This invention relates to a novel method of preparing an extended release matrix tablet for oral administration, wherein the release rate of active ingredient is independent of pH and gastric residence time.
Treatment of a disease or infection in most cases demands maintaining a desired drug concentration in plasma over a prolonged period of time, usually running in days to months. Such clinical needs are satisfied generally with the use of multiple dose therapy involving frequent dosing of 2-4 doses- per day. It is usually very difficult for patients to stick to such stringent routines and this leads to instances of missed doses very often. As a consequence, the pharmacokinetic profile of drug may fall below the minimum

therapeutic/inhibitory concentration leading to inadequate relief or development of tolerance or resistance to the drug.
Most common approach of minimizing patient noncompliance is by the use of extended release drug delivery systems thereby reducing the number of doses to be taken per day
One useful approach in this regard involves the use of polymer-based matrix in which the drug is uniformly dispersed or dissolved. The release rate of drug through the matrix is usually governed by the rate of dissolution of drug, in the surrounding media from the exposed surfaces and the rate of diffusion, from the interior regions of the matrix to the surface.
The normal pH in human gastrointestinal tract, varies from about pH 1.0 (in fasted stomach) to about pH 8 (in lower large intestine). For drugs, which have pH dependent solubility, the time of residence of the delivery system at a particular site becomes important. Such drugs can have varying release rates between the stomach and distal regions of intestinal tract depending on the pH at the absorption site and gastric residence time.
Therefore extended release matrices, which can provide drug release independent of pH and gastric residence time, are particularly needed.
One such matrix drug delivery system has been described in U. S. Pat. No. 6,150.410. U. S. Pat. No. 6,150,410 discloses an extended release matrix comprising a combination of neutral water swellable hydrophilic polymer and acid soluble polymer which is swellable
above pH 5. This matrix provides enhanced rate of release of the acidic pharmacologic agent in the stomach where the pH of gastric juices is low and diminished release rate at neutral or slightly alkaline pH in the intestinal tract.
Further U. S. Pat. No. 5,695,781 describe the combination of an alginate compound, an enteric polymer and a gelling polymer and U. S. Pat. No. 6,083,532 describes combination of a pH dependent gelling polymer, an enteric polymer and a pH independent gelling polymer for extended release matrix formulation.
U. S. Pat. No. 6,251,430 describes the use of ethyl cellulose or Eudragit® RS or RL in combination with hydroxypropyl methylcellulose and sodium alginate to provide controlled release.
Accordingly, the present invention relates to a method for the preparation of an extended release matrix tablet for oral administration, comprising the steps of:
a) preparing a blend of
i) active ingredient,
ii) 10 to 50% of water swellable cellulose derivative, such as herein
described, iii) 0.1 to 15 % of alginic acid and/or its physiologically acceptable salt, such
as herein described iv) 0.1 to 15% by weight of cationic polymer, such as herein described, and v) optionally pharmaceutically inert excipient, such as herein described; and.
b) processing into a tablet, such as herein described,
wherein above percentages relate to total weight of tablet.
The use of this unique polymer combination provides desirable extended release matrix for oral administration, from which active ingredient is released independent of pH and gastric residence time. In the acidic environment of the stomach the cellulose polymer absorb water and swell to form a viscous consistency, which thereby retards the release of the drug. On the other hand the cationic polymer dissolve at the lower pH conditions causing the erosion of matrix exposing more drug to the dissolution media and consequently enhancing release rate. In the lower regions of the gastrointestinal tract as the pH rises, the solubility of cationic polymer decreases and it starts swelling whereas the alginic acid derivatives start dissolving causing erosion of the matrix. In this way, the present delivery system maintains a uniform rate of drug release independent of pH and gastric residence time, throughout the gastrointestinal tract.
The pH independent release thus makes it immaterial whether the formulation is taken in fasted or fed state. Hence, the technology can be used for a wide range of drugs including those having restrictions of administration in the fed or fasted state. The extended release matrix of the present invention may comprise from about 10% to about 80% by weight of the total formulation.
The term pH independent release as used herein refers to similar drug release rates varying not more than 20% when compared in acidic (0.1N HCI) and near neutral (pH 6.8) environments.
The drug delivery system of the present invention can be used for drugs independent of their solubility characteristics. Preferred active ingredients of the present invention may be selected from the group comprising of antibiotics, sympathomimetics, sympatholytic agents, cholinergic agents, antimuscarinics, gastro-intestinal drugs, gentio-urinary smooth muscle relaxants, cardiac drugs, anticonvulsants, tranquilizers, sedatives.
The water swellable cellulose derivatives of the present invention may be selected from hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, carboxy methylcellulose, hydroxy methylcellulose, hydroxy ethylcellulose and mixtures thereof. The preferred cellulose derivative is hydroxypropyl methylcellulose. Hydroxypropyl methylcellulose is commercially available as Methocel® (manufactured by Dow Chemicals) in various grades. The preferred grades of Methocel® are K-4 MCR, K100V, K4MP, K15MP, K100MP, E4MP, E10MP-CR, E5. The water swellable cellulose derivative may constitute about 10% to about 50% by weight of the total weight of formulation.
Alginic acid derivatives of the present invention include both alginic acid and its physiologically acceptable salts such as those of sodium, potassium, magnesium and calcium. These are commercially available in different grades. The preferred grades are Keltone LVCR and KELACID (marketed by ISP Alginates). The concentration of alginic acid derivatives may vary from about 0.1% to about 15% by weight of the total weight of formulation.
The cationic polymers useful for the present invention include methacrylic acid derivatives with a dimethylaminoethyl ammonium group. The preferred ones being Eudragit® E100 and Eudragit® EPO (marketed by Rohm Pharma). The weight of cationic polymer in the formulation may vary from about 0.1% to about 15% by weight with respect to the total weight of formulation.
The dosage form of the present invention may also contain other pharmaceutical^ inert excipients such as binders, diluents, lubricants, glidants and coloring agents
Binders of the present invention may be selected from methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.
Diluents of the present invention may be selected from calcium carbonate, calcium phosphate-dibasic, calcium phosphateJtribasic, calcium sulfate, cellulose-microcrystalline, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners and mixtures thereof.
Lubricants and glidants of the present invention may be selected from colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated caster oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax and the like.
The colors of the present invention may be selected from any FDA approved colors for internal use.
The formulation of the present invention may optionally be coated, if desired.
The drug delivery system of the present invention can be prepared by blending diluent ana control release polymers into a homogenous blend; incorporating drug into the blend in geometric progression: mixing with lubricant and glidant, and directly compressing into tablets.
Alternatively, dry granulation or wet granulation methods can also be employed
The invention is further illustrated by the following examples but they should not be construed as limiting the scope of the invention any wa.y.
EXAMPLE 1

(Table Removed)
Process:
1. Lactose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium alginate and Eudragit® EPO were sieved through #BSS 44 and mixed in double cone blender for 20 minutes.-
2. Cefaclor was passed through sieve #BSS 44 and blended with tne above mixture for 20 minutes.
3. The blend of step 3 was then mixed with talc and colloidal anhydrous silica for 10 minutes.
4. The mixture of step 4 was lubricated by mixing with magnesium stearate for 5 minutes and compressed to form tablets.
EXAMPLE 2
(Table Removed)
Process:
1. Lactose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium alginate, alginic acid and Eudragit® EPO were sieved through #BSS 44 and mixed in double cone blender for 20 minutes.
2. Carvedilol was passed through sieve #BSS 44 and blended with the above mixture for 20 minutes.
3. The blend of step 3 was mixed with talc and colloidal anhydrous silica for 10 minutes.
4. The mixture of step 4 was lubricated by mixing with magnesium stearate for 5 minutes and compressed to form tablets.
EXAMPLE 3
(Table Removed)
Process:
1. Carvedilol, lactose and a part of hydroxypropyl methylcellulose (low viscosity) were sieved by passing through #BSS 44 and blended.
2. The blend was granulated by mixing with water followed by drying at 60LC and sizing through sieve #BSS 30.
3. Hydroxypropyl cellulose, remaining part of hydroxypropyl methylcellulose, alginic acid derivatives and Eudragit® EPO were passed through sieve #BSS 44 and blended in double cone blender for 10 minutes.
4. The granules of step 2 were then mixed with the blend of step 3 for 20 minutes
5 Talc and colloidal anhydrous silica were passed through # BSS44 and mixed with
the blend of step 4 for 5 minutes. 6, The mixture of step 5 was finally lubricated by mixing with magnesium stearate
(passed through #BSS44) for 5 minutes and compressed to form tablets.
Figure 1 and 2 represent the in vitro release profiles of Carvedilol from the tablets prepared as per the compositions and processes of Example 2 and 3 respectively, in both
acidic (0.1N HCI) and near neutral (Tri-sodium orthophosphate buffer with 1% sodium lauryl sulfate, pH 6.8) environments. The overlapping nature of the profiles clearly indicate the efficacy of the delivery system in maintaining similar release rates independent of pH.

WE CLAIM:
1. A method for the preparation of an extended release matrix tablet for oral administration,
comprising the steps of:
a) preparing a blend of
i) active ingredient,
ii) 10 to 50% of water swellable cellulose derivative, such as herein described,
iii) 0,1 to 15 % of alginic acid and/or its physiologically acceptable salt, such as
herein described
iv) 0.1 to 15% by weight of cationic polymer, such as herein described, and
v) optionally pharmaceutically inert excipient, such as herein described; and
b) processing into a tablet, such as herein described,
wherein above percentages relate to total weight of tablet
2. The method as claimed in claim 1 wherein active ingredient is selected from the group
consisting of antibiotics, sympathomimetics, sympatholytic agents, cholinergic agents,
antimuscarinics, gastro-intestinal drugs, gentio-urinary smooth muscle relaxants, cardiac
drugs, anticonvulsants, tranquilizers and sedatives.
3 The method as claimed in claim 2 wherein active ingredient is selected from an antibiotic and sympatholytic agent.
4 The method as claimed in claim 3 wherein antibiotic is cefaclor.
5 The method as claimed in claim 3 wherein sympatholytic agent is Carvedilol

6. The method as claimed in claim 1 wherein water swellable cellulose derivative is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxy methylcellulose, hydroxymethyl cellulose and hydroxyethyl cellulose.
7. The method as claimed in claims wherein water swellable cellulose derivative is hydroxypropyl methylcellulose and/or hydroxypropyl cellulose.
8. The method as claimed in claim 1 wherein physiologically acceptable alginic acid salt is selected from the group consisting of sodium, potassium, calcium and magnesium salt of alginic acid.
9. The method as claimed in claim 8 wherein physiologically acceptable alginic acid salt is sodium alginate.
10. The method as claimed in claim 1 wherein cationic polymer is a methacrylic acid derivative having a dimethylaminoethyl ammonium group.
11. The method as claimed in claim 1, wherein pharmaceutically inert excipient is selected from the group consisting of binders, diluents, lubricants, glidants and colors
12. The method as claimed in claim 1 step b) wherein processing into tablet is done by a method selcected from the group consisting of wet granulation, dry granulation, and direct compression.
13. A method for the preparation of an extended release matrix tablet for oral administration, as described and illustrated by the examples herein.