WO2006123213A1 - Modified release formulations of gliclazide - Google Patents

Modified release formulations of gliclazide Download PDF

Info

Publication number
WO2006123213A1
WO2006123213A1 PCT/IB2006/001241 IB2006001241W WO2006123213A1 WO 2006123213 A1 WO2006123213 A1 WO 2006123213A1 IB 2006001241 W IB2006001241 W IB 2006001241W WO 2006123213 A1 WO2006123213 A1 WO 2006123213A1
Authority
WO
WIPO (PCT)
Prior art keywords
formulation
gliclazide
modified release
binders
cellulose
Prior art date
Application number
PCT/IB2006/001241
Other languages
French (fr)
Inventor
Deepak Murpani
Ashish Madan
Original Assignee
Ranbaxy Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2006123213A1 publication Critical patent/WO2006123213A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Definitions

  • the present invention relates to modified release formulations of gliclazide or salts thereof and processes for their preparation.
  • Modified release formulations have many advantages over standard immediate release pharmaceutical compositions. For example, modified release formulations have the ability to maintain a desired blood level of a medicament over an extended period of time by minimizing the peak to trough variations in plasma concentrations. They also may increase patient compliance by reducing the number of administrations necessary to achieve a desired therapeutic effect.
  • modified release formulations have been reported for soluble drugs; however, moderately to poorly soluble drugs have properties which render them unsuitable for incorporation into modified release formulations. It is often difficult to predict whether a particular modified release formulation will provide the desired release profile for a relatively insoluble drug, and it has generally been found that for such drugs it is necessary to carry out considerable experimentation to obtain modified release formulations having the desired bioavailability when ingested.
  • sulfonylurea class of antidiabetic drugs.
  • Gliclazide is an antidiabetic drag from the sulfonylurea class that has been widely administered orally in the form of tablets.
  • the usual average prescription regimen is two tablets per day in two administrations, but may vary from 1 to 4 tablets per day in several administrations depending upon the severity of the diabetes.
  • Modified release sulfonylurea formulations with improved dissolution properties and extended release profiles are therefore a desirable addition to the medical treatment of diabetes.
  • the prior art discloses the use of acidified and/or alkalized excipient or an inert polar solvent to improve the dissolution profile of the drug or to improve the bioavailability of the drag from immediate/controlled release formulations.
  • U.S. 4,696,815 describes immediate release tablets of sulfonylurea drags based on an acidified and/or alkalized excipient and an inert polar solvent, such as polyethylene glycol.
  • an inert polar solvent such as polyethylene glycol.
  • immediate release formulations are described as improving the dissolution of acidic, amphoteric or basic antidiabetic sulfonylurea compounds.
  • the alkalized excipient is said to improve the dissolution of glipizide, which is an acid compound.
  • U.S. 6,056,977 discloses a sustained release oral dosage form of sulfonylurea or a salt or derivative thereof in a matrix. Further, this patent teaches the use of an alkalizing agent to obtain complete bioavailability of the drug from the matrix dosage form.
  • U.S. 6,733,782 discloses a prolonged release matrix tablet of gliclazide.
  • the patent teaches that a continuous and consistent drug release may be achieved which is insensitive to variations in the pH of the dissolution medium.
  • the patent also teaches the use of a glucose syrup, for example maltodextrin, along with cellulose polymers to achieve a controlled and complete release of gliclazide from the formulation.
  • the prior art teaches the use of specific combinations of glucose syrup and cellulose polymers so as to enable the release of gliclazide in a prolonged and controlled manner.
  • glucose syrup or any other sugar based compound as excipients in the preparation of formulations to be administered for the treatment of diabetes.
  • the use of such excipients may increase the blood sugar levels in diabetic patients.
  • gliclazide may be obtained using one or more binders along with one or more controlled release polymers.
  • These formulations were found to be bioequivalerit with the innovator formulation (Diamicron ® MR, Les Lab., France) which includes glucose syrup. Further, it was surprisingly observed that by varying the proportion of the one or more binders and the particle size of gliclazide, it is possible to obtain formulations with enhanced bioavailability when compared to the innovator formulation. These formulations are cost effective and easy to manufacture on a commercial scale without requiring complex processing steps.
  • the modified release formulation includes gliclazide or a salt thereof, one or more controlled release polymers, one or more binders and optionally one or more pharmaceutically acceptable excipients.
  • Embodiments of the formulation may include one or more of the following features.
  • the gliclazide or salt thereof may have a D 9 Q range between less than about 70 ⁇ m to greater than about 18 ⁇ m or a Dg 0 less than about 18 ⁇ m.
  • the controlled release polymer may be one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof.
  • the one or more controlled release polymers may be present at a concentration of between about 10% and about 40%, based on the weight of the formulation.
  • the one or more binders may be one or more of vinylpyrrolidone, cellulose, carbopol, gum and mixtures thereof.
  • the one or more binders may be present at a concentration of less than about 10%, based on the weight of the formulation or between about 1% and 6.5%, based on the weight of the formulation.
  • the pharmaceutically acceptable excipients may be one or more of diluents, lubricants, glidants and mixtures thereof.
  • a process for the preparation of a modified release formulation includes the steps of: a) mixing gliclazide or a salt thereof with one or more binders and optionally one or more pharmaceutically acceptable excipients to obtain a blend; b) wet granulating the blend of step a) followed by drying to obtain granules; c) mixing the granules of step b) with one or more controlled release polymers to obtain a final blend; and d) compressing the blend of step c) into tablets.
  • Embodiments of the process may include one or more of the following features.
  • the one or more binders may be one or more of vinylpyrrolidone, cellulose, carbopol, gum and mixtures thereof.
  • the one or more binders may be present at a concentration of less than about 10%, based on the weight of the formulation or between about 1% and 6.5%, based on the weight of the formulation.
  • the one or more controlled release polymers may be one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, - A -
  • the one or more controlled release polymers may be present at a concentration of between about 10% and about 40%, based on the weight of the formulation.
  • the gliclazide or salt thereof may have a D 90 range between less than about 70 ⁇ m to greater than about 18 ⁇ m or it may have a D 90 less than about 18 ⁇ m.
  • a method of treating diabetes includes administering a modified release formulation of gliclazide.
  • the formulation includes gliclazide or a salt thereof, one or more controlled release polymers, one or more binders and optionally one or more pharmaceutically acceptable excipients.
  • Embodiments of the method may include one or more of the following features.
  • the one or more binders may be one or more of vinylpyrrolidone, cellulose, carbopol, gum and mixtures thereof.
  • the one or more binders may be present at a concentration of less than about 10%, based on the weight of the formulation or at a concentration of between about 1% and 6.5%, based on the weight of the formulation.
  • the one or more controlled release polymers may be one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof.
  • the one or more controlled release polymers may be present at a concentration of between about 10% and about 40%, based on the weight of the formulation.
  • the gliclazide or salt thereof may have a D 90 range between less than about 70 ⁇ m to greater than about 18 ⁇ m or it may have a D 90 of less than about 18 ⁇ m.
  • the present invention provides for a modified release formulation of gliclazide.
  • the pharmaceutical formulation includes gliclazide or a salt thereof, one or more controlled release polymers, one or more binders and optionally one or more additional pharmaceutically acceptable excipients.
  • the formulations provide a prolonged and substantially complete release of gliclazide or a salt thereof over a specified period of time.
  • the modified release formulation is bioequivalent to the innovator's formulation. Surprisingly, this could be achieved using one or more binders and one or more controlled release polymers.
  • the proportion of binder may be less than about 6% (by weight), between about 0.5% to about 6 %, or between about 1% to about 4%.
  • the formulation includes gliclazide wherein the particle size distribution has a D 90 range from less than about 70 ⁇ m to greater than about 18 ⁇ m, from less than about 61 ⁇ m to greater than about 18 ⁇ m, or is about 30 + 12 ⁇ m.
  • the modified release formulations provide superior bioavailability than innovator formulation.
  • the proportion of the one or more binders may be greater than about 6% (by weight), preferably from about 6.5% to about 10%, more preferably from about 7% to about 9%.
  • the formulation includes gliclazide having a particle size distribution in which the D 90 is less than about 18 ⁇ m.
  • the modified release formulation as described herein may be in the form of a tablet, capsule or granules.
  • the modified release formulation is a tablet.
  • novator formulation refers to tablet formulation, commercially available in France under the trade name Diamicron ® MR manufactured by Les Lab., France.
  • the amount of gliclazide in the formulation may range from about 30 mg to about 120 mg, preferably from about 30 to about 60 mg.
  • the particle size of gliclazide may be measured by any methods known in the art, for example, using a Malvern Mastersizer. .
  • the one or more binders may include one or more of vinylpyrrolidone, cellulose, carbopol, gums and mixtures thereof.
  • the binder may be polyvinylpyrrolidone.
  • the one or more controlled release polymers may include one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof.
  • the controlled release polymer may be hydroxypropyl methylcellulose or a mixture of hydroxypropyl methylcelluloses of different viscosities. Hydroxypropyl methylcellulose with a viscosity of 100 cPs and hydroxypropyl methylcellulose with a viscosity of 4000 cPs may be used.
  • the amount of controlled release polymer may range from about 10% to about 40% by weight.
  • the modified release formulation may optionally contain one or more pharmaceutically acceptable excipients.
  • the one or more pharmaceutically acceptable excipients may include one or more of diluents, lubricants, glidants and mixtures thereof.
  • the diluents may include one or more of dicalcium hydrogen phosphate dihydrate, microcrystalline cellulose, lactose, starch and mixtures thereof.
  • the lubricants and glidants may include one or more of talc, colloidal silicon dioxide, magnesium stearate and mixtures thereof.
  • the formulations may be prepared by a wet granulation method, dry granulation/slugging method or a direct compression method.
  • step 3 The blend of step 2 was transferred into a granulator and mixed to obtain a homogenous powder mix.
  • step 3 The powder mix of step 3 was granulated using purified water.
  • step 4 The granules of step 4 were dried in a dryer for suitable time and then screened.
  • Hydroxypropyl methylcellulose Kl 00LV and hydroxypropyl methylcellulose K4M CR were sifted through a suitable sieve to obtain a blend.
  • step 7 Granules of step 5 were mixed with the blend of step 6.
  • Magnesium Stearate and colloidal silicon dioxide were sifted through a suitable sieve, separately, and mixed with the blend of step 7 to obtain a final blend.
  • Test (A) Gliclazide 30 mg MR tablets
  • Treatments* A: Single oral dose of Test product (Fasting) B: Single oral dose of Test product (Fasting) C: Single oral dose of Reference product (Fasting)
  • step 3 The blend of step 2 was transferred into a granulator and mixed to obtain a homogenous powder mix. 4. The powder mix of step 3 was granulated using purified water.
  • step 4 The granules of step 4 were dried in a dryer for suitable time and then screened.
  • Hydroxypropyl methylcellulose Kl 00LV and hydroxypropyl methylcellulose K4M CR were sifted through a suitable sieve to obtain a blend.
  • step 5 The granules of step 5 were mixed with the blend of step 6. 8.
  • Magnesium stearate and colloidal silicon dioxide were sifted through a suitable sieve, separately, and mixed with the blend of step 7 to obtain a final blend.
  • Treatments* T: Single oral dose of Test product (Fasting)
  • step 3 The blend of step 2 was transferred into a granulator and mixed to obtain a homogenous powder mix.
  • step 3 The powder mix of step 3 was granulated using purified water.
  • step 4 The granules of step 4 were dried in a dryer for suitable time and then screened. 6. Hydroxypropyl methylcellulose KlOOLV and hydroxypropyl methylcellulose K4M
  • step 7 The granules of step 5 were mixed with the blend of step 6.
  • step 2 Gliclazide, polyvinylpyrrolidone and dibasic calcium hydrogen phosphate dihydrate were sifted through a suitable mesh to obtain a blend. 3. The blend of step 2 was transferred into a granulator and mixed to obtain a homogenous powder mix.
  • step 3 The powder mix of step 3 was granulated using purified water.
  • step 4 The granules of step 4 were dried in a dryer for suitable time and then screened.
  • Hydroxypropyl methylcellulose Kl 00LV, hydroxypropyl methylcellulose K4M CR and colloidal silicon dioxide were sifted through a suitable sieve to obtain a blend.
  • step 7 The granules of step 5 were mixed with the blend of step 6.
  • step 3 The blend of step 2 was transferred in to a granulator and mixed to obtain a homogenous powder mix.
  • step 4 The powder mix of step 3 was granulated using purified water. 5. The granules of step 4 were dried in a dryer for suitable time and then screened.
  • step 6 Hydroxypropyl methylcellulose Kl 00LV, hydroxypropyl methylcellulose K4M CR and colloidal silicon dioxide were sifted through a suitable sieve to obtain a blend. 7. Granules of step 5 were mixed with the blend of step 6.
  • Magnesium Stearate was sifted through a suitable sieve and mixed with the blend of step 7 to obtain a final blend.
  • Test (A) Gliclazide 30 mg MR tablets
  • Gliclazide as per Example 7 is bioequivalent to the innovator.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to modified release formulations of gliclazide or salt thereof and processes for their preparation.

Description

MODIFIED RELEASE FORMULATIONS OF GLICLAZIDE
Field of the Invention
The present invention relates to modified release formulations of gliclazide or salts thereof and processes for their preparation. Background of the Invention
Modified release formulations have many advantages over standard immediate release pharmaceutical compositions. For example, modified release formulations have the ability to maintain a desired blood level of a medicament over an extended period of time by minimizing the peak to trough variations in plasma concentrations. They also may increase patient compliance by reducing the number of administrations necessary to achieve a desired therapeutic effect. Several modified release formulations have been reported for soluble drugs; however, moderately to poorly soluble drugs have properties which render them unsuitable for incorporation into modified release formulations. It is often difficult to predict whether a particular modified release formulation will provide the desired release profile for a relatively insoluble drug, and it has generally been found that for such drugs it is necessary to carry out considerable experimentation to obtain modified release formulations having the desired bioavailability when ingested. An example of a relatively insoluble class of drugs, which is difficult to formulate into modified release formulations, is the sulfonylurea class of antidiabetic drugs. Gliclazide is an antidiabetic drag from the sulfonylurea class that has been widely administered orally in the form of tablets. The usual average prescription regimen is two tablets per day in two administrations, but may vary from 1 to 4 tablets per day in several administrations depending upon the severity of the diabetes. Modified release sulfonylurea formulations with improved dissolution properties and extended release profiles are therefore a desirable addition to the medical treatment of diabetes.
The prior art discloses the use of acidified and/or alkalized excipient or an inert polar solvent to improve the dissolution profile of the drug or to improve the bioavailability of the drag from immediate/controlled release formulations. For example, U.S. 4,696,815 describes immediate release tablets of sulfonylurea drags based on an acidified and/or alkalized excipient and an inert polar solvent, such as polyethylene glycol. The pH _ . _
- 2 - regulated, immediate release formulations are described as improving the dissolution of acidic, amphoteric or basic antidiabetic sulfonylurea compounds. For example, the alkalized excipient is said to improve the dissolution of glipizide, which is an acid compound. U.S. 6,056,977 discloses a sustained release oral dosage form of sulfonylurea or a salt or derivative thereof in a matrix. Further, this patent teaches the use of an alkalizing agent to obtain complete bioavailability of the drug from the matrix dosage form.
U.S. 6,733,782 discloses a prolonged release matrix tablet of gliclazide. The patent teaches that a continuous and consistent drug release may be achieved which is insensitive to variations in the pH of the dissolution medium. The patent also teaches the use of a glucose syrup, for example maltodextrin, along with cellulose polymers to achieve a controlled and complete release of gliclazide from the formulation.
The prior art teaches the use of specific combinations of glucose syrup and cellulose polymers so as to enable the release of gliclazide in a prolonged and controlled manner. Generally, it is undesirable to use glucose syrup or any other sugar based compound as excipients in the preparation of formulations to be administered for the treatment of diabetes. The use of such excipients may increase the blood sugar levels in diabetic patients.
Surprisingly, we have found that the desired controlled, and substantially complete, release of gliclazide may be obtained using one or more binders along with one or more controlled release polymers. These formulations were found to be bioequivalerit with the innovator formulation (Diamicron® MR, Les Lab., France) which includes glucose syrup. Further, it was surprisingly observed that by varying the proportion of the one or more binders and the particle size of gliclazide, it is possible to obtain formulations with enhanced bioavailability when compared to the innovator formulation. These formulations are cost effective and easy to manufacture on a commercial scale without requiring complex processing steps.
Summary of the Invention
In one general aspect there is provided a modified release formulation. The modified release formulation includes gliclazide or a salt thereof, one or more controlled release polymers, one or more binders and optionally one or more pharmaceutically acceptable excipients.
Embodiments of the formulation may include one or more of the following features. For example, the gliclazide or salt thereof may have a D9Q range between less than about 70 μm to greater than about 18 μm or a Dg0 less than about 18 μm.
The controlled release polymer may be one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof. The one or more controlled release polymers may be present at a concentration of between about 10% and about 40%, based on the weight of the formulation.
The one or more binders may be one or more of vinylpyrrolidone, cellulose, carbopol, gum and mixtures thereof. The one or more binders may be present at a concentration of less than about 10%, based on the weight of the formulation or between about 1% and 6.5%, based on the weight of the formulation. The pharmaceutically acceptable excipients may be one or more of diluents, lubricants, glidants and mixtures thereof.
In another general aspect there is provided a process for the preparation of a modified release formulation. The process includes the steps of: a) mixing gliclazide or a salt thereof with one or more binders and optionally one or more pharmaceutically acceptable excipients to obtain a blend; b) wet granulating the blend of step a) followed by drying to obtain granules; c) mixing the granules of step b) with one or more controlled release polymers to obtain a final blend; and d) compressing the blend of step c) into tablets.
Embodiments of the process may include one or more of the following features. For example, the one or more binders may be one or more of vinylpyrrolidone, cellulose, carbopol, gum and mixtures thereof. The one or more binders may be present at a concentration of less than about 10%, based on the weight of the formulation or between about 1% and 6.5%, based on the weight of the formulation.
The one or more controlled release polymers may be one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, - A -
carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof. The one or more controlled release polymers may be present at a concentration of between about 10% and about 40%, based on the weight of the formulation.
The gliclazide or salt thereof may have a D90 range between less than about 70 μm to greater than about 18 μm or it may have a D90 less than about 18 μm.
In yet another general aspect there is provided a method of treating diabetes. The method includes administering a modified release formulation of gliclazide. The formulation includes gliclazide or a salt thereof, one or more controlled release polymers, one or more binders and optionally one or more pharmaceutically acceptable excipients. Embodiments of the method may include one or more of the following features.
For example, the one or more binders may be one or more of vinylpyrrolidone, cellulose, carbopol, gum and mixtures thereof. The one or more binders may be present at a concentration of less than about 10%, based on the weight of the formulation or at a concentration of between about 1% and 6.5%, based on the weight of the formulation. The one or more controlled release polymers may be one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof. The one or more controlled release polymers may be present at a concentration of between about 10% and about 40%, based on the weight of the formulation. The gliclazide or salt thereof may have a D90 range between less than about 70 μm to greater than about 18 μm or it may have a D90 of less than about 18 μm.
The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims. Detailed Description of the Invention
The present invention provides for a modified release formulation of gliclazide. The pharmaceutical formulation includes gliclazide or a salt thereof, one or more controlled release polymers, one or more binders and optionally one or more additional pharmaceutically acceptable excipients. The formulations provide a prolonged and substantially complete release of gliclazide or a salt thereof over a specified period of time.
According to one embodiment, the modified release formulation is bioequivalent to the innovator's formulation. Surprisingly, this could be achieved using one or more binders and one or more controlled release polymers. The proportion of binder may be less than about 6% (by weight), between about 0.5% to about 6 %, or between about 1% to about 4%. The formulation includes gliclazide wherein the particle size distribution has a D90 range from less than about 70 μm to greater than about 18 μm, from less than about 61 μm to greater than about 18 μm, or is about 30 + 12 μm. According to another embodiment, the modified release formulations provide superior bioavailability than innovator formulation. Surprisingly, it was observed that by varying the proportion of the one or more binders and by decreasing the particle size of gliclazide, superior bioavailability than innovator formulation could be achieved. The proportion of the one or more binders may be greater than about 6% (by weight), preferably from about 6.5% to about 10%, more preferably from about 7% to about 9%. The formulation includes gliclazide having a particle size distribution in which the D90 is less than about 18 μm.
The term "about" is used herein to mean approximately, in the region of, roughly, or around. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a standard deviation of + 2.
The modified release formulation as described herein may be in the form of a tablet, capsule or granules. Preferably, the modified release formulation is a tablet.
The term "innovator formulation" as used herein refers to tablet formulation, commercially available in France under the trade name Diamicron® MR manufactured by Les Lab., France.
The amount of gliclazide in the formulation may range from about 30 mg to about 120 mg, preferably from about 30 to about 60 mg. The particle size of gliclazide may be measured by any methods known in the art, for example, using a Malvern Mastersizer. .
- 6 -
The one or more binders may include one or more of vinylpyrrolidone, cellulose, carbopol, gums and mixtures thereof. For example, the binder may be polyvinylpyrrolidone.
The one or more controlled release polymers may include one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof. For example the controlled release polymer may be hydroxypropyl methylcellulose or a mixture of hydroxypropyl methylcelluloses of different viscosities. Hydroxypropyl methylcellulose with a viscosity of 100 cPs and hydroxypropyl methylcellulose with a viscosity of 4000 cPs may be used. The amount of controlled release polymer may range from about 10% to about 40% by weight.
The modified release formulation may optionally contain one or more pharmaceutically acceptable excipients. The one or more pharmaceutically acceptable excipients may include one or more of diluents, lubricants, glidants and mixtures thereof. The diluents may include one or more of dicalcium hydrogen phosphate dihydrate, microcrystalline cellulose, lactose, starch and mixtures thereof. The lubricants and glidants may include one or more of talc, colloidal silicon dioxide, magnesium stearate and mixtures thereof.
The formulations may be prepared by a wet granulation method, dry granulation/slugging method or a direct compression method.
The following non-limiting examples further illustrate the modified release formulations of gliclazide or salt thereof and process of making such formulations.
Examples 1-2
Figure imgf000008_0001
Process of preparation:
1. All ingredients were accurately weighed.
2. Gliclazide, polyvinylpyrrolidone and dibasic calcium hydrogen phosphate dihydrate were sifted through a suitable mesh to obtain a blend.
3. The blend of step 2 was transferred into a granulator and mixed to obtain a homogenous powder mix.
4. The powder mix of step 3 was granulated using purified water.
5. The granules of step 4 were dried in a dryer for suitable time and then screened.
6. Hydroxypropyl methylcellulose Kl 00LV and hydroxypropyl methylcellulose K4M CR were sifted through a suitable sieve to obtain a blend.
7. Granules of step 5 were mixed with the blend of step 6.
8. Magnesium Stearate and colloidal silicon dioxide were sifted through a suitable sieve, separately, and mixed with the blend of step 7 to obtain a final blend.
9. Tablets were compressed using the final blend of step 8. _
- 8 -
The above modified release formulations of gliclazide show the following in vitro dissolution profile in 900 ml pH 7.4 phosphate buffer, at 100 rpm using USP type I method:
Table 1
Figure imgf000009_0001
Table 2 Pharmacokinetic study design
Test (A) : Gliclazide 30 mg MR tablets
Manufactured by Ranbaxy Research Lab. Ltd., India Example No. 1
Test (B): Gliclazide 30 mg MR tablets
Manufactured by Ranbaxy Research Lab. Ltd., India Example No. 2
Reference (C): Diamicron® 30 mg MR tablets
Manufactured by Les Lab., France & Distributed by Servier Laboratories Ltd. UK
Treatments*: A: Single oral dose of Test product (Fasting) B: Single oral dose of Test product (Fasting) C: Single oral dose of Reference product (Fasting)
*Number of subjects (Human volunteers) = 12 in each case. Table 3
Summary Statistics of Gliclazide Bioequivalence Studies*
Figure imgf000010_0001
Product/Statistics Cmax (ng/mL) Tmax (h) (ng.h/mL) (ng.h/mL)
Product A
Mean 2067.432 61463.852 66447.012 10.125
CV (%) 27.9 38.1 35.2 49.1
Product B
Mean 2047.464 58011.037 64985.246 7.917
CV (%) 33.0 22.3 27.1 36.7
Product C
Mean 1938.953 56135.382 61645.336 8.000
CV (%) 21.4 25.9 28.6 41.3
Ratio of least squares mean
A/C (%) 104.62 106.39 109.17 -
B/C (%) 102.27 103.88 105.54 -
90% Confidence intervals (A/C)
Lower limit 92.84 95.82 97.69 -
Upper limit 117.91 118.13 121.99 -
90% Confidence intervals (B/C)
Lower limit 90.75 93.56 94.82 -
Upper limit 115.26 115. 35 117.47 -
* Number of subjects (Human volunteers) = 12 in each case.
Example 3
Figure imgf000011_0001
Process of preparation: 1. All ingredients were accurately weighed.
2. Gliclazide, polyvinylpyrrolidone and dibasic calcium hydrogen phosphate dihydrate were sifted through a suitable mesh to obtain a blend.
3. The blend of step 2 was transferred into a granulator and mixed to obtain a homogenous powder mix. 4. The powder mix of step 3 was granulated using purified water.
5. The granules of step 4 were dried in a dryer for suitable time and then screened.
6. Hydroxypropyl methylcellulose Kl 00LV and hydroxypropyl methylcellulose K4M CR were sifted through a suitable sieve to obtain a blend.
7. The granules of step 5 were mixed with the blend of step 6. 8. Magnesium stearate and colloidal silicon dioxide were sifted through a suitable sieve, separately, and mixed with the blend of step 7 to obtain a final blend.
9. Tablets were compressed using the final blend of step 8. The above modified release formulation of gliclazide shows the following in vitro dissolution profile in 900 ml pH 7.4 phosphate buffer, at 100 rpm using USP type I method:
Table 4
Figure imgf000012_0001
Pharmacokinetic study design:
Table 5
Products evaluated
Test (T): Gliclazide 30 mg MR tablets
Manufactured by Ranbaxy Research Lab. Ltd., India Example No. 3
Reference (R): Diamicron® 30 mg MR tablets
Manufactured by Les Lab., France & Distributed by Servier i Laboratories Ltd. UK
Treatments*: T: Single oral dose of Test product (Fasting)
R: Single oral dose of Reference product (Fasting)
* Number of subjects (Human volunteers) = 12 in each case. Table 6
Summary Statistics of Gliclazide Bioequivalence Studies*
Figure imgf000013_0001
Product/Statistics 5 Cmax (ng/niL) Tmax (h) (ng.h/mL) (ng.h/mL)
Product T
Mean 2133.639 51299.820 65842.034 7.417
CV (%) 27.6 42.9 58.8 36.2
Product R
Mean 1821.219 42549.526 55185.114 7.125
CV (%) 28.8 50.4 63.4 34.3
Ratio of least squares mean
T/R (%) 117.50 124.88 122.61 -
90% Confidence intervals (T/R)
Lower limit 105.41 104.76 96.94 -
Upper limit 130.98 148.85 155.08 -
* Number of subjects (Human volunteers) = 12 in each case.
Figure imgf000013_0002
Process of preparation:
1. All ingredients were accurately weighed.
2. Gliclazide, polyvinylpyrrolidone and dibasic calcium hydrogen phosphate dihydrate were sifted through a suitable mesh to obtain a blend. - .
- 13 -
3. The blend of step 2 was transferred into a granulator and mixed to obtain a homogenous powder mix.
4. The powder mix of step 3 was granulated using purified water.
5. The granules of step 4 were dried in a dryer for suitable time and then screened. 6. Hydroxypropyl methylcellulose KlOOLV and hydroxypropyl methylcellulose K4M
CR were sifted through a suitable sieve to obtain a blend.
7. The granules of step 5 were mixed with the blend of step 6.
8. Magnesium stearate and colloidal silicon dioxide were sifted through a suitable sieve, separately, and mixed with the blend of step 7 to obtain a final blend. 9. Tablets were compressed using the final blend of step 8.
An alternative process of preparation of the modified release tablets is described below:
1. All ingredients were accurately weighed.
2. Gliclazide, polyvinylpyrrolidone and dibasic calcium hydrogen phosphate dihydrate were sifted through a suitable mesh to obtain a blend. 3. The blend of step 2 was transferred into a granulator and mixed to obtain a homogenous powder mix.
4. The powder mix of step 3 was granulated using purified water.
5. The granules of step 4 were dried in a dryer for suitable time and then screened.
6. Hydroxypropyl methylcellulose Kl 00LV, hydroxypropyl methylcellulose K4M CR and colloidal silicon dioxide were sifted through a suitable sieve to obtain a blend.
7. The granules of step 5 were mixed with the blend of step 6.
8. Magnesium stearate was sifted through a suitable sieve and mixed with the blend of step 7 to obtain a final blend. 9. Tablets were compressed using the final blend of step 8. Example 7
Figure imgf000015_0001
Process of preparation:
1. AU ingredients were accurately weighed. 2. Gliclazide, polyvinylpyrrolidone and dibasic calcium hydrogen phosphate dihydrate were sifted through a suitable mesh to obtain a blend.
3. The blend of step 2 was transferred in to a granulator and mixed to obtain a homogenous powder mix.
4. The powder mix of step 3 was granulated using purified water. 5. The granules of step 4 were dried in a dryer for suitable time and then screened.
6. Hydroxypropyl methylcellulose Kl 00LV, hydroxypropyl methylcellulose K4M CR and colloidal silicon dioxide were sifted through a suitable sieve to obtain a blend. 7. Granules of step 5 were mixed with the blend of step 6.
8. Magnesium Stearate was sifted through a suitable sieve and mixed with the blend of step 7 to obtain a final blend.
9. Tablets were compressed using the final blend of step 8. Table 7 Pharmacokinetic study design
Products evaluated:
Test (A) : Gliclazide 30 mg MR tablets
Manufactured by Ranbaxy Research Lab. Ltd., India
Example No. 7 Reference (B): Diamicron® LM 30 mg MR tablets
Manufactured by Les Laboratoires Servier,
Distributed by Servier, Portugal
Studies: 1. Single oral dose of Test & Reference (Fasting)
2. Single oral dose of Test & Reference (Fed)
3. Multiple oral dose of Test & Reference (Fed)
Table 8
Study 1: Single oral dose of Test & Reference (Fasting)
Summary Statistics of Gliclazide Bioequivalence Studies
Figure imgf000016_0001
Product/Statistics Cmax (μg/mL) Tmax (h) (μg.h/mL) (μg.h/mL)
Product A
Mean 1.3988 35.3416 37.7058 8.61
CV (%) 19.79 32.69 35.56 30.84
Product B
Mean 1.2979 34.3007 36.5858 9.45
CV (%) 22.98 32.83 35.77 24.27 Table 9
Figure imgf000017_0002
Table 10 Study 2: Single oral dose of Test & Reference (Fed)
Summary Statistics of Gliclazide Bioequivalence Studies 5
Figure imgf000017_0001
Product/Statistics Cmax(μg/mL) Tmax (h) (μg.h/mL) (μg.h/mL)
Product A
Mean 1.8480 44.4950 47.6903 6.05
CV (%) 17.31 35.80 39.08 23.70
Product B
Mean 1.8074 45.3233 48.8308 7.53
CV (%) 16.10 37.95 41.61 18.08
Table 11
Figure imgf000017_0003
Table 12 Study 2: Multiple oral dose of Test & Reference (Fed)
Summary Statistics of Gliclazide Bioequivalence Studies
Figure imgf000018_0001
Product/Statistic Tmax (h)
(μg/mL) (μg/mL) (μg.h/mL) Product A
Mean 3.5579 1.8585 44.6048 5.78 CV (%) 34.80 39.37 39.37 21.65 Product B
Mean 3.5473 1.8711 44.9052 5.72 CV (%) 38.08 41.73 41.73 21.86
Table 13
Figure imgf000018_0002
As evident from the above pharmacokinetic data, modified release formulation of
Gliclazide as per Example 7 is bioequivalent to the innovator.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.

Claims

We claim: 1. A modified release formulation comprising gliclazide or a salt thereof, one or more controlled release polymers, one or more binders and optionally one or more pharmaceutically acceptable excipients.
2. The modified release formulation of claim 1, wherein the gliclazide or salt thereof has a D90 range between less than about 70 μm to greater than about 18 μm.
3. The modified release formulation of claim 2, wherein the gliclazide or salt thereof has a D90 less than about 18 μm.
4. The modified release formulation of claim 1, wherein the controlled release polymer comprises one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof.
5. The modified release formulation of claim 5, wherein the one or more controlled release polymers comprise between about 10% and about 40%, based on the weight of the formulation.
6. The modified release formulation of claims 1, wherein the one or more binders comprise one or more of vinylpyrrolidone, cellulose, carbopol, gum and mixtures thereof.
7. The modified release formulation of claim 6, wherein the one or more binders comprise less than about 10%, based on the weight of the formulation.
8. The modified release formulation of claim 7, wherein the one or more binders ' comprise between about 1% and 6.5%, based on the weight of the formulation.
9. The modified release formulation of claim 1 , wherein the pharmaceutically acceptable excipients comprise one or more of diluents, lubricants, glidants and mixtures thereof.
10. A process for the preparation of a modified release formulation, the process comprising the steps of: a) mixing gliclazide or salt thereof with one or more binders and optionally one or more pharmaceutically acceptable excipients to obtain a blend; b) wet granulating the blend of step a) followed by drying to obtain granules; c) mixing the granules of step b) with one or more controlled release polymers to obtain a final blend; and d) compressing the blend of step c) into tablets.
11. The process of claim 10, wherein the one or more binders comprise one or more of vinylpyrrolidone, cellulose, carbopol, gum and mixtures thereof.
12. The process of claim 11 , wherein the one or more binders comprise less than about 10%, based on the weight of the formulation.
13. The process of claim 12, wherein the one or more binders comprise between about 1 % and 6.5%, based on the weight of the formulation.
14. The process of claim 10, wherein the one or more controlled release polymers comprise one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof.
15. The process of claim 14, wherein the one or more controlled release polymers comprise between about 10% and about 40%, based on the weight of the formulation.
16. The process of claim 15, wherein the gliclazide or salt thereof has a D90 range between less than about 70 μm to greater than about 18 μm.
17. The process of claim 16, wherein the gliclazide or salt thereof has a D90 less than about 18 μm.
18. A method of treating diabetes in a patient in need thereof, the method comprising administering a modified release formulation of gliclazide, the formulation comprising gliclazide or a salt thereof, one or more controlled release polymers, one or more binders and optionally one or more pharmaceutically acceptable excipients.
19. The method of claim 18, wherein the one or more binders comprise one or more of vinylpyrrolidone, cellulose, carbopol, gum and mixtures thereof.
20. The method of claim 18, wherein the one or more binders comprise less than about 10%, based on the weight of the formulation.
21. The method of claim 20, wherein the one or more binders comprise between about 1% and about 6.5%, based on the weight of the formulation.
22. The method of claim 18, wherein the one or more controlled release polymers comprise one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof.
23. The method of claim 22, wherein the one or more controlled release polymers comprise between about 10% and about 40%, based on the weight of the formulation.
24. The method of claim 18, wherein the gliclazide or salt thereof has a D90 range between less than about 70 μm to greater than about 18 μm.
25. The method of claim 24, wherein the gliclazide or salt thereof has a D90 less than about 18 μm.
PCT/IB2006/001241 2005-05-18 2006-05-11 Modified release formulations of gliclazide WO2006123213A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1277DE2005 2005-05-18
IN1277/DEL/2005 2005-05-18

Publications (1)

Publication Number Publication Date
WO2006123213A1 true WO2006123213A1 (en) 2006-11-23

Family

ID=36764325

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2006/001241 WO2006123213A1 (en) 2005-05-18 2006-05-11 Modified release formulations of gliclazide

Country Status (1)

Country Link
WO (1) WO2006123213A1 (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TR200704897A1 (en) * 2007-07-13 2009-02-23 Sanovel �La� Sanay� Ve T�Caret Anon�M ��Rket� Glyclazide formulations providing extended release @
WO2009004654A3 (en) * 2007-07-02 2009-02-26 Actavis Group Ptc Ehf Modified release dosage form of sulfonylurea compound
WO2009082359A1 (en) * 2007-12-26 2009-07-02 Ali Raif Ilac Sanayi Ve Ticaret A.S. Extended release gliclazide tablet
WO2009098195A1 (en) * 2008-02-05 2009-08-13 Valpharma S.A. Oral pharmaceutical formulations containing gliclazide
EP2181705A1 (en) 2008-10-31 2010-05-05 Disphar International B.V. Sustained-release formulation of gliclazide
EP2514413A1 (en) 2011-04-22 2012-10-24 Sanovel Ilaç Sanayi Ve Ticaret Anonim Sirketi Controlled-Release Gliclazide Formulations
ITFI20130184A1 (en) * 2013-08-01 2015-02-02 Valpharma Internat S P A PHARMACEUTICAL FORMULATION OF GLYCLAZIDE WITH MODIFIED RELEASE, ADMINISTRABLE BY ORAL ROUTE, AND ITS PRODUCTION METHOD.

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2177318C1 (en) * 2000-12-21 2001-12-27 Открытое акционерное общество "Химико-фармацевтический комбинат "Акрихин" Pharmaceutical composition with antidiabetic effect and method of its preparing
US6475521B1 (en) * 1998-03-19 2002-11-05 Bristol-Myers Squibb Co. Biphasic controlled release delivery system for high solubility pharmaceuticals and method
US6524618B1 (en) * 2001-06-12 2003-02-25 Vijai Kumar Directly compressible extended-release matrix formulation for metformin hydrochloride
WO2005009412A1 (en) * 2003-07-24 2005-02-03 Wockhardt Limited Oral compositions for treatment of diseases
WO2005107717A2 (en) * 2004-05-11 2005-11-17 Ranbaxy Laboratories Limited Oral dosage form for the extended release of biguanide and sulfonylurea
RU2004118448A (en) * 2004-06-21 2006-01-10 Открытое Акционерное общество "Химико-фармацевтический комбинат "АКРИХИН" (ОАО "АКРИХИН") (RU) PHARMACEUTICAL COMPOSITION WITH PROLONGED GLYCLAZIDE RELEASE
WO2006061697A1 (en) * 2004-12-06 2006-06-15 Themis Laboratories Private Limited Sulfonylurea compositions and a process for its preparation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6475521B1 (en) * 1998-03-19 2002-11-05 Bristol-Myers Squibb Co. Biphasic controlled release delivery system for high solubility pharmaceuticals and method
RU2177318C1 (en) * 2000-12-21 2001-12-27 Открытое акционерное общество "Химико-фармацевтический комбинат "Акрихин" Pharmaceutical composition with antidiabetic effect and method of its preparing
US6524618B1 (en) * 2001-06-12 2003-02-25 Vijai Kumar Directly compressible extended-release matrix formulation for metformin hydrochloride
WO2005009412A1 (en) * 2003-07-24 2005-02-03 Wockhardt Limited Oral compositions for treatment of diseases
WO2005107717A2 (en) * 2004-05-11 2005-11-17 Ranbaxy Laboratories Limited Oral dosage form for the extended release of biguanide and sulfonylurea
RU2004118448A (en) * 2004-06-21 2006-01-10 Открытое Акционерное общество "Химико-фармацевтический комбинат "АКРИХИН" (ОАО "АКРИХИН") (RU) PHARMACEUTICAL COMPOSITION WITH PROLONGED GLYCLAZIDE RELEASE
WO2006061697A1 (en) * 2004-12-06 2006-06-15 Themis Laboratories Private Limited Sulfonylurea compositions and a process for its preparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE EPODOC EUROPEAN PATENT OFFICE, THE HAGUE, NL; XP002398027 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009004654A3 (en) * 2007-07-02 2009-02-26 Actavis Group Ptc Ehf Modified release dosage form of sulfonylurea compound
TR200704897A1 (en) * 2007-07-13 2009-02-23 Sanovel �La� Sanay� Ve T�Caret Anon�M ��Rket� Glyclazide formulations providing extended release @
EP2087884A2 (en) 2007-07-13 2009-08-12 Sanovel Ilac Sanayi ve Ticaret A.S. Extended Release Gliclazide Formulations
EP2090299A2 (en) 2007-07-13 2009-08-19 Sanovel Ilaç Sanayi Ve Ticaret Anonim Sirketi Extended Release Gliclazide Formulations
EP2090299A3 (en) * 2007-07-13 2010-11-24 Sanovel Ilaç Sanayi Ve Ticaret Anonim Sirketi Extended Release Gliclazide Formulations
WO2009082359A1 (en) * 2007-12-26 2009-07-02 Ali Raif Ilac Sanayi Ve Ticaret A.S. Extended release gliclazide tablet
WO2009098195A1 (en) * 2008-02-05 2009-08-13 Valpharma S.A. Oral pharmaceutical formulations containing gliclazide
EP2181705A1 (en) 2008-10-31 2010-05-05 Disphar International B.V. Sustained-release formulation of gliclazide
EP2514413A1 (en) 2011-04-22 2012-10-24 Sanovel Ilaç Sanayi Ve Ticaret Anonim Sirketi Controlled-Release Gliclazide Formulations
ITFI20130184A1 (en) * 2013-08-01 2015-02-02 Valpharma Internat S P A PHARMACEUTICAL FORMULATION OF GLYCLAZIDE WITH MODIFIED RELEASE, ADMINISTRABLE BY ORAL ROUTE, AND ITS PRODUCTION METHOD.
WO2015014987A1 (en) 2013-08-01 2015-02-05 Valpharma International S.P.A. A modified-release oral pharmaceutical formulation containing gliclazide

Similar Documents

Publication Publication Date Title
EP0747050B2 (en) Pharmaceutical compositions containing irbesartan
AU2003229705C1 (en) High drug load tablet
CN106943355B (en) Pharmaceutical composition
EP2448561B1 (en) Solid pharmaceutical fixed dose compositions comprising irbesartan and amlodipine, their preparation and their therapeutic application
US20090124702A1 (en) Pharmaceutical Compositions of Metformin
CA2740146A1 (en) Immediate release dosage forms of sodium oxybate
MX2007001706A (en) Extended release tablet formulation containing pramipexole or a pharmaceutically acceptable salt thereof, method for manufacturing the same and use thereof.
EP3313187B1 (en) Sustained release formulation and tablets prepared therefrom
US20060240101A1 (en) Orally disintegrating pharmaceutical tablet formulations of olanzapine
WO2006123213A1 (en) Modified release formulations of gliclazide
WO2006103551A1 (en) Controlled release formulations of oxycodone
US20030104059A1 (en) Controlled release tablets of metformin
AU2014295098B2 (en) Anti-tuberculosis stable pharmaceutical composition in a form of a coated tablet comprising granules of isoniazid and granules of rifapentine and its process of preparation
CN109125270B (en) Solid preparation and preparation method thereof
RU2613192C1 (en) Tablets of clozapine with sustained release
EP2696857A1 (en) Pharmaceutical composition comprising bosentan
WO2003082261A1 (en) Extended release venlafaxine formulations
US20090149543A1 (en) Solid pharmaceutical compositions comprising lumiracoxib
CA2481377A1 (en) Antihistamine-decongestant pharmaceutical compositions
KR20160141045A (en) Pharmaceutical composition containing of Bosentan
HU231592B1 (en) Pharmaceutical composition comprising favipiravir, production and use thereof
HK1169309B (en) Solid pharmaceutical fixed dose compositions comprising irbesartan and amlodipine, their preparation and their therapeutic application
WO2016042570A1 (en) Extended release formulation of acetaminophen
KR20150057263A (en) A sustained release formulation including levetiracetam or pharmaceutically acceptable salt thereof, and Method preparing the same

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

NENP Non-entry into the national phase

Ref country code: RU

WWW Wipo information: withdrawn in national office

Country of ref document: RU

122 Ep: pct application non-entry in european phase

Ref document number: 06744692

Country of ref document: EP

Kind code of ref document: A1