WO2004096182A1

WO2004096182A1 - Extended release matrix tablets of carvedilol

Info

Publication number: WO2004096182A1
Application number: PCT/IB2004/001268
Authority: WO
Inventors: Girish Kumar Jain; Om Anand; Ashok Rampal
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2003-04-30
Filing date: 2004-04-27
Publication date: 2004-11-11

Abstract

The present invention relates to extended release matrix tablets for oral administration that include a cationic polymer, x such a methacrylic acid derivative with a dimethylaminoethyl ammonium group such as a water-swellable cellulose derivative and an alginic acid derivative to cause the release rate of the active ingredient of the talbets to be S independent of pH and gastric residence time. The present invention also relates to a dual release matrix tablet of carvedilol. The pharmaceutical composition includes carvedilol formulated into an extended release core wherein a portion of the core is surrounded by a second immediate release layer of carvedilol.

Description

EXTENDEDRELEASEMATRIXTABLETS OFCARVEDILOL

Field of the Invention

The present invention relates to extended release matrix tablets for oral administration that include a cationic polymer, a water-swellable polymer, and an alginic acid derivative to cause the release rate of the active ingredient of the tablets to be independent of pH and gastric residence time.

The present invention also relates to a dual release matrix tablet of carvedilol. The pharmaceutical composition includes carvedilol formulated into an extended release core wherein a portion of the core is surrounded by a second immediate release layer of carvedilol.

Background of the Invention

Treatment of a disease or infection in most cases requires maintaining a desired drug plasma concentration level over a prolonged period of time. Such clinical needs often are satisfied by a multiple dose therapy, which can involve frequent dosing of two to four doses per day. It can be very difficult for patients to stick to such stringent routines, which can lead to poor patient compliance and, consequently, the desired drug plasma concentration level can be below the acceptable minimum therapeutic concentration. This can lead to inadequate relief and/or the development of a tolerance or resistance to the drug. The most common approach to minimizing patient noncompliance is by using extended release drug delivery systems to decrease the number of doses that must be taken each day. One useful approach in this regard involves using a polymer-based matrix in which the drug is uniformly dispersed or dissolved. The release rate of the drug through the matrix is usually governed by the rate of dissolution of drug from the exposed surfaces and the rate of diffusion from the interior regions of the matrix to the surface.

The normal pH in the human gastrointestinal tract varies from about pH 1.0 (in fasted stomach) to about pH 8 (in lower large intestine). For drugs that 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 the distal regions of the intestinal tract depending on the pH at the absorption site and the gastric residence time. Carvedilol is an example of drag which has pH dependent solubility resulting in a deviation in the release rates into the alimentary tract. Hence, for drugs exhibiting a decreased solubility in an environment of high pH, an ideal sustained release dosage form would undergo an appropriate change in the permeation of the rate controlling layers and the rate of erosion of matrix layers. Thereby, the release rate fluctuates accordingly with the change in pH of the release environment.

Therefore, extended release matrices that can provide drug release independent of pH and gastric residence time are of particular need. One such matrix drug delivery system has been described in U.S. Patent No. 6,150,410. This patent discloses extended release pharmaceutical compositions of acidic pharmacological agents that have reduced dependence of the release rate upon pH and gastric residence time. The extended release compositions comprise a combination of water-swellable, hydrophilic polymer and acid soluble polymer which is swellable above pH 5. These compositions provide an enhanced rate of release of the acidic pharmacological agent in the stomach where the pH of the gastric juices is low and diminished release rate at neutral or slightly alkaline pH of the intestines.

Further, U.S. Patent Nos. 5,695,781 and 6,083,532 disclose a three component, release rate controlling matrix composition that includes a pH dependent gelling polymer such as an alginate component, an enteric polymer and a pH independent gelling polymer. Additionally, U.S. Patent 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 for a controlled release.

Development of a extended release dosage form whose permeation characteristics change with pH of release environment is a complicated process requiring a critical proportion of polymers of varied nature. Choice of such a combination of polymers is also a tedious and lengthy process.

Carvedilol is primarily absorbed from the intestine, particularly the small intestine because of its larger surface area. Therefore, it is necessary to provide a uniform release of carvedilol throughout the intestinal regions. Such extended release dosage forms may be formulated to achieve a uniform release in the intestine by providing an enteric coating layer over a sustained release core. Drugs indicated for treatment of cardiovascular diseases demand a quick onset of action i.e., attainment of the therapeutic plasma concentration as soon as possible. Hence, to avoid a delay in onset of action, these extended release cores may be layered with a second immediate release layer of carvedilol.

Despite these efforts, there remains a need for extended release pharmaceutical compositions for oral administration, from which a wide range of drugs can be released, irrespective of pH and gastric residence time.

Summary of the Invention hi one general aspect there is provided a dual release matrix tablet for oral administration. The tablet includes an extended release matrix core and an immediate release layer surrounding at least a portion of the core. The core includes carvedilol, one or more water swellable derivatives, one or more alginic acid derivatives, and one or more cationic polymers. The immediate release layer includes carvedilol. The extended release matrix may be present from about 10% to about 80% by weight of the total core weight.

The immediate release carvedilol layer may be present from about 5% to about 50% of the total dose of carvedilol. In particular, the immediate release carvedilol layer comprises about 30% of the total dose of carvedilol.

The water swellable cellulose derivative may include one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxy methylcellulose, hydroxy methylcellulose and hydroxy ethylcellulose. The water swellable cellulose derivative may be hydroxypropyl methylcellulose. In another embodiement, the water swellable cellulose derivative may be hydroxypropyl cellulose.

The alginic acid derivative includes one or more alginic acid and its physiologically acceptable salts. The physiologically acceptable alginic acid salts may include one or more of sodium, potassium, calcium and magnesium salts of alginic acid. The physiologically acceptable alginic acid salt may be sodium alginate.

The cationic polymer includes one or more methacrylic acid derivative with a dimethylaminoethyl ammonium group. The methacrylic acid derivative with a dimethylatninoethyl ammonium group may be Eudragit® E 100. In another embodiment, the methacrylic acid derivative with a dimethylaminoethyl ammonium group may be Eudragit® EPO. The methacrylic acid copolymers may include one or more of Eudragit L 100-55, Eudragit L30 D-55, Eudragit L 100, Eudragit S 100; and mixtures thereof. In another embodiment, an enteric layer between may be included between the core and the immediate release layer. The enteric coating layer may include one or more enteric polymers. The enteric polymer(s) may include one or more of cellulose acetate phthalate, cellulose acetate, hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate phthalate, hydroxy propyl phthalate, hydroxypropylmethyl phthalate, hydroxypropyl methylcellulose acetate succinate; methacrylic acid copolymers. The enteric polymer may be Eudragit L 100-55. The enteric coating layer may be used at a concentration of from about 1% to about 60% by weight of total core weight. In > particular, the enteric coating layer maybe present at concentrations from about 1% to about 20 % by weight of total core weight.

The immediate release carvedilol layer my further include one or more film forming agents. The film forming agents may include one or more of ethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes; and methacrylic acid polymers such as Eudragit ® RL and RS. The film forming agent may be hydroxypropyl methylcellulose.

The dual release matrix tablet may also include one or more pharmaceutically inert excipients. The pharmaceutically inert excipients may include one or more of binders, diluents, lubricants, glidants and colors.

The binders may include one or more of methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvmylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate and propylene glycol. The diluents may include one or more of calcium carbonate, calcium phosphate- dibasic, calcium phosphate-tribasic, 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 The lubricants and glidants may include one or more of colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated caster oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax and white beeswax. In another general aspect there is provided a process for the preparation of a dual release matrix tablet of carvedilol. The process includes blending an extended release portion of carvedilol with one or more water swellable derivatives, one or more alginic acid derivatives, and one or more cationic polymers. Optionally granulating the blend. Compressing into a suitable size core and coating the core with an immediate release carvedilol layer.

The process may further include coating the core with an enteric layer.

The blend may be granulated using a wet granulation or dry granulation method.

In particular, the granulation may be done using a wet granulation method. The enteric and the immediate release carvedilol layers may be applied as a solution/dispersion. The solution/dispersion may be prepared in solvents including one or more of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and combinations thereof. In particular, the enteric and the immediate release carvedilol layers may be applied using the hot melt technique. In another general aspect there is provided a method for the treatment of congestive heart failure and/or hypertension in a subject in need of. The method includes administering to the subject a dual release matrix tablet. The tablet includes one or more water swellable derivatives, one or more alginic acid derivatives, and one or more cationic polymers formed into a core and an immediate release layer surrounding at least a portion of the core. The immediate release layer may include carvedilol.

Detailed Description of the Invention

There is a pH gradient along the gastrointestinal tract that varies between the acidity of the stomach, the weakly acidic environment of the duodenum, and the neutral environment of the small intestine. In addition to this general variation in pH, there are fluctuations in pH arising from dietary changes. For example, fed and fasting states both affect the acidic environment of the stomach, and likewise would affect a drug product with a pH-dependent drug release if the drug were taken with or between meals. Extended release products providing pH independent drug release avoid bioavailability variations occurring due to these fluctuations of gastrointestinal pH. Therefore, it is desirable to achieve an extended release rate of a drag which is independent of pH and gastric residence time. Accordingly, there is provided an extended release matrix tablet that includes a water swellable cellulose derivative, an alginic acid derivative, and a cationic polymer, from which an active ingredient is released at a controlled rate.

The use of this polymer combination provides a 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 absorbs water and swells to form a viscous consistency, which thereby retards the release of the drag. On the other hand the cationic polymer dissolves at the lower pH conditions causing the erosion of matrix, which exposes more drug to the dissolution media and consequently enhances the 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.

Also provided is a dual release matrix tablet of carvedilol for oral administration which includes an extended release matrix core as above coated with a second immediate release carvedilol layer. An enteric coating layer may be applied between the core and enteric coating layer.

On administration, the dual release matrix pharmaceutical composition provides a quick onset of action, with the release of carvedilol in the stomach from the immediate release layer, followed by an extended release of carvedilol from the core over a prolonged period of time. For dosage forms coated with an enteric layer, upon decent into the intestinal region, the enteric layer erodes exposing the core to intestinal contents. For enteric coated tablets, the release of carvedilol initiates from the extended release core in the intestinal region. However, by properly controlling the thickness of enteric layer, the site for initiation of extended release from the core may be varied. In cases, where an unexpected delay in gastric emptying can be predicted, the enteric coating thickness be altered to initiate carvedilol release from the core in the stomach itself. This maintains the plasma concentration above the minimum therapeutic level for a longer period of time and prevents fluctuations in therapeutic levels due to inconsistent gastric emptying. The term "carvedilol" as used herein includes both carvedilol and pharmaceutically acceptable salts thereof. The core may include from about 50% to about 95% of the total dose of carvedilol. Thus, the immediate release layer may include from about 5% to about 50% of the total dose of carvedilol. In particular, the immediate release layer may include about 30% of the total dose of carvedilol.

The term 'dual release" as used herein refers to two different phases of carvedilol release, with or without a lag time between the two phases. The first phase includes an immediate release of carvedilol from the immediate release layer and the second phase includes an extended release from the extended release core.

The term "pH independent release" as used herein refers to similar drug release rates varying not more than 20% when compared in acidic (0. IN HCI) and near neutral (pH 6.8) environments. The extended release matrix tablet can be used for drugs independent of their solubility characteristics. Preferred active ingredients may be selected from one or more of antibiotics, sympathomimetics, sympatholytic agents, cholinergic agents, antimuscarinics, gastro-intestinal drags, gentio-urinary smooth muscle relaxants, cardiac drugs, anticonvulsants, tranquilizers, and sedatives. The water swellable cellulose derivatives that are used in the extended release tablet may be selected from one or more of hydroxypropyl methylcellulose, hydroxypropyleellulose, methylcellulose, carboxy methyleellulose, hydroxy methylcellulose, and hydroxy ethylcellulose. hi particular, a suitable cellulose derivative is hydroxypropyl methylcellulose. Hydroxypropyl methylcellulose is commercially available as MethocelO, which is manufactured by Dow Chemicals and available in various grades. The preferred grades of Methocel@ are K-4 MCR, K1OOV, K4MP, K15MP,KlOOMP,E4MP,ElOMP-CR,E5. The water swellable cellulose derivative may constitute about 10% to about 50% by weight of the total weight of formulation.

The alginic acid derivatives that are used in the extended release tablets include both alginic acid and its physiologically acceptable salts such as those of sodium, potassium, magnesium and calcium. These compounds are commercially available in different grades. The preferred grades are Keltone LVCR and KELACID, which are 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 that are used in the extended release tablets include methacrylic acid derivatives with a dimethylaminoethyl ammonium group, h particular, Eudragit® E 100 and Eudragit® EPO, both of which are marketed by Rohm Pharma, may be selected. 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 the formulation. According to the fourth addition of the Handbook of Pharmaceutical Excipients 'Eudragit E is a cationic polymer based on dimethylaminoethyl methacrylate and other neutral methacrylic acid esters. It is soluble in gastric fluid as well as in weakly acidic buffer solutions (up to pH of approximately 5). The structure of Eudragit E is given in the handbook as:

where: R¹ = R³ = CH₃

R = CH₃, C₄H₉

The dosage form may also contain other pharmaceutically inert excipients such as binders, diluents, lubricants, glidants and coloring agents. Suitable binders may be selected from one or more of methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvmylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate and propylene glycol. Suitable diluents may be selected from one or more of calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, 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 may be selected from one or more of colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated caster oil, sucrose esters of fatty acid, macrocrystalline wax, yellow beeswax and white beeswax. Suitable colors may be selected from any FDA approved colors for internal use. The formulation may optionally be coated, if desired.

In embodiments relating to dual release matrix tablets of carvedilol, the immediate release layer may comprise from about 5% to about 50% by weight of the total dose of carvedilol, a film forming agent, with or without other pharmaceutically inert excipients.

Alternatively, commercially available coating compositions marketed under various trade names, such as Opadry® may also be used for the coating purpose.

Suitable film forming agents include ethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes, such as, polyethylene glycol; methacrylic acid polymers, such as, Eudragit ® RL and RS; and the like; and combinations thereof. hi embodiments relating to the dual release matrix tablets of carvedilol, the enteric layer may include one or more enteric polymers with or without other pharmaceutically inert excipients. Examples of enteric polymer include one or more of cellulose acetate phthalate, cellulose acetate, hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl phthalate, hydroxypropylmethyl phthalate, hydroxypropyl methylcellulose acetate succinate; methacrylic acid copolymers, such as, Eudragit^® L 100-55, Eudragit^® L30 D-55, Eudragit^® L 100, Eudragit^® S 100; and the like, and combinations thereof. The enteric layer may constitute from about 1% to about 60% by weight of total core weight. In particular, the enteric layer may constitute from about 1% to about 20% by weight of total core weight.

The extended release matrix tablet may be prepared by blending the diluent and the control release polymers into a homogenous blend; incorporating the active drag ingredient 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.

Mixing solid ingredients in a geometric progression generally refers to a process of adding almost equal amounts of two ingredients and then mixing to form a homogenous mixture of the two. This process is repeated by further mixing equal amounts to the mixture until the entire first ingredient is consumed. The entire mixture then is divided into, for example, four equal proportions and small amounts are taken from each portion and mixed thoroughly. This mixing is continued by adding from each portion until all the portions are completely used. The mixture then is further divided into two portions and the above process is repeated and ultimately the entire mixture is mixed randomly. In one embodiment, a process for preparing extended release matrix tablets includes (a) dry blending the mixture of control release polymers and active drag ingredient into a homogeneous blend; (b) dry granulating the drug mixture from step (a); and (c) compressing the granules to form tablets.

In another embodiment, a process for preparing extended release matrix tablets includes (a) dry blending the mixture of control release polymers and active drag ingredient into a homogeneous blend; (b) wet granulating the dry mixture from step (a); (c) drying and sizing the wet granules from step (b); and (d) compressing the granules to form tablets. hi a further embodiment, a process for preparing extended release matrix tablets includes (a) dry blending the mixture of control release polymers and active drag ingredient into a homogeneous blend; and (b) directly compressing into tablets.

In other embodiments, the dual release matrix tablet of carvedilol is prepared by coating the extended release matrix core (tablet) prepared in any of the embodiments above with enteric and immediate release layers. Coating of the core with enteric layer involves preparing a solution and/or dispersion of the coating materials in an aqueous or non-aqueous solvent or mixtures thereof; and layering of the solution or dispersion over the cores using any conventional coating teclmique known in the art, such as, spray coating in a conventional coating pan or fluidized bed process or dip coating. Alternatively, coating can also be performed using the hot melt technique whenever possible. Hot melt preparation may involve dispersing or dissolving carvedilol and/or film forming agents and pharmaceutically inert excipients in a hot melt of a suitable polymer, such as, polyethylene glycol.

The enteric coated cores may be layered with immediate release carvedilol layer using the immediate release portion of carvedilol, film forming agent(s) with or without other pharmaceutically inert excipients in the same manner as above. Suitable solvents for granulation or coating processes include one or more of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water, and the like, and combinations thereof.

Also provided is a method for the treatment of congestive heart failure and/or hypertension in a subject wherein the method includes administering to a subject in need thereof, a dual release matrix tablet of carvedilol for oral administration. The pharmaceutical composition includes an extended release matrix core including carvedilol coated with an immediate release carvedilol layer.

The subject may be a mammal, and in particular a human.

The following examples further exemplify the inventions and are not intended to limit the scope of the inventions.

EXAMPLE 1

Process:

1. Lactose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium alginate and Eudragit® EPO were sieved through #BSS 44 and mixed in a double cone blender for 20 minutes.

Cefaclor was passed through sieve #BSS 44 and blended with the above mixture for 20 minutes.

The blend of step 3 was then mixed with talc and colloidal anhydrous silica for ten minutes.

4. The mixture of step 4 was lubricated by mixing with magnesium stearate for five minutes and compressed to form tablets.

EXAMPLE 2

Process:

1. Lactose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium alginate, alginic acid and Eudragit® EPO were sieved through #BSS 44 and mixed in a 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 ten minutes.

The mixture of step 4 was lubricated by mixing with magnesium stearate for five minutes and compressed to form tablets.

EXAMPLE 3

Process:

1. Carvedilol, lactose and 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 60 C and sizing through sieve #BSS 30.

3. Hydroxypropyl cellulose, hydroxypropyl methylcellulose, alginic acid derivatives and Eudragit® EPO were passed through sieve #BSS 44 and blended in double cone blender for ten 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 five minutes.

6. The mixture of step 5 was finally lubricated by mixing with magnesium stearate (passed through #BSS44) for five 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 HCl) and near neutral (Tri-sodium orthophosphate buffer with 1% sodium lauryl sulfate, pH 6.8) environments. The overlapping nature of the profiles clearly indicates the efficacy of the delivery system in maintaining similar release rates independent of pH.

EXAMPLE 4 (!) Extended Release Matrix Core

Intra granular Carvedilol 35.21 mg Lactose 69.79 mg

Hydroxypropyl methylcellulose 14.00 mg Water qs

Extra granular

Hydroxypropyl methylcellulose 66.9 mg Sodium alginate 4.90 mg

Alginic acid 7.00 mg

Eudragit^® EPO 14.00 mg

Magnesium stearate 2.10 mg

Talc 1.40 mg Colloidal silicon dioxide 0.70 mg (ii) Enteric Layer

Eudragit^® L 100-55 41.25 g

Sodium Hydroxide 0.563 g

Polyethylene glycol 300 4.125 g Talc 12.375 g

Titanium dioxide 0.70 g

Water qs

(iii) Immediate Release Layer Carvedilol 15.00 mg

Polyethylene glycol 6000 15.00 mg

Polyvinyl pyrrolidone 2.00 mg

Hydroxypropyl methyl cellulose 10.00 mg

Water qs Procedure:

I. Extended Release Matrix Core

Intragranular carvedilol, lactose and hydroxypropyl methylcellulose were mixed and granulated with water. The granules were dried and sieved. Extragranular hydroxypropyl methylcellulose, sodium alginate, alginic acid and Eudragit^® EPO were blended together and mixed with the granules. Talc and colloidal silicon dioxide were mixed with the blend. The blend was finally blended with magnesium stearate and compressed into extended release core tablets.

II. Enteric Layer

Eudragit was mixed in water to prepare a homogenous dispersion. The dispersion was made alkaline by adding sodium hydroxide solution to it.

Polyethylene glycol, titanium dioxide and talc were dispersed in the dispersion to prepare a final homogenous dispersion used for coating, up to a weight build up of about 5% of the total core weight.

III. Immediate Release Layer Carvedilol was mixed homogenously in a melt of polyethylene glycol and then dried to obtain a solid dispersion. The dried solid dispersion was crashed in to small pieces and dispersed in water. Hydroxypropyl methylcellulose and polyvmylpyrrolidone were homogenously mixed in dispersion to prepare the final coating composition for coating. Table 1 illustrates the in vitro release profile of carvedilol from the tablets prepared according to example 4, using USP apparatus - 1, at 100 rpm, and 1000 ml phosphate buffer (pH 6.8, 1.1% sodium lauryl sulphate).

Table 1. In vitro release pattern of carvedilol from matrix tablets prepared according to Example 4

EXAMPLE 5 (i) Extended Release Matrix Core (tablet) Intra granular

Carvedilol 35.0 mg

Lactose 70.0 mg

Hydroxypropyl methylcellulose 14.0 mg

Water qs

Extra granular

Hydroxypropyl methylcellulose 81.0 mg

Hydroxypropylcellulose 17.5 mg

Sodium alginate 4.9 mg

Alginic acid 7.0 mg

Eudragit^® EPO 14.0 mg

Magnesium stearate 2.1 mg

Talc 1.4 mg

Colloidal silicon dioxide 0.7 mg (ii) Enteric Layer

Eudragit^® L 100-55 41.25 g

Sodium Hydroxide 0.563 g

Polyethylene glycol 300 4.125 g

Talc 12.375 g

Titanium dioxide 0.70 g

Water qs (iii) Immediate Release Layer

Carvedilol 15.00 mg

Opadry^® OY-S-58910 15.00 mg

Water qs Procedure:

I. Extended Release Matrix Core (tablet)

Intragranular carvedilol, lactose and hydroxypropyl methylcellulose were mixed and granulated with water. The granules were dried and sieved. Extragranular hydroxypropyl methylcellulose, hydroxypropylcellulose, sodium alginate, alginic acid and Eudragit^® EPO were blended together and mixed with the granules. Talc and

Colloidal silicon dioxide were mixed with the blend and then blended with magnesium stearate and compressed into extended release core tablets.

II. Enteric Layer

Polyethylene glycol, titanium dioxide and talc were dispersed in the dispersion to prepare a final homogenous dispersion used for coating, up to a weight build up of about 8% of the total core weight.

III. Immediate Release Layer A solution of carvedilol and Opadry^® was prepared in water.

The solution was used for final coating of the enteric coated tablets with the immediate release layer.

Table 2 illustrates the in vitro release pattern of carvedilol from the tablets prepared according to example 2, using USP apparatus - 1, at 100 rpm, and 1000 ml phosphate buffer (pH 6.8, 1.1% sodium lauryl sulphate). Table 2. In vitro release pattern of carvedilol from matrix tablets prepared according to Example 2

While several particular forms of the invention have been described, it will be apparent that various modifications and combinations of the invention detailed in the text can be made without departing from the spirit and scope of the invention. Accordingly, it is not intended that the invention be limited, except as by the appended claims.

Claims

We Claim: 1. A dual release matrix tablet for oral administration, the tablet comprising: an extended release matrix core comprising carvedilol, one or more water swellable derivatives, one or more alginic acid derivatives, and one or more cationic polymers; and an immediate release layer surrounding at least a portion of the core, the immediate release layer comprising carvedilol.

2. The dual release matrix tablet of claim 1, further comprising an enteric layer between the core and the immediate release layer.

3. The dual release matrix tablet of claim 1, wherein the water swellable cellulose derivative comprises one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxy methylcellulose, hydroxy methylcellulose and hydroxy ethylcellulose.

4. The dual release matrix tablet of claim 3, wherein the water swellable cellulose derivative comprises hydroxypropyl methylcellulose.

5. The dual release matrix tablet of claim 3, wherein the water swellable cellulose derivative comprises hydroxypropyl cellulose.

6. The dual release matrix tablet of claim 1, wherein the alginic acid derivative comprises alginic acid and its physiologically acceptable salts.

7. The dual release matrix tablet of claim 6, wherein the physiologically acceptable alginic acid salts comprise one or more of sodium, potassium, calcium and magnesium salts of alginic acid.

8. The dual release matrix tablet of claim 7, wherein the physiologically acceptable alginic acid salt comprises sodium alginate.

9. The dual release matrix tablet of claim 1, wherein the cationic polymer comprises a methacrylic acid derivative with a dimethylaminoethyl ammonium group.

10. The dual release matrix tablet of claim 9, wherein the methacrylic acid derivative with a dimethylatninoethyl ammonium group comprises Eudragit® E 100.

11. The dual release matrix tablet of claim 9, wherein the methacrylic acid derivative with a dimethylaminoethyl ammonium group comprises Eudragit® EPO.

12. The dual release matrix tablet of claim 1 , wherein the extended release matrix comprises from about 10% to about 80% by weight of the total core weight.

13. The dual release matrix tablet of claim 2, wherein the enteric coating layer comprises an enteric polymer.

14. The dual release matrix tablet of claim 13, wherein enteric polymer is selected from cellulose acetate phthalate, cellulose acetate, hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate phthalate, hydroxy propyl phthalate, hydrόxypropylmethyl phthalate, hydroxypropyl methylcellulose acetate succinate; methacrylic acid copolymers.

15. The dual release matrix tablet of claim 14, wherein the methacrylic acid copolymers comprise one or more of Eudragit^® L 100-55, Eudragit^® L30 D-55, Eudragit^® L 100, Eudragit^® S 100; and mixtures thereof.

16. The dual release matrix tablet of claim 15 wherein enteric polymer is Eudragit^® L 100-55.

17. The dual release matrix tablet of claim 2, wherein the enteric coating layer comprises from about 1% to about 60% by weight of total core weight.

18. The dual release matrix tablet of claim 17, wherein the enteric coating layer comprises from about 1% to about 20 % by weight of total core weight.

19. The dual release matrix tablet of claim 1, wherein the immediate release carvedilol layer comprises from about 5% to about 50% of the total dose of carvedilol.

20. The dual release matrix tablet of claim 19, wherein the immediate release carvedilol layer comprises about 30% of the total dose of carvedilol.

21. The dual release matrix tablet of claim 1 , wherein the immediate release carvedilol layer further comprises one or more film forming agent.

22. The dual release matrix tablet of claim 21 , wherein the film forming agent comprises one or more of ethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes; and methacrylic acid polymers such as Eudragit ® RL and RS.

23. The dual release matrix tablet of claim 22, wherein the film forming agent comprises hydroxypropyl methylcellulose.

24. The dual release matrix tablet of claim 1, wherein the tablet further comprises one or more pharmaceutically inert excipients.

25. The dual release matrix tablet of claim 24, wherein the pharmaceutically inert excipients comprise one or more of binders, diluents, lubricants, glidants and colors.

26. The dual release matrix tablet of claim 25, wherein the binders comprise one or more of methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvmylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate and propylene glycol.

27. The dual release matrix tablet of claim 25, wherein the diluents comprise one or more of calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, 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

28. The dual release matrix tablet of claim 25, wherein lubricants and glidants comprise one or more of colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated caster oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax and white beeswax.

29. A process for the preparation of dual release matrix tablet of carvedilol, the process comprising: a) blending an extended release portion of carvedilol with one or more water swellable derivatives, one or more alginic acid derivatives, and one or more cationic polymers; b) optionally granulating the blend; c) compressing into a suitable size core; and d) coating the core with an immediate release carvedilol layer.

30. The process for the preparation of dual release matrix tablet of carvedilol of claim 29, wherein the core is coated with an enteric layer.

31. The process for the preparation of dual release matrix tablet of carvedilol of claim 29, wherein the blend is granulated using a wet granulation or dry granulation method.

32. The process for the preparation of dual release matrix tablet of carvedilol of claim 31 , wherein the granulation is done by wet granulation method.

33. The process for the preparation of dual release matrix tablet of carvedilol of claim 29, wherein the enteric and the immediate release carvedilol layers are applied as a solution/dispersion.

34. The process for the preparation of dual release matrix tablet of carvedilol of claim 33, wherein the solution/dispersion is prepared in solvents comprising one or more of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and combinations thereof.

35. The process for the preparation of dual release matrix tablet of carvedilol of claim 29, wherein the enteric and the immediate release carvedilol layers are applied using hot melt technique.

36. A method for the treatment of congestive heart failure and or hypertension in a subject in need of, the method comprising administering to the subject a dual release matrix tablet, the tablet comprising: one or more water swellable derivatives, one or more alginic acid derivatives, and one or more cationic polymers; and an immediate release layer surrounding at least a portion of the core, the immediate release layer comprising carvedilol.