pharmaceutical dosage form according to any previous claims, characterized in that the process steps comprise of following steps: A) Sifting & Mixing of Gliclazide, with diluent and release controlling polymer.

B) Lubrication of step A with lubricant.

C) Optionally compressing the content obtained from step B.

11. A stable solid oral controlled release pharmaceutical dosage form of Gliclazide as claimed in claim 1 wherein the said dosage form is free from binder.

12. A stable solid oral controlled release pharmaceutical dosage form of Gliclazide as claimed in claim 1 wherein the said dosage form is additionally substantially free from binder.

V

13. A stable solid oral controlled release pharmaceutical dosage form of Gliclazide characterized in that dosage form comprises of one or more release controlling polymer, anhydrous calcium hydrogen phosphate and without using polyvinyl pyrrolidone and saccharide component.