WO2005084636A2

WO2005084636A2 - A process for the preparation of controlled-release pharmaceutical composition of metoprolol

Info

Publication number: WO2005084636A2
Application number: PCT/IB2005/000501
Authority: WO
Inventors: Rajeev Singh Raghuvanshi; Pramod Kharwade; Prashant Manohar Mandaogade; Ashok Rampal
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2004-02-27
Filing date: 2005-02-25
Publication date: 2005-09-15
Also published as: WO2005084636A3

Abstract

The present invention relates to processes for preparing an oral controlled-release pharmaceutical composition of metoprolol succinate comprising a plurality of beads, which comprise a water soluble or water swellable inert core. Further, the present invention relates to processes of preparing oral controlled-release pharmaceutical compositions of metoprolol succinate comprising a plurality of beads, which comprise an inert core and one or more drug layers comprising metoprolol, wherein the soluble component of inert core and one or more drug layers comprise less than 95% w/w of a salt of metoprolol.

Description

A PROCESS FOR THE PREPARATION OF CONTROLLED-RELEASE PHARMACEUTICAL COMPOSITION OF METOPROLOL Field of the Invention The present invention relates to processes for preparing an oral controlled-release pharmaceutical composition of metoprolol succinate comprising a plurality of beads, which comprise a water soluble or water swellable inert core. Further, the present invention relates to processes of preparing oral controlled-release pharmaceutical compositions of metoprolol succinate comprising a plurality of beads, which comprise an inert core and one or more drug layers comprising metoprolol, wherein the soluble component of inert core and one or more drug layers comprise less than 95% w/w of a salt of metoprolol. Background of the Invention Metoprolol, which is a beta adrenoreceptor antagonist, is available in various salt forms, such as tartrate, fumarate, succinate, hydrochloride, benzoate etc. These salts differ in their solubility, e.g., succinate, fumarate and benzoate salts have solubility less than 600 mg/ml in water at 25°C, whereas hydrochloride and tartrate are very soluble in water. Generally salts with less solubility are preferred for the preparation of controlled-release pharmaceutical compositions. Metoprolol is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. Metoprolol is also indicated in the long-term treatment of angina pectoris and stable, symptomatic (NYHA Class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin. Metoprolol is rapidly and completely absorbed, but plasma levels achieved are highly variable after oral administration. Besides, it also has relatively short elimination half-lives, e.g., 3-7 hours in adults. Frequent dosing is thus necessary to maintain reasonably stable plasma concentrations. However, frequent dosing results in inconvenience to the patient and leads to poor compliance. Moreover, widely fluctuating plasma concentrations of the drug also result in availability of erratic amounts of drug. A solution to the above problem is oral controlled-release pharmaceutical composition comprising metoprolol succinate that leads to reduced frequency of drug being administered and thereby helps in maintaining a reasonably stable plasma concentration. U.S. Patent Nos. 4,927,640 and 4,957,745 disclose a controlled-release preparation containing a number of beads comprising insoluble cores coated with metoprolol. The beads have a high content of metoprolol in the range of 95-100% w/w of the soluble part of the bead. Insoluble cores, such as silicon dioxide and small particles of core, are used. In addition, hydrophobic core particles develop excessive static charge that lead to problems during processing. U.S. Patent Publication 2003/0185887 discloses a controlled or sustained release dosage formulation of propranolol where the inert core is coated with a solution of propranolol, water insoluble binder and filler. The active core so produced is further coated with a release controlling layer. However, there remains a need for new processes in preparing controlled-release pharmaceutical compositions of metoprolol having desirable release profiles. Summary of the Invention Provided herein are oral controlled-release pharmaceutical compositions of metoprolol succinate comprising a plurality of beads comprising: a water soluble, water swellable or water-insoluble inert core; one or more drug layers comprising metoprolol; and one or more polymeric coatings surrounding the one or more drug layers. Embodiments of the pharmaceutical compositions can include one or more if the following features. For example, the one or more drug layers can further comprise a binding agent selected from polymethacrylates, ethylcellulose, povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose or mixtures thereof. The inert core can have a diameter from about 150-600 μm. The water-soluble inert core can comprises sugar or salt. The sugar can be glucose, mannitol, lactose, xylitol, dextrose, sucrose or mixtures thereof, and the salt can be sodium chloride, potassium chloride or mixtures thereof. The water-swellable core can comprise hydroxypropyl methylcellulose, microcrystalline cellulose, starch or mixtures thereof. The water-insoluble inert core can comprise silicon dioxide, small particles of glass, plastic resin particles or mixtures thereof. The one or more polymeric coatings can comprise one or more extended release polymers selected from one or more water soluble polymers, one or more water insoluble polymer or mixtures thereof. The one or more water-soluble polymers can be polyvinylpyrrolidine, hydroxypropylcellulose, hydroxypropyl methylcellulose, methylcellulose, vinyl acetate copolymers, polysaccharides, polyethylene oxide, methacrylic acid copolymers, aleic anhydride/methyl vinyl ether copolymers or derivatives or mixtures thereof. The water-insoluble polymers can be acrylates; cellulose derivatives; polyethylene, and high molecular weight polyvinylalcohols. The acrylates can be methacrylates, acrylic acid copolymers or mixtures thereof; and the cellulose derivatives are selected from ethylcellulose, cellulose acetate or mixtures thereof. The pharmaceutical composition can further comprise one or more pharmaceutically inert excipients selected from the group consisting of surfactants, binders, diluents, disintegrants, lubricants, glidants, plasticizers, stabilizers, coloring agents or mixtures thereof. The pharmaceutical composition can also further comprise one or more non-functional coatings. The one or more non-functional coatings comprise polyethylene glycol. The beads of the pharmaceutical compositions can have a diameter ranging from 500- 850 μm. The beads can be processed into a solid dosage form selected from a tablet, a capsule or a sachet. The pharmaceutical composition can be free of any diluent. The pharmaceutical composition can also be free of microcrystalline cellulose.

Also provided herein are oral controlled-release pharmaceutical compositions of metoprolol succinate comprising a plurality of beads comprising: an inert core; one or more drug layers comprising metoprolol; and one or more polymeric coatings surrounding the core, wherein the inert core comprises a soluble component, and the soluble component of the inert core and one or more drug layers comprise less than 95% w/w of a salt of metoprolol. The soluble component can be 60-90% w/w. Also provided herein are processes for preparing oral controlled-release pharmaceutical compositions of metoprolol succinate, as described herein, wherein the processes involve the steps of: a) preparing a solution or dispersion of metoprolol in one or more solvents; b) spraying the above-prepared solution or dispersion onto a water soluble or swellable inert core and drying off the solvent; c) preparing a solution or dispersion of a polymeric mixture in one or more solvents; d) coating the core obtained in step b) with a polymeric solution or dispersion obtained in step c) and drying off the solvent, e) optionally coating the core obtained in step d) with one or more non-functional coating such as polyethylene glycol.

The one or more solvents use in these processes can be dichloromethane, isopropyl alcohol, acetone, methanol, ethanol, water or mixture thereof. Detailed Description of the Invention Generally provided herein are controlled-release pharmaceutical compositions having desirable release profiles, as well as processes to prepare same. In particular, provided herein are oral controlled-release pharmaceutical compositions of metoprolol succinate comprising a plurality of beads comprising an inert core and one or more drug layers wherein the soluble component comprises 60-80% w/w of a salt of metoprolol. Also provided herein are processes for preparing oral controlled-release pharmaceutical compositions of metoprolol succinate comprising a plurality of beads comprising a water soluble or water swellable inert core. Therefore, in one aspect, provided herein are oral controlled-release pharmaceutical compositions of metoprolol succinate comprising a plurality of beads comprising a) a water soluble or water swellable inert core; b) one or more drug layers comprising metoprolol; and c) one or more polymeric coatings surrounding the one or more drug layers. In another aspect, provided herein are processes for preparing oral controlled-release pharmaceutical compositions of metoprolol succinate comprising a plurality of beads comprising: a) a water soluble or water swellable inert core; b) one or more drug layers comprising metoprolol; and c) one or more polymeric coatings surrounding the one or more drug layers. In another aspect, provided herein are oral controlled-release pharmaceutical compositions of metoprolol succinate comprising a plurality of beads comprising a) a water soluble or water swellable inert core; b) one or more drug layers comprising metoprolol; and c) one or more polymeric coatings surrounding the one or more drug layers; d) optionally, one or more non-functional coatings surrounding the one or more polymeric coatings, wherein the one or more drug layers are free of any diluent. In another aspect, provided herein are processes for preparing oral controlled-release pharmaceutical compositions of metoprolol succinate comprising a plurality of beads comprising: a) a water soluble or water swellable inert core; b) one or more drug layers comprising metoprolol; and c) one or more polymeric coatings surrounding the one or more drug layers; d) optionally, one or more non-functional coatings surrounding the one or more polymeric coatings, wherein the one or more drug layers are free of any diluent. In one aspect, provided herein are oral controlled-release pharmaceutical compositions of metoprolol succinate comprising a plurality of beads comprising: a) an inert core; b) one or more drug layers comprising metoprolol; and c) one or more polymeric coatings surrounding the core; d) optionally, one or more non-functional coatings surrounding the one or more polymeric coatings, wherein the soluble component of inert core and the one or more drug layers comprise less than 95% w/w of a salt of metoprolol. In one aspect, provided herein are processes for preparing oral controlled-release pharmaceutical compositions of metoprolol succinate comprising a plurality of beads comprising: a) an inert core; b) one or more drug layers comprising metoprolol; and c) one or more polymeric coatings surrounding the core; d) optionally, one or more non-functional coatings surrounding the one or more polymeric coatings, wherein the soluble component of inert core and the one or more drug layers comprises less than 95% w/w of a salt of metoprolol. In another aspect, provided herein are oral controlled-release pharmaceutical compositions of metoprolol succinate comprising a plurality of beads comprising: a) an inert core; b) one or more drug layers comprising metoprolol; and c) one or more polymeric coatings surrounding the core; d) optionally, one or more non-functional coatings surrounding the one or more polymeric coatings, wherein the one or more drug layers are free of any diluent and the soluble component of inert core and one or more drug layers comprise less than 95% w/w of a salt of metoprolol. In another aspect, provided herein are processes for preparing oral controlled-release pharmaceutical compositions of metoprolol succinate comprising a plurality of beads comprising: a) an inert core; b) one or more drug layers comprising metoprolol; and c) one or more polymeric coatings surrounding the core; d) optionally, one or more non- functional coatings surrounding the one or more polymeric coatings, wherein the one or more drug layers are free of any diluent and the soluble component of inert core and the one or more drug layers comprise less than 95% w/w of a salt of metoprolol. The phrase "pharmaceutical composition," as used herein, includes solid dosage forms such as tablets, capsules, pills and like. For example, tablets can be prepared by techniques known in the art and contain a therapeutically effective amount of metoprolol and such excipients as are necessary to form the tablet. The phrase "controlled-release pharmaceutical composition," as used herein, includes any pharmaceutical composition that achieves slow release of drug over an extended period of time, and includes both prolonged and sustained-release compositions. The phrase "inert core," as used herein, includes water insoluble, soluble and swellable cores. The phrase "soluble component of inert core and drug layer," as used herein, includes material that is soluble or swellable in water. Typically, the soluble component of the inert core and one or more drug layers comprise less than 95% w/w of a salt of metoprolol, and particularly 60-90% w/w. The inert core can be, for example, water-insoluble, water-soluble and water-swellable cores. Water-insoluble cores include, for example, silicon dioxide, small particles of glass, or plastic resin particles, e.g., polypropylene or polyethylene. Water-soluble cores include, for example, sugar spheres, e.g., glucose, mannitol, lactose, xylitol, dextrose or sucrose, and salt cores, e.g., sodium chloride or potassium chloride. Water swellable core may be made up of hydroxypropyl methylcellulose, microcrystalline cellulose (Celphere ), starch or mixtures thereof. Inert cores may have diameters ranging from about 150-600 μm, preferably from about 250-425 μm. Inert cores can be coated with one or more drug layers comprising metoprolol. Drug layers may further comprise one or more binding agents to give proper adhesion of the drug layer(s) to inert core. Binding agents include, for example, water-insoluble or water-soluble binding agents that are commonly known in the art, e.g., hydroxypropyl methylcellulose, povidone, hydroxypropyl cellulose, polymethacrylates, ethylcellulose, or mixtures thereof, and in particular hydroxypropyl methylcellulose, e.g. , Methocel E5. Drug layers can be applied onto the inert core by techniques, for example, spray coating in a conventional coating pan or fluidized bed processor or dip coating from a solution or dispersion of the drug. Beads coated with one or more drug layers can then be coated with one or more polymeric coatings, which include coating with one or more extended release polymers (to obtain desired release profile), one or more non-functional coatings, or mixtures thereof. Examples of extended release polymer include water soluble polymers, water insoluble polymers or mixtures thereof. The phrase "water soluble polymer," as used herein, means a polymer that is soluble in water dependent or independent of the pH. Examples of water- soluble polymers include, but are not limited to, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropyl methylcellulose, methylcellulose, vinyl acetate copolymers, polysaccharides (e.g., alginate, xanthum gum, etc.), polyethylene oxide, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers and derivatives or mixtures thereof. Examples of water-insoluble polymers include acrylates (e.g., methacrylates, acrylic acid copolymers); cellulose derivatives (e.g., ethylcellulose or cellulose acetate); polyethylene; and high molecular weight polyvinylalcohols. Non-functional coatings (e.g., polyethylene glycol) can facilitate in forming a smooth surface and better appearance of a pharmaceutical composition. Non-functional coatings can also help in overcoming common problems, including rupturing or cracking of release-controlling layers/membrane or fragmentation of the core due to mechanical stress generated during compression of cores into tablets or filling into capsules/sachets. Beads so obtained can have a diameter ranging from about 500-850 μm. Coating solutions may be applied using techniques, for example, spray coating in a conventional coating pan or fluidized bed processor or dip coating. Solutions or dispersions of polymers can be prepared in solvents, for example, dichloromethane, isopropyl alcohol, acetone, methanol, ethanol, water or mixtures thereof. Alternatively, polymeric coating may be applied using commercially available coating mixtures, for example, Opadry^®. Coating solutions may further comprise other pharmaceutically acceptable ingredients, for example, plasticizers, coloring agents and surfactants. Examples of suitable plasticizers include acetyl triethyl citrate, dibutyl phthalate, tributyl citrate, triethyl citrate, acetyl tributyl citrate, propylene glycol, triacetin, polyethylene glycol, diethyl phthalate or mixtures thereof. The thickness and number of polymeric coatings can vary widely to give the desired release characteristics of the cores and will depend on the particular polymer or mixture thereof chosen. The thickness and number of polymeric coatings can be readily determined by one skilled in the art using dissolution profile data. In one embodiment, metoprolol succinate can be dissolved into a suitable solvent (e.g., dichloromethane, isopropyl alcohol, acetone, methanol, ethanol, water or mixture thereof), sprayed onto the insoluble core in a coating pan or in a fluidized bed, and the solvent can be dried off. The resulting beads can be coated with one or more polymeric layers by dissolving a polymeric mixture into a solvent (e.g., dichloromethane, isopropyl alcohol, acetone, methanol, ethanol, water or mixtures thereof) and repeating if necessary. Spraying can be done by any of the above-mentioned techniques or any other technique known to the sldlled artisan. The beads so obtained may be further coated with one or more non-functional coatings (e.g., polyethylene glycol). Preparations may also be formulated as granules filled into hard gelatin capsules or sachets, or formed into tablets. The coated beads can be processed into tablet dosage forms by various techniques.

For example, the coated beads can be processed into tablet dosage form comprising the steps of blending pharmaceutically inert excipient; granulating with a granulating fluid or solution/dispersion of binder; drying and sizing the granules; optionally blending with other pharmaceutically inert extragranular excipients; blending with metoprolol succinate beads; lubricating the granules/blend; compressing the lubricated blend into suitable sized tablets and; optionally coating with film forming polymer and coating additives. The coated beads can also be processed into tablet dosage form by wet granulation technique, comprising the steps of blending metoprolol succinate beads with pharmaceutically inert excipient; granulating with a granulating fluid or solution/dispersion of binder; drying and sizing the granules; optionally blending with other pharmaceutically inert extragranular excipients; lubricating the granules/blend; compressing the lubricated blend into suitable sized tablets and; optionally coating with film forming polymer and coating additives. The coated beads can also be processed into tablet dosage form, comprising the steps of blending pharmaceutically inert excipient; compacting the blend by roller compactor or slugging; sizing the compacts to obtain granules and blending the slugs of inert excipients with metoprolol succinate beads; lubricating the granules/blend; compressing the lubricated blend into suitable sized tablets and; optionally coating with film forming polymer and coating additives. The coated beads can also be processed into tablet dosage form by direct compression technique, comprising the steps of blending metoprolol succinate beads and pharmaceutically inert excipient; lubricating the blend; directly compressing the lubricated blend into suitable sized tablets and; optionally coating with film forming polymer and coating additives. The phrase "pharmaceutically acceptable inert excipients," as used herein, includes all excipients used in the art of manufacturing solid dosage forms. Examples of pharmaceutically acceptable inert excipients include binders, diluents, surfactants, lubricants/glidants, coloring agents, and the like. Suitable binders include, for example, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like, or mixtures thereof. Suitable diluents include, for example, 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 the like or mixtures thereof. Suitable surfactants include, for example, both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical dosage forms. Such surfactants include, for example, polyethoxylated fatty acids and its derivatives, e.g., polyethylene glycol 400 distearate, polyethylene glycol - 20 dioleate, polyethylene glycol 4 - 150 mono dilaurate, polyethylene glycol - 20 glyceryl stearate; alcohol - oil transesterifϊcation products, e.g., polyethylene glycol - 6 corn oil; polyglycerized fatty acids, e.g., polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, e.g., propylene glycol monocaprylate; mono and diglycerides, e.g., glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, e.g., polyethylene glycol - 20 sorbitan monooleate, sorbitan monolaurate; polyethylene glycol alkyl ether or phenols, e.g., polyethylene glycol - 20 cetyl ether, polyethylene glycol - 10 - 100 nonyl phenol; sugar esters, e.g., sucrose monopalmitate; polyoxyethylene - polyoxypropylene block copolymers known as "poloxamer"; ionic surfactants, e.g., sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate disodium, palmitoyl carnitine; and the like. Suitable lubricants/glidants include, for example, colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like. Coloring agents include any FDA approved colors for oral use. The tablet dosage form may optionally be coated with one or more functional and/or non-functional layers comprising film-forming polymers, if desired. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention. The examples mentioned below demonstrate some illustrative synthetic procedures for preparing the pharmaceutical compositions described herein. The examples are provided to illustrate particular aspect of the disclosure and do not limit the scope of the present invention as defined by the claims.

Examples

EXAMPLE 1

PELLETS Weight (mg/tab)

(i) Inert core Sugar spheres (40/60) 47.5

(ii) Drug layer Metoprolol Succinate 190.0 Opadry clear 19.0

(iii) Extended Release Coat Ethyl cellulose 20 cp 25.65 Opadry clear 6.41

(iv) Polyethylene Glycol 6000 layer PEG 6000 21.64

TABLETS Polyethylene Glycol 6000 55.10 Silicified MCC 229.47 Crospovidone 80.45 Magnesium Stearate 4.78

Procedure: 1. A dispersion of drug was prepared by adding metoprolol and Opadry in water with continuous stirring using a mechanical stirrer. 2. Sugar spheres were loaded in a fluidized bed and coated with drug dispersion of step 1. 3. A dispersion of ethyl cellulose and Opadry was prepared in a mixture of isopropyl alcohol and water. 4. Drug loaded beads of step 2 were then coated with dispersion of step 3 using a fluidized bed to obtain the controlled-release units. 5. Controlled-release units were then further coated with a solution of PEG 6000 in a mixture of isopropyl alcohol and water to obtain the desired plurality of beads. 6. Plurality of beads were then blended with PEG 6000, silicified MCC, crospovidone and magnesium stearate and directly compressed into suitable sized tablets. In vitro dissolution study

In vitro release of extended release tablets of metoprolol as per a composition of Example 1 was done using 500 mL phosphate buffer (pH 6.8) in USP type II apparatus at a paddle speed of 50 rpm. The results are shown in table 1.

Table 1: Drug release profile of metoprolol extended release tablets.

EXAMPLE 2

PELLETS Weight (mg/bead)

(i) Inert core Celphere 203 53.17 (ii) Drug layer Metoprolol Succinate 190.0 Opadry clear 19.0

(iii) Seal Coat Opadry clear 10.07

(iv) Extended Release Coat Ethyl cellulose 20 cps 77.95 Methocel E5 8.66 Triacetin 8.66 Procedure: 1. A dispersion of drug was prepared by adding metoprolol and Opadry in water with continuous stirring using a mechanical stirrer. 2. Celphere 203 were loaded in a fluidized bed and coated with drug dispersion of step 1. 3. A dispersion of Opadry was prepared in water. 4. Drug loaded beads of step 2 were then coated with dispersion of step 3 using a fluidized bed. 5. A solution of ethyl cellulose, methocel and triacetin was prepared in a mixture of isopropyl alcohol and methylene chloride. 6. Beads of step 4 were then coated with dispersion of step 5 using a fluidized bed to obtain the controlled-release units.

In vitro dissolution study In vitro release of extended release beads of metoprolol as per a composition of Example 2 was done using 500 mL phosphate buffer (pH 6.8) in USP type II apparatus at a paddle speed of 50 rpm. The results are shown in table 2.

Table 2: Drug release profile of metoprolol extended release beads of example 2.

EXAMPLE 3

PELLETS Weight (mg/bead)

(i) Inert core Sucrose (60/80) 27.85

(ii) Drug layer Metoprolol Succinate 190.0 Opadry clear 19.0

(iii) Extended Release Coat Ethyl cellulose 20 cp 42.47 Methocel E5 5.31 PEG 400 5.31

Procedure: 1. A dispersion of drug was prepared by adding metoprolol and Opadry in water with continuous stirring using a mechanical stirrer. 2. Sucrose crystals were loaded in a fluidized bed and coated with drug dispersion of step 1. 3. A solution of ethyl cellulose, methocel and PEG 400 was prepared in a mixture of isopropyl alcohol and water. 4. Drug loaded beads of step 2 were then coated with dispersion of step 3 using a fluidized bed to obtain the controlled-release units.

In vitro dissolution study In vitro release of extended release beads of metoprolol as per a composition of Example 3 was done in 500 ml phosphate buffer (pH 6.8) in USP type II apparatus at a paddle speed of 50 rpm. The results are shown in table 3.

Table 3: Drug release profile of metoprolol extended release beads of example 3.

EXAMPLE 4

PELLETS Weight (mg/bead) (i) Inert core Sucrose (60/80) 47.65

(ii) Drug layer Metoprolol Succinate 190.0 Opadry clear 19.0

(iii) Extended Release Coat Ethyl cellulose 20 cp 86.65 Methocel E5 21.66

Procedure: 1. A dispersion of drug was prepared by adding metoprolol and Opadry in water with continuous stirring using a mechanical stirrer. 2. Sucrose crystals were loaded in a fluidized bed and coated with drug dispersion of step 1. 3. A solution of ethyl cellulose and methocel was prepared in a mixture of isopropyl alcohol and water. 4. Drug loaded beads of step 2 were then coated with solution of step 3 using a fluidized bed to obtain the controlled-release units.

In vitro dissolution study In vitro release of extended release beads of metoprolol as per a composition of Example 4 was done using 500 mL phosphate buffer (pH 6.8) in USP type II apparatus at a paddle speed of 50 rpm. The results are shown in table 4.

Table 4: Drug release profile of metoprolol extended release beads of example 4.

EXAMPLE 5 PELLETS Weight (mg/bead)

(i) Inert core Sugar sphere 95.0

(ii) Drug layer Metoprolol Succinate 190.0 Opadry clear 19.0

(iii) Extended Release Coat Ethyl cellulose 20 cp 62.72 Methocel E5 7.84 PEG 400 7.84

Procedure: 1. A dispersion of drug was prepared by adding metoprolol and Opadry in water with continuous stirring using a mechanical stirrer. 2. Sugar sphere were loaded in a fluidized bed and coated with drug dispersion of step 1. 3. A dispersion of ethyl cellulose and methocel was prepared in a mixture of isopropyl alcohol and water. 4. Drug loaded beads of step 2 were then coated with solution of step 3 using a fluidized bed to obtain the controlled-release units.

In vitro dissolution study In vitro release of extended release beads of metoprolol as per a composition of Example 5 was done using 500 mL phosphate buffer (pH 6.8) in USP type II apparatus at a paddle speed of 50 rpm. The results are shown in table 5.

Table 5: Drug release profile of metoprolol extended release beads of example 5.

Claims

We Claim: 1. An oral controlled-release pharmaceutical composition of metoprolol succinate comprising a plurality of beads comprising a) a water soluble, water swellable or water-insoluble inert core; b) one or more drug layers comprising metoprolol; and c) one or more polymeric coatings surrounding the one or more drug layers.

2. The pharmaceutical composition of claim 1 , wherein the one or more drug layers further comprise a binding agent selected from polymethacrylates, ethylcellulose, povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose or mixtures thereof.

3. The pharmaceutical composition of claim 1, wherein the inert core has a diameter from about 150-600 μm.

4. The pharmaceutical composition of claim 1, wherein the water-soluble inert core comprises sugar or salt.

5. The pharmaceutical composition of claim 4, wherein the sugar is selected from glucose, mannitol, lactose, xylitol, dextrose, sucrose or mixtures thereof, and the salt is selected from sodium chloride, potassium chloride or mixtures thereof

6. The pharmaceutical composition of claim 1, wherein water-swellable core comprises hydroxypropyl methylcellulose, microcrystalline cellulose, starch or mixtures thereof.

7. The pharmaceutical composition of claim 1, wherein water-insoluble inert core comprises silicon dioxide, small particles of glass, plastic resin particles or mixtures thereof.

8. The pharmaceutical composition of claim 1, wherein the one or more polymeric coatings comprise one or more extended release polymers selected from one or more water soluble polymers, one or more water insoluble polymer or mixtures thereof.

9. The pharmaceutical composition of claim 8, wherein the one or more water-soluble polymers are selected from polyvinylpyrrolidine, hydroxypropylcellulose, hydroxypropyl methylcellulose, methylcellulose, vinyl acetate copolymers, polysaccharides, polyethylene oxide, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers or derivatives or mixtures thereof.

10. The pharmaceutical composition of claim 8, wherein water-insoluble polymers are selected from acrylates; cellulose derivatives; polyethylene, and high molecular weight polyvinylalcohols.

11. The pharmaceutical composition of claim 10, wherein the acrylates are selected from methacrylates, acrylic acid copolymers or mixtures thereof; and the cellulose derivatives are selected from ethylcellulose, cellulose acetate or mixtures thereof.

12. The pharmaceutical composition of claim 1 further comprising one or more pharmaceutically inert excipients selected from the group consisting of surfactants, binders, diluents, disintegrants, lubricants, glidants, plasticizers, stabilizers, coloring agents or mixtures thereof.

13. The pharmaceutical composition of claim 1 further comprising one or more non- functional coatings.

14. The pharmaceutical composition of claim 13, wherein the one or more non- functional coatings comprise polyethylene glycol.

15. The pharmaceutical composition according to claim 1, wherein the beads have diameter ranging from 500-850 μm.

16. The pharmaceutical composition of claim 1, wherein the beads are processed into a solid dosage form selected from a tablet, a capsule or a sachet.

17. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is free of any diluent.

18. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is free of microcrystalline cellulose.

19. An oral controlled-release pharmaceutical composition of metoprolol succinate comprising a plurality of beads comprising a) an inert core; b) one or more drug layers comprising metoprolol; and c) one or more polymeric coatings surrounding the core, wherein the inert core comprises a soluble component, and the soluble component of the inert core and one or more drug layers comprise less than 95% w/w of a salt of metoprolol.

20. The pharmaceutical composition according to claim 19, wherein the soluble component is 60-90% w/w.

21. A process for preparation of an oral controlled-release pharmaceutical composition of metoprolol succinate according to claim 1 wherein process involves the steps of: a) preparing a solution or dispersion of metoprolol in one or more solvents; b) spraying the above-prepared solution or dispersion onto a water soluble or swellable inert core and drying off the solvent; c) preparing a solution or dispersion of a polymeric mixture in one or more solvents; d) coating the core obtained in step b) with a polymeric solution or dispersion obtained in step c) and drying off the solvent, e) optionally coating the core obtained in step d) with one or more non-functional coating such as polyethylene glycol.

22. The process of claim 21, wherein the one or more solvents is dichloromethane, isopropyl alcohol, acetone, methanol, ethanol, water or mixture thereof