DESC:TECHNICAL FIELD OF THE INVENTION
The invention relates to modified release pharmaceutical composition comprising glipizide or pharmaceutically acceptable salt thereof and suitable pharmaceutically acceptable excipients. By judicious selection of pharmaceutical acceptable excipients along with one or more osmogent, it is possible to develop composition to achieve desired release profile of glipizide or pharmaceutically acceptable salt thereof. The invention also provides process for preparing said composition and further, the said composition is useful for the treatment of diabetes mellitus.

BACKGROUND OF THE INVENTION
Diabetes mellitus is a common disorder and more prevalent in developed countries. It is a metabolic disease in which, there is a high blood sugar level over a prolonged period. There are number of therapeutic options available in the market to treat diabetes mellitus, but treatment of type 2 diabetes with oral administration of medicament by oral route is easier and improves patient compliance.

The advantage of modified release formulations are well known in the pharmaceutical art and include the ability to maintain a desirable level of medicament in the blood over an extended period up to 24 hours. Also, patient compliance is increased by reducing the number of administrations necessary to achieve a desired therapeutic effect.

Glipizide is used in the treatment of diabetes mellitus, specifically for the treatment of type 2 diabetes. Glipizide is chemically known as N-[2-[4-[[[(cyclohexylamino) carbonyl]amino] sulfonyl] phenyl]ethyl]-5-methyl pyrazinecarboxamide and represented by the following chemical structure:

Glipizide

Glipizide is marketed by Pfizer under the trade name Glucotrol in the USA, having doses of 5 and 10 mg in immediate release dosage form. The extended release formulation of glipizide is marketed by Pfizer under the trade name Glucotrol XL having doses of 2.5, 5, and 10 mg.

U.S. Patent No. 6,361,795 relates to method for treating hyperglycemia in a patient using glipizide composition.

U.S. Patent No. RE44,459 relates to method for treating hyperglycemia in a patient by orally administering to the patient a glipizide composition with specific excipients.

U.S. Patent No. 4,612,008 relates to an osmotic device for the delivery at a controlled rate a beneficial agent.

U.S Patent No. 4,792,448 relates to device for the controlled release of one or more active substances.

US Patent No. 6,270,797 relates to sustained release glipizide composition and process of producing a sustained release glipizide composition.

There are several dosage forms which are available in the market that provides controlled release of glipizide. But still there exist a need to develop alternative cost effective and robust modified release pharmaceutical composition of glipizide or pharmaceutically acceptable salt thereof with specific pharmaceutical excipients to provide desired release profile of glipizide or pharmaceutically acceptable salt thereof.

SUMMARY OF THE INVENTION
The invention relates to modified release pharmaceutical composition comprising glipizide or pharmaceutically acceptable salt thereof, wherein the modified release composition comprises specific pharmaceutically acceptable excipients along with one or more osmogents. The specific pharmaceutical acceptable excipients in the composition provide desired release profile of glipizide or pharmaceutically acceptable salt thereof.

In one general aspect, there is provided a modified release pharmaceutical composition comprising:
(i) a drug layer comprising glipizide or pharmaceutically acceptable salt thereof;
(ii) a push layer;
wherein the drug layer and push layer form a bi-layer core which is devoid of hydroxypropyl methylcellulose;
(iii) optionally one or more coating layers to the core, wherein the coating layer comprises cellulose acetate and one or more pharmaceutically acceptable excipients.

In another general aspect, there is provided modified release pharmaceutical composition comprising: (i) a drug layer comprising glipizide or pharmaceutically acceptable salt thereof; (ii) a push layer comprising an osmogent, wherein the drug layer and push layer form a core; and (iii) optionally one or more coating layers applied over the core, wherein the coating layer comprises cellulose acetate and one or more pharmaceutically acceptable excipients and wherein the composition is devoid of hydroxypropyl methylcellulose.

In another general aspect, there is provided modified release pharmaceutical composition comprising: (i) a drug layer comprising glipizide or pharmaceutically acceptable salt thereof; (ii) a push layer comprising an osmogent; (iii) one or more coating layer; and (iv) one or more passageway, wherein the coating layer comprises cellulose acetate and one or more pharmaceutically acceptable excipients and composition is devoid of hydroxypropyl methylcellulose.

In another general aspect, there is provided modified release pharmaceutical composition comprising: (i) a drug layer comprising glipizide or pharmaceutically acceptable salt thereof; (ii) a push layer comprises an osmogent; (iii) optionally, one or more coating layer; and (iv) one or more passageway.

In another general aspect, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein the drug layer comprises a glipizide of pharmaceutically acceptable salt thereof, polyethylene oxide, polyvinylpyrrolidone, magnesium stearate, Isoropyl alcohol and pharmaceutically acceptable salt thereof which is devoid of hydroxypropyl methylcellulose.

In another general aspect, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein the push layer comprises osmogent, polyethylene oxide, polyvinylpyrrolidone, magnesium stearate, Isoropyl alcohol and pharmaceutically acceptable salt thereof which is devoid of hydroxypropyl methylcellulose, wherein the osmogent is sodium chloride.

In another general aspect, there is provided modified release pharmaceutical composition comprising glipizide of pharmaceutically acceptable salt thereof present in drug layer, wherein the amount of glipizide or pharmaceutically acceptable salt thereof present in a amount of 2.0 mg to 50 mg. More specifically present in the amount of about 2.5mg, 5mg and 10mg.

In another general aspect, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein the drug layer present in the range of 35 % w/w to 60 % w/w of the composition. Preferably the drug layer present in the range of 40% w/w to 55% w/w of the composition.

In another general aspect, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein the push layer present in the range of 20 % w/w to 45 % w/w of the composition. More preferably, present in the range of 25 % w/w to 40 % w/w of the composition.

In another general aspect, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein drug layer comprises glipizide and polyethylene oxide in the ratio of 1:10 % w/w to 1:50 % w/w of the composition.

In another general aspect, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein drug layer comprises glipizide and polyethylene oxide in the ratio of 1:12 % w/w to 1:30 % w/w of the composition.

In another general aspect, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein drug layer comprises glipizide and polyvinylpyrrolidone in the ratio of about 1:1 % w/w to about 1:10 % w/w of the composition.

In another general aspect, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein the drug layer comprises amount of polyethylene oxide in the range of 30 % w/w to 50 % w/w of the composition. Preferably, present in the range of 35% w/w to 45 % w/w of the composition.

In another general aspect, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein the drug layer comprises amount of polyvinylpyrrolidone in the range of 1 % w/w to 10 % w/w of the composition. Preferably, present in the range of 1 % w/w to 8 % w/w of the composition.

In another general aspect, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein the push layer comprises amount of polyethylene oxide in the range of 10 % w/w to 30 % w/w of the composition. Preferably, present in the range of 15% w/w to 30 % w/w of the composition.

In another general aspect, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein push layer comprises polyvinylpyrrolidone in the range of 0.5 % w/w to 5% w/w of the composition. More preferably present in the range of 1 % w/w to 4 % w/w of the composition.

In another general aspect, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein push layer comprises sodium chloride in the range of 2 % w/w to 15 % w/w of the composition. Preferably present in the range of 3 % w/w to 12 % w/w of the composition.

In another general aspect, there is provided modified release pharmaceutical composition comprising: (i) a drug layer comprising glipizide or pharmaceutically acceptable salt thereof; (ii) a push layer comprising an osmogent; wherein the drug layer and push layer form a core which is devoid of hydroxypropyl methylcellulose; (iii) seal coating (iv) extended release coating; and (v) one or more passageway; wherein the drug layer present in the range of 40 % w/w to 55 % w/w of the composition.

In another general aspect, there is provided modified release pharmaceutical composition comprising: (i) drug layer comprising glipizide or pharmaceutically acceptable salt thereof; (ii) push layer comprising an osmogent; wherein the wherein the osmogent is sodium chloride.

In another general aspect, there is provided modified release pharmaceutical composition comprising: (i) a drug layer comprising: (a) glipizide or pharmaceutically acceptable salt thereof, (b) polyethylene oxide 35% to 45% w/w of the composition;
(ii) a push layer composition comprising: (a) polyethylene oxide 15% to 30% w/w of the composition, (b) sodium chloride 3% to 12% w/w of the composition;
(iii) seal coating;
(iv) extended release coating comprising cellulose acetate;
(v) one or more passageway; and
(vi) optionally film coating.

In another general aspect, there is provided modified release pharmaceutical composition comprising drug layer consisting of glipizide or pharmaceutically acceptable salt thereof and push layer, wherein the drug layer and push layer form an core; said core further coated with a first membrane of an seal coating polymer, second membrane of a extended release coating polymer and third membrane of film coating polymer.

In another general aspect, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein the drug layer and push layer form a core which is devoid of hydroxypropyl methylcellulose; the said core further coated with a first membrane of an seal coating polymer, second membrane of a extended release coating polymer and third membrane of film coating polymer. Optionally, the extended release coating membrane comprises one or more orifice to release the drug from the core.

In another general aspect, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein the drug layer of the core provides one or more passageway by laser drilling to release the drug over extended period of time.

In another general aspect, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein the laser drilling provide diameter of passageway is about 0.6±0.2 mm for the release of the drug over extended period of time.

In another general aspect, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein the composition is in the form of tablet, capsule, pellets, bilayer tablet or trilayer tablet.

In another general aspect, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein the composition provided in the form of tablet dosage form.

In another general aspect, there is provided modified release pharmaceutical composition comprising drug layer and push layer with one or more pharmaceutically acceptable excipients; wherein the one or more pharmaceutically acceptable excipients are selected from Polyethylene oxide, polyethylene glycol, iron oxide red, polyvinylpyrrolidone, magnesium stearate, sodium chloride, magnesium stearate, polyethylene glycol and cellulose acetate.

In another general aspect, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein the composition is used for the treatment of lowering blood glucose level by administering said composition to the patient in need thereof.

In another general aspect, there is provided modified release composition; wherein the composition exhibits dissolution profile such that not more than 30% of the glipizide is released within 4 hours, between 25% to 65% of the glipizide is released within 8 hours, between 55% to 85% of the glipizide is released within 12 hours and not less than 80% of the glipizide is released within 20 hours when the release rate is measured in USP type 2 dissolution apparatus using 900 ml of simulated Intestinal fluid without pancreatin of pH 7.5 at temperature 37°C ± 0.5°C.

In another general aspect, there is provided process for preparing modified release composition comprising glipizide or pharmaceutically acceptable salt thereof, wherein the process comprises:
(a) preparation of drug layer granules;
(b) preparation of push layer granules;
(c) compression of the granules obtained in step (a) and step (b) to get bi-layer core, and
(d) at least one coating layer over the core obtained in step (c);
(g) optionally one or more laser drilling to the core and further film coating over the core.

In another general aspect, there is provided process for preparing modified release composition comprising glipizide or pharmaceutically acceptable salt thereof, wherein the process comprises:
(a) preparation of drug layer granules;
(b) preparation of push layer granules;
(c) compression of the granules obtained in step (a) and step (b) to get bi-layer core, and
(d) at least one coating layer over the core obtained in step (c); wherein the one or more coating comprises: (i) seal coating and (ii) extended release coating;
(g) optionally one or more laser drilling to the core and further film coating to the core.

In another general aspect, there is provided process for preparing modified release composition comprising glipizide or pharmaceutically acceptable salt thereof, wherein the composition is in the form of tablet dosage form.

DETAILED DESCRIPTION OF THE INVENTION
The inventors of the invention surprisingly found that judicious selection of specific pharmaceutically acceptable excipients along with one or more osmogent provides modified release pharmaceutical composition having desired release profile of glipizide or pharmaceutically acceptable salt thereof by oral administration.

The term "modified release" as used in the invention refers to release of glipizide over a period of at least about 8 hours, preferably at least about 20 hours after oral administration and is taken to encompass controlled release, sustained release, prolonged release, timed release, retarded release, extended release and delayed release. Particularly The drug-release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as a solution or an immediate release dosage form.

The term "sustained release" as used in the invention refers to release of active ingredient at such a rate that blood levels are maintained within the therapeutic range but below toxic levels over an extended period of time e.g. 12 to 24 hours or greater.

The term "extended release" as used in the invention refers to a composition that makes the drug available over an extended period after ingestion, and preferably, although not necessarily, results in substantially constant blood levels of the drug over an extended time period. The term extended release used in context of the invention includes, but not limited to, zero order release of the drug.

The modified release pharmaceutical composition comprising glipizide or pharmaceutically acceptable salt thereof may additionally comprises one or more pharmaceutically acceptable excipients selected from one or more binders, fillers or filler-binders, disintegrants, lubricants/glidants, antiadherents, osmogent, rate-controlling excipients or polymers, solvent, sweeteners, flavouring and colouring agents.

Examples of the binders suitable for use in the said pharmaceutical composition of the invention may be selected from one or more of polyvinyl pyrrolidone (povidone), copolymers of vinylpyrrolidone with other vinylderivatives (copovidone), hydroxypropyl cellulose, methylcellulose, powdered acacia, gelatin, guar gum and carbomer such as carbopol, polymethacrylates and starch.

Examples of the fillers or filler-binder suitable for use in the said pharmaceutical composition of the invention may be selected from starches, such as potato starch, rice starch, maize starch, wheat starch, pregelatinized starch, fully pregelatinized starch, cellulose, such as microcrystalline cellulose or silicified microcrystalline cellulose, mannitol, erythritol, calcium salts, such as calcium hydrogen phosphate dihydrate, anhydrous dibasic calcium phosphate, xylitol, sorbitol, or mixtures thereof.

Examples of the lubricants/glidants suitable for use in the said pharmaceutical composition of the invention may be selected from one or more of stearic acid, talc, siliconised talc, micronised talc, sodium stearyl fumarate and magnesium stearate. Preferable lubricant/glidants is micronised talc.

Examples of the osmogent suitable for use in the said pharmaceutical composition of the invention may be selected from fructose, lactose-fructose, sucrose-fructose, mannitol-socrose, dextrose-fructose, sodium chloride, potassium sulfate, potassium chloride, mannitol, sodium phosphate dibasic 7H2O sodium phosphate monobasic H2O or mixtureof.

Examples of the rate-controlling excipients including polymers having pH dependent solubility used for coating comprising methyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, cellulose acetate, Polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate, methyl methacrylate-methacrylic acid copolymers or combination thereof.

The invention relates to modified release pharmaceutical composition comprising
(a) a drug layer comprising glipizide or pharmaceutically acceptable salt thereof present in drug layer
(b) a push layer; and
(c) optionally, at least one coating layer comprises cellulose acetate and one or more pharmaceutically acceptable salt thereof; wherein the said drug layer and push layer form a core and said core is coated with at least one modified-release polymer.

Preferably an amount of glipizide or pharmaceutically acceptable salt thereof present in the range of 2 mg to 50 mg per dosage unit. Specific amounts per unit dosage form contemplated herein include 2.5mg, 5mg and 10mg of glipizide base; however overages may be added as and when required according to composition and release profile requirements.

In particular, the invention relates to modified release composition comprising glipizide or pharmaceutically acceptable salt thereof and specific pharmaceutical excipients to provides desired release profile for glipizide or pharmaceutically acceptable salt thereof and improve patient compliance. The invention also provides process for preparing said composition. Further, the invention is used in the treatment of diabetes mellitus by administering said composition to a patient in need thereof.

In one embodiment, there is provided a modified release pharmaceutical composition comprising:
(i) a drug layer comprising of glipizide or pharmaceutically acceptable salt thereof;
(ii) a push layer; wherein the drug layer and push layer form a bi-layer core which is devoid of hydroxypropyl methylcellulose;
(iii) one or more coating layers over the core, wherein the coating layer comprises cellulose acetate and one or more pharmaceutically acceptable excipients; and
(iv) one or more passageway.

In another embodiment, there is provided modified release pharmaceutical composition comprising: (i) a drug layer comprising glipizide or pharmaceutically acceptable salt thereof; (ii) a push layer comprising an osmogent, wherein the drug layer and push layer form a core; and (iii) optionally one or more coating layers applied over the core, wherein the coating layer comprises cellulose acetate and one or more pharmaceutically acceptable excipients and wherein the composition is devoid of hydroxypropyl methylcellulose.

In another embodiment, there is provided modified release pharmaceutical composition comprising: (i) a drug layer comprising glipizide or pharmaceutically acceptable salt thereof; (ii) a push layer comprising an osmogent; (iii) one or more coating layer; and (iv) one or more passageway, wherein the coating layer comprises cellulose acetate and one or more pharmaceutically acceptable excipients and composition is devoid of hydroxypropyl methylcellulose.

In another embodiment, there is provided modified release pharmaceutical composition comprising: (i) a drug layer comprising glipizide or pharmaceutically acceptable salt thereof; (ii) a push layer comprises an osmogent; (iii) optionally, one or more coating layer; and (iv) one or more passageway.

In another embodiment, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein the drug layer comprises a glipizide of pharmaceutically acceptable salt thereof, polyethylene oxide, polyvinylpyrrolidone, magnesium stearate, Isoropyl alcohol and pharmaceutically acceptable salt thereof which is devoid of hydroxypropyl methylcellulose.

In another embodiment, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein the push layer comprises osmogent, polyethylene oxide, polyvinylpyrrolidone, magnesium stearate, Isoropyl alcohol and pharmaceutically acceptable salt thereof which is devoid of hydroxypropyl methylcellulose, wherein the osmogent is sodium chloride.

In another embodiment, there is provided modified release pharmaceutical composition comprising glipizide of pharmaceutically acceptable salt thereof present in drug layer, wherein the amount of glipizide or pharmaceutically acceptable salt thereof present in a amount of 2.0 mg to 50 mg. More specifically present in the amount of about 2.5mg, 5mg and 10mg.

In another embodiment, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein the drug layer present in the range of 35 % w/w to 60 % w/w of the composition. Preferably the drug layer present in the range of 40% w/w to 55% w/w of the composition.

In another embodiment, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein the push layer present in the range of 20 % w/w to 45 % w/w of the composition. More preferably, present in the range of 25% w/w to 40% w/w of the composition.

In another embodiment, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein drug layer comprises glipizide and polyethylene oxide in the ratio of 1:10 % w/w to 1:50 % w/w of the composition.

In another embodiment, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein drug layer comprises glipizide and polyethylene oxide in the ratio of 1:12 % w/w to 1:30 % w/w of the composition.

In another embodiment, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein drug layer comprises glipizide and polyvinylpyrrolidone in the ratio of about 1:1 % w/w to about 1:10 % w/w of the composition.

In another embodiment, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein the drug layer comprises amount of polyethylene oxide in the range of 30 % w/w to 50 % w/w of the composition. Preferably, present in the range of 35% w/w to 45 % w/w of the composition.

In another embodiment, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein the drug layer comprises polyvinylpyrrolidone in the range of 1 % w/w to 10 % w/w of the composition. Preferably, present in the range of 1 % w/w to 8 % w/w of the composition.

In another embodiment, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein the push layer comprises amount of polyethylene oxide in the range of 10 % w/w to 30 % w/w of the composition. Preferably, present in the range of 15% w/w to 30 % w/w of the composition.

In another embodiment, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein push layer comprises polyvinylpyrrolidone in the range of 0.5 % w/w to 5% w/w of the composition. More preferably present in the range of 1 %w/w to 4% w/w of the composition.

In another embodiment, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein push layer comprises sodium chloride in the range of 2 % w/w to 15 % w/w of the composition. Preferably present in the range of 3 % w/w to 12 % w/w of the composition.

In another embodiment, there is provided modified release pharmaceutical composition comprising: (i) a drug layer comprising glipizide or pharmaceutically acceptable salt thereof; (ii) a push layer comprising an osmogent; wherein the drug layer and push layer form a core which is devoid of hydroxypropyl methylcellulose; (iii) seal coating (iv) extended release coating; and (v) one or more passageway; wherein the drug layer present in the range of 40% w/w to 55 % w/w of the composition.

In another embodiment, there is provided modified release pharmaceutical composition comprising: (i) a drug layer comprising: (a) glipizide or pharmaceutically acceptable salt thereof, (b) polyethylene oxide 35% to 45% w/w of the composition;
(ii) a push layer composition comprising: (a) polyethylene oxide 15% to 30% w/w of the composition, (b) sodium chloride 3% to 12 % w/w of the composition;
(iii) seal coating;
(iv) extended release coating comprising cellulose acetate;
(v) one or more passageway; and
(vi) optionally film coating.

In another embodiment, there is provided modified release pharmaceutical composition comprising drug layer consisting of glipizide or pharmaceutically acceptable salt thereof and push layer, wherein the drug layer and push layer form an core; said core further coated with a first membrane of an seal coating polymer, second membrane of a extended release coating polymer and third membrane of film coating polymer.

In another embodiment, there is provided modified release pharmaceutical composition comprising drug layer consisting of glipizide or pharmaceutically acceptable salt thereof and push layer, wherein the drug layer and push layer form an core; said core further coated with a first membrane of an seal coating polymer, second membrane of a extended release coating polymer and third membrane of film coating polymer. Optionally, the extended release coating membrane comprises one or more orifice to release the drug.

In another embodiment, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein the drug layer of the core provides one or more passageway by laser drilling to release the drug over extended period of time. The said laser drilling provides diameter of orifice is about 0.6±0.2 mm for the release of the drug over extended period of time.

In another embodiment, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein the composition can provide therapeutically effective plasma concentration over a period of up to 24 hours to treat diabetes when administered to a patient in need thereof.

In another embodiment, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein the composition is in the form of tablet, capsule, pellets, bilayer tablet or trilayer tablet. Preferably the composition provides in tablet dosage form.

In another embodiment, there is provided modified release pharmaceutical composition comprising drug layer and push layer with one or more pharmaceutically acceptable excipients; wherein the one or more pharmaceutically acceptable excipients are selected from polyethylene oxide, polyethylene glycol, iron oxide red, polyvinylpyrrolidone, magnesium stearate, sodium chloride, magnesium stearate, polyethylene glycol and cellulose acetate.

In another embodiment, there is provided modified release pharmaceutical composition comprising drug layer and push layer, wherein the composition is used for the treatment of lowering blood glucose level by administering said composition to the patient in need thereof.

In another embodiment, there is provided modified release composition; wherein the composition exhibits dissolution profile such that not more than 30% of the glipizide is released within 4 hours, between 25% to 65% of the glipizide is released within 8 hours, between 55% to 85% of the glipizide is released within 12 hours and not less than 80% of the glipizide is released within 20 hours when the release rate is measured in USP type 2 dissolution apparatus using 900 ml of simulated Intestinal fluid without pancreatin of pH 7.5 at temperature 37°C ± 0.5°C.

In another embodiment, there is provided process for preparing modified release composition comprising glipizide or pharmaceutically acceptable salt thereof, wherein the process comprises:
(a) preparation of drug layer granules;
(b) preparation of push layer granules;
(c) compression of the granules obtained in step (a) and step (b) to get bi-layer core, and
(d) at least one coating layer over the core obtained in step (c);
(g) optionally one or more laser drilling to the core and further film coating over the core.

In another embodiment, there is provided process for preparing modified release composition comprising glipizide or pharmaceutically acceptable salt thereof, wherein the process comprises:
(a) preparation of drug layer granules;
(b) preparation of push layer granules;
(c) compression of the granules obtained in step (a) and step (b) to get bi-layer core, and
(d) at least one coating layer over the core obtained in step (c); wherein the one or more coating comprises: (i) seal coating and (ii) extended release coating;
(g) optionally one or more laser drilling to the core to form passageway.

In another embodiment, there is provided process for preparing modified release composition comprising glipizide or pharmaceutically acceptable salt thereof, wherein the composition is in the form of tablet.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

The invention now will be described in particularity with the following illustrative examples; however, the scope of the invention is not intended to be, and shall not be, limited to the exemplified embodiments below.

EXAMPLES
Example 1: Modified release tablet containing glipizide.
Table 1
Sr. No. Ingredients Qty/Tablet (mg)
Drug Layer Composition
1 Glipizide Micronized 2.75*
2 Polyethylene oxide (Sentry Polyox WSR N80) 81.75
3 Polyvinylpyrrolidone 15.0
4 Magnesium Stearate 0.50
5 Isopropyl alcohol q.s.
Drug Layer Weight (mg) 100.00
Push Layer Composition
6 Polyethylene Oxide (Sentry Polyox WSR 303) 37.80
7 Iron oxide Red 0.50
8 Polyvinylpyrrolidone 8.50
9 Sodium Chloride 23.00
10 Magnesium Stearate 0.20
11 Isopropyl alcohol q.s.
Target Push Layer Weight (mg) 70.00
Core Tablet Wt (mg) 170.00
Seal Coating Composition
12 Hydroxypropyl Cellulose (HPC-SSL) 4.85
13 Polyethylene Glycol 400 (Lutrol 400) 0.25
14 Isopropyl alcohol q.s.
15 Target weight build up (% w/w) 3
Seal Coated Tablet Wt (mg) 175.10
Extended Release Coating Composition
16 Cellulose Acetate USP (CA-398-10) 22.78
17 Polyethylene Glycol 3350 1.73
18 Acetone q.s.
19 Solvent (Purified water) q.s.
20 Target weight build up (% w/w) 14
ER Coated Tablet Weight (mg) 199.61
Film Coating
21 Opadry Blue 85F505085 IH 13.97
22 Target weight build up (% w/w) 7
Film Coated Tablet Weight (mg) 213.59
Imprinting
23 Opacode Black Ink S-1-17823 q.s.
*Quantity may vary as per salt form or overages

Process:
1. Micronized glipizide was mixed with polyethylene oxide (PEO), Polyvinylpyrrolidone and iron oxide red and sifted through sieve.
2. Mixed the material of step 1 in rapid mixer granulator (RMG) and further granulated the blend by using isopropyl alcohol.
3. The blend obtained in step 2 were dried and sifted through sieve.
4. The granules obtained in step 3 were milled and lubricated.
5. Sodium chloride, PEO and iron oxide red were milled, sifted through sieve and mixed.
6. Granulated the mixture obtained in step 5 by using isopropyl alcohol
7. The granules obtained in step 6 were dried and further sifted through sieve.
8. The granules obtained in step 7 were lubricated by using magnesium stearate.
9. The granules obtained in step 4 and steps 8 were compressed to get tablet dosage form.
10. Seperately, polyethylene oxide was added in isopropyl alcohol and mixed.
11. Hydroxypropyl cellulose was added to the solution obtained in step 10 under stirring and stir this solution till 1 hour or till clear solution obtained.
12. The tablets obtained in step 9 were coated by using coating solution obtained in step 11.
13. Mixed polyethylene glycol in purified water to get solution.
14. Separately acetone and cellulose acetate were mixed.
15. The solution obtained in step 13 and step 14 was mixed and stirs slowly till clear solution obtained.
16. The coated tablets obtained in 12 were further coated by using solution obtained in the step 15.
17. The tablets obtained in step 16 were drilled by laser drilling.
18. Film coating solution was prepared by dispersing opadry system in purified water separately.
19. The tablets obtained in step 17 were coated by using solution obtained in step 18.
20. Optionally, tablets obtained in step 19 were printed.

Example 2: Modified release tablet containing glipizide.
Table 2
Sr. No. Ingredients Qty/Tablet (mg)
Drug Layer Composition
1 Glipizide Micronized 2.75*
2 Polyethylene oxide (Sentry Polyox WSR N80) 93.25
3 Polyvinylpyrrolidone 3.50
4 Magnesium Stearate 0.50
5 Isopropyl alcohol q.s.
Drug Layer Weight (mg) 100.00
Push Layer Composition
6 Polyethylene Oxide (Sentry Polyox WSR 303) 52.90
7 Iron oxide Red 0.40
8 Polyvinylpyrrolidone 6.50
9 Sodium Chloride 10.00
10 Magnesium Stearate 0.20
11 Isopropyl alcohol q.s.
Target Push Layer Weight (mg) 70.00
Core Tablet Wt (mg) 170.00
Seal Coating Composition
12 Hydroxypropyl Cellulose (HPC-SSL) 4.65
13 Polyethylene Glycol 400 (Lutrol 400) 0.45
14 Isopropyl alcohol q.s.
15 Target weight build up (% w/w) 3
Seal Coated Tablet Wt (mg) 175.10
Extended Release Coating Composition
16 Cellulose Acetate USP (CA-398-10) 24.18
17 Polyethylene Glycol 3350 0.33
18 Acetone q.s.
19 Solvent (Purified water) q.s.
20 Target weight build up (% w/w) 14
ER Coated Tablet Weight (mg) 199.61
Film Coating
21 Opadry White 85F18422 IH 13.97
22 Target weight build up (% w/w) 7
Film Coated Tablet Weight (mg) 213.59
Imprinting
23 Opacode Black Ink S-1-17823 q.s.
*Quantity may vary as per salt form or overages

Process: Same as mentioned in Example 1
Example 3: Modified release tablet containing glipizide.
Table 3
Sr. No. Ingredients Qty/Tablet (mg)
Drug Layer Composition
1 Glipizide Micronized 11.0*
2 Polyethylene oxide (Sentry Polyox WSR N80) 177.99
3 Iron oxide Red 0.01
4 Polyvinylpyrrolidone 10.0
5 Magnesium Stearate 1.0
6 Isopropyl alcohol q.s.
Drug Layer Weight (mg) 200.00
Push Layer Composition
7 Polyethylene Oxide (Sentry Polyox WSR 303) 95.60
8 Iron oxide Red 1.0
9 Polyvinylpyrrolidone 7.0
10 Sodium Chloride 36.0
11 Magnesium Stearate 0.4
12 Isopropyl alcohol q.s.
Target Push Layer Weight (mg) 140.00
Core Tablet Wt (mg) 340.00
Seal Coating Composition
13 Hydroxypropyl Cellulose (HPC-SSL) 9.690
14 Polyethylene Glycol 400 (Lutrol 400) 0.510
15 Isopropyl alcohol q.s.
16 Target weight build up (% w/w) 3
Seal Coated Tablet Wt (mg) 175.10
Extended Release Coating Composition
17 Cellulose Acetate USP (CA-398-10) 31.107
18 Polyethylene Glycol 3350 2.162
19 Acetone q.s.
20 Solvent (Purified water) q.s.
21 Target weight build up (% w/w) 9.5
ER Coated Tablet Weight (mg) 383.469
Film Coating
22 Opadry White 85F18422 IH 26.843
23 Target weight build up (% w/w) 7
Film Coated Tablet Weight (mg) 410.312
Imprinting
24 Opacode Black Ink S-1-17823 q.s.
*Quantity may vary as per salt form or overages
Process: Same as mentioned in Example 1
,CLAIMS:1. A modified release pharmaceutical composition comprising:
(i) a drug layer comprising glipizide or pharmaceutically acceptable salt thereof; (ii) a push layer comprising an osmogent, wherein the drug layer and push layer form a core; and (iii) optionally one or more coating layers applied over the core, wherein the coating layer comprises cellulose acetate and one or more pharmaceutically acceptable excipients and wherein the composition is devoid of hydroxypropyl methylcellulose.

2. The pharmaceutical composition of claim 1, wherein the drug layer comprises a glipizide or pharmaceutically acceptable salt thereof and polyethylene oxide in the ratio of 1:12 % w/w to 1:30 % w/w of the composition.

3. The pharmaceutical composition of claim 1, wherein the osmogent is sodium chloride.

4. A modified release pharmaceutical composition comprising:
(i) a drug layer comprising glipizide or pharmaceutically acceptable salt thereof; (ii) a push layer comprising an osmogent; (iii) one or more coating layer; and (iv) one or more passageway, wherein the coating layer comprises cellulose acetate and one or more pharmaceutically acceptable excipients and wherein said composition is devoid of hydroxypropyl methylcellulose.

5. The modified release pharmaceutical composition of claim 4, wherein the osmogent is sodium chloride.

6. The modified release pharmaceutical composition of claim 4, wherein the push layer comprises polyvinylpyrrolidone in the range of 1% w/w to 6% w/w of the composition.

7. The modified release pharmaceutical composition of claim 4, wherein the one or more coating comprises seal coating and extended release coating.

8. A modified release pharmaceutical composition comprising: (i) a drug layer comprising glipizide or pharmaceutically acceptable salt thereof; (ii) push layer comprising an osmogent; wherein the drug layer and push layer form a core which is devoid of hydroxypropyl methylcellulose; (iii) seal coating (iv) extended release coating; (v) one or more passageway; wherein the drug layer present in the range of 40% w/w to 55 % w/w of the composition.

9. A process for preparing modified release composition comprising glipizide or pharmaceutically acceptable salt thereof, wherein the process comprises steps of:
(a) preparation of drug layer granules;
(b) preparation of push layer granules;
(c) compression of the granules obtained in step (a) and step (b) to get bi-layer core, and;
(d) at least one coating layer over the core obtained in step (c);
(e) Optionally one or more laser drilling to the core and further optionally film coating over the core; wherein the process provides tablet dosage form.

10. A modified release pharmaceutical composition comprising:
(i) a drug layer comprising;
(a) glipizide or pharmaceutically acceptable salt thereof,
(b) polyethylene oxide 35% to 45% w/w of the composition;

(ii) a push layer composition comprising;
(a) polyethylene oxide 15% to 30% w/w of the composition,
(b) sodium chloride 3% to 12% w/w of the composition;

(iii) seal coating;
(iv) extended release coating comprising cellulose acetate;
(v) one or more passageway; and
(vi) optionally film coating.