FORM 2
THE PATENT ACT 1970
(39 of 1970) &
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
EXTENDED RELEASE METOPROLOL COMPOSITIONS
2. APPLICANT (S):
(a) NAME: AJANTA PHARMA LIMITED.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Ajanta House, Charkop, Kandivali (West), Mumbai - 400 067.
3. PREAMBLE TO THE DESCRIPTION
The present invention relates to extended release solid pharmaceutical composition comprising antihypertensives, in particular, Metoprolol succinate or pharmaceutically acceptable derivatives thereof and a process for preparing such a formulation. I he present invention is a composition comprising Metoprolol succinate or its pharmaceutical ly acceptable derivatives thereof and the composition releases the drug over 24 hours. The composition comprises a rate controlling hydrophilic and
hydrophobic polymer in the core, further control of release is achieved by coating the

compressed cores with an aqueous dispersion of a hydrophobic polymer in
combination with a release rate controlling hydrophilic polymer. The present invention describes an extended release tablet having a pi 1 independent release profile.
The following specification particularly describes the invention and the manner in
which it is to be performed.

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The present invention provides novel extended release compositions suitable for oral administration comprising at least one antihypertensive such as mctoprolol succinate or its pharmaceutically acceptable derivative. The said composition further comprises metoprolol succinate or its pharmaceutically acceptable derivative along with a hydrophilic polymer matrix in combination with a rate controlling hydrophobic polymer and other suitable pharmaceutically acceptable excipients. The said composition is further coated with an aqueous dispersion of a hydrophobic polymer and a release rate controlling hydrophilic polymer, followed by a film coat. I'he said composition releases the drug over 24 hours.
Beta - blockers or beta-adrenergic blocking agents are a class of drugs used to treat a variety of cardiovascular conditions and certain other diseases. They block the action of epinephrine and norepinephrine on beta - adrenergic receptors in the body (primarily in the heart, peripheral blood vessels, bronchi, pancreas, and liver). The hormones and neurotransmitters stimulate the sympathetic nervous system by acting on these receptors. There arc three types of beta receptors: beta receptors located mainly in the heart, beta receptors located all over the body, but predominantly in the lungs, muscles and arterioles and beta1 receptors which are less well characterised, but have a role in fat metabolism. Activation of beta1 receptors by epinephrine increases the heart rate and the blood pressure, and the heart consumes more oxygen. Drugs that block these receptors therefore have the reverse effect: they lower the heart rate and blood pressure and hence are used in conditions when the heart itself is deprived of oxygen. They are routinely prescribed in patients with ischemic heart disease. In addition, beta-blockers prevent the release of

renin, which is a hormone produced by the kidneys which leads to constriction of blood vessels.
The beta-adrenergic blockers have an important role in the pharmacotherapy of ischemic heart disease, heart failure, arrhythmia, and hypertension. The beta-adrenergic blockers vary in their lipid solubility, selectivity for the beta1 adrenergic receptor subtype, presence of partial agonist or intrinsic sympathomimetic activity, and membrane-stabilizing properties. Regardless of these differences, almost all of the beta-adrenergic receptor antagonists are also equally effective as antihypertensive agents. The beta-blockers act as competitive antagonists at the adrenergic beta1 receptors. The newer agents tend to be more selective for the cardiac (beta1) receptors, which allows for decreased systemic side effects.
Beta-adrenergic blockers effectively reduce the blood pressure of many patients with combine systolic and diastolic hypertension and of elderly patients with isolated systolic hypertension. The mechanism of the antihypertensive effects of beta-blocking agents has not been elucidated. However, several possible mechanisms have been proposed: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output; (2) a central effect leading to reduced sympathetic outflow to the periphery; and (3) suppression of rennin activity. Commonly used beta-blockers include Acebutol, Atenolol, Bctaxolol. Bisoprolol. Cartelol, Carvcdilol, Ksmolol. Labetolol, Mctoprolol, Nadolol, Penbutolol. Pindolol. Propranolol. Timolol and the like.
Mctoprolol is first selective beta-adrenergic blocker devoid of intrinsic sympathomimetic activity and at higher plasma concentrations; mctoprolol also inhibits beta^
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adrenorcceptors, chiefly located in the bronchial and vascular musculature. Metoprolol is a potent inhibitor of beta-receptor mediated effects mainly involving beta; adrenorcceptors. Such effects include not only reduction of exercise-induced tachycardia but also antihypertensive and cardiac antianginal and antiarrhythmic effects. Clinical pharmacology studies have confirmed the beta-blocking activity of metoprolol in man, as shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2) reduction of systolic blood pressure upon exercise, (3) inhibition of isoprotcrenol-induccd tachycardia, and (4) reduction of reflex orthostatic tachycardia. Metoprolol is chemically a secondary amine and is widely employed in the form of its succinate salt, namely (.t-.) l-(isopropylamino)-3-|p-(2-methoxycthyl)phenoxy|-2-propanol succinate. Metoprolol is a basic drug with pKa of 9.6. I lowever it's succinate salt shows a pi I in the range of 6-7 (2% w/v aqueous solution). The succinate salt is freely soluble in water.
The in vivo absorption of metoprolol is rapid and complete. The plasma metoprolol levels following administration of extended release metoprolol succinate are characterized by lower peaks, longer time to peak and significantly lower peak to trough variation. The peak plasma levels following once daily administration of modified release metoprolol succinate average one-fourth to one-half the peak plasma levels obtained following a corresponding dose of conventional metoprolol. administered once daily or in divided doses. At steady state the average bioavailability of metoprolol following administration of extended release metoprolol succinate, across the dosage range of 50 to 400 mg once daily, was 77% relative to the corresponding single or divided doses of conventional metoprolol. Several formulations of beta-adrenergic blockers have been reported in the
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literature, many of which relate to formulations of mctoprolol. For example, formulations relating to oral, controlled release and pulse release compositions for mctoprolol or its salts and derivatives have been reported. Examples of patents describing such formulations arc as follows.
U.S. Pat. No. 4,871,549 assigned to Fujisawa Pharmaceuticals Inc.. describes a time controlled explosion system comprising mctoprolol, a swelling agent such as a low substituted hydroxypropyl cellulose, sodium starch glycolate or carboxymethyl cellulose sodium, coated with a water-insoluble coating material so that drug release is caused by the explosion of the membrane after a definite time period. This explosion of the outer membrane is caused by the power of swelling occurred when swelling agent absorbs the fluid. The specification illustrates metoprolol tartrate and not mctoprolol succinate. U.S. Pat. No. 4,957,745 assigned to Aktiebolaget Hassle describes a controlled release metoprolol. The preparation includes a plurality of beads comprising metoprolol coated with a polymeric membrane comprising ethyl cellulose with or without hydroxypropyl methylcellulose. Metoprolol or its salts such as tartrate, succinate or fumaratc are used in the invention. The drug may be sprayed on the beads and then coated with polymers and finally filled into capsules or compressed as tablets. The process involves many steps and hence is complex and may not be preferred on commercial scale.
U.S. Pat. No. 5,081,154 assigned to Aktiebolaget I lassie is directed to mctoprolol succinate in an oral composition coated with an anionic polymer soluble at pi I over 5.5 and a water insoluble quaternary ammonium substituted acrylic polymer. Further. U.S. Pat. Nos. 5.399,358 and 5,399.362, both the patents assigned to Id ward Mendell Co. Inc., disclose a sustained release oral solid dosage form of mctoprolol.
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which includes a sustained release excipient including a gelling agent, an inert pharmaceutical diluent, and a cationic cross-linking agent. The sustained release component comprises of one heteropolysaccharide gum along with one homopolysaccharide gum capable of cross-linking with the heteropolysaccharide gum. The formulation provides release of metoprolol for at least about 24 hours. US application 20030228361 (Pcnwcst Pharmaceuticals Co) describes sustained release oral dosage forms of metoprolol tartrate. The said formulation comprises of metoprolol tartrate along with a sustained release excipient comprising a gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide gum capable of cross-linking. The said heteropolysaccharide gum when exposed to environmental fluid and the said dosage form providing a mean Cmax of about 10-40 ng/ml per 100 mg metoprolol tartrate over 24 hours after oral administration. The said formulation is overcoatcd with a hydrophobic coating polymer. The invention describes xanthan gum as the heteropolysaccharide gum and locust bean gum as homopolysaccharide gum. The combination of these two as described in the invention exhibits synergism producing a higher viscosity and faster hydration than that which would be expected by cither of the gums alone, the resultant gel being faster-forming and more rigid.
Metoprolol succinate is freely soluble in water and hence judicious selection of release retarding excipients is necessary to achieve a constant in vivo input rate of the drug. 1 he most commonly used method of modulating the drug release is to include it in a matrix system.
Hydrophilic matrix systems are widely used in oral controlled drug delivery because of their flexibility to obtain a desirable drug release profile, cost-effectiveness, and broad
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regulatory acceptance. The drug release for extended duration, particularly for highly water-soluble drugs, using a hydrophilic matrix system is restricted due to rapid diffusion of the dissolved drug through the hydrophilic gel network. Upon administration, a rapid dissolution of the drug from the surface of the tablet is usually observed. The release rate of the drug from such systems is markedly influenced by the percentage and the type of the gum used. Liberation rate also depends on physical and chemical properties of the drug.
Therefore, despite the availability of different technologies for modified release preparation containing highly soluble drug such as metoprolol succinate, there is a clinical need for better modified released preparations with simple, stable, and easily manufactured compositions giving improved patient compliance, better and more uniform clinical effects and possible enhanced bioavailability.
The present invention reports extended release composition of metoprolol succinate or its pharmaceutical^ acceptable derivatives thereof using hydrophilic polymer matrix comprising a mixture of a rate controlling hydrophilic polymer and a rate controlling hydrophobic polymer which are compressed to yield core tablets. These matric based compressed tablets arc further coated with an aqueous dispersion comprising a hydrophobic polymer containing a hydrophilic polymer as a release rate controlling component. The final composition has a pi I independent release profile. The said composition releases the drug over 24 hours.
Accordingly, it is an object of the present invention to provide an oral extended or modified release pharmaceutical composition and a process for preparing the same for
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administration of antihypertensives to patients suffering from hypertension and other related disorders.
It is a further object of the present invention to provide an oral extended or modified release formulation of metoprolol succinate or pharmaceutical^ acceptable derivatives thereof suitable for once-a-day oral administration, which releases metoprolol succinate over a time period of at least about 24 hours in the gastrointestinal tract. Yet another object of the present invention is an extended or modified metoprolol succinate composition comprised of metoprolol succinate or its pharmaceutical derivatives thereof in a core formed by the drug and a mixture of hydrophilic and hydrophobic polymer matrix, which is coated with an aqueous dispersion of a hydrophobic and hydrophilic release rate controlling polymers. The present invention, therefore also provides a pharmaceutical extended or modified release formulation comprising at least one antihypertensive such as metoprolol succinate or pharmaceutical^ acceptable derivatives thereof along with a hydrophilic hydrophobic polymer matrix and other pharmaceutical^ acceptable excipients. This 'matrix core" is coated with an aqueous dispersion of a hydrophobic polymer comprising a hydrophilic polymer as a release rate-controlling component.
The present invention further provides a method of administering to a subject in need of treatment a pharmaceutical product or formulation substantially as hereinbefore described and in particular an extended or modified release composition which can be administered orally and as such is particularly suited for the treatment of hypertension and other related disorders. The present invention therefore provides core comprised of metoprolol succinate or its
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pharmaceutical ly acceptable derivative thereof with hydrophilic hydrophobic polymeric matrix and other pharmaceutical ly acceptable excipients, wherein the drug and the polymer and other suitable excipients are mixed together, granulated using suitable methods of granulation known in the art and then compressed together to yield tablets. These compressed tablets are then coated with a hydrophobic polymer comprising a hydrophilic release rate-controlling component to achieve drug delivery over a period of 24 hours.
The present invention further provides use of at least one antihypertensive such as metoprolol succinate or its pharmaceutical^ acceptable derivative thereof in the manufacture of a medicament for the treatment of hypertension and other related disorders. Such a medicament according to the present invention comprises an extended or modified release formulation substantially as hereinafter described. Yet. another aspect of the present invention is the process of manufacturing the sustained or modified release composition. In particular, the invention provides a sustained or modified release composition comprising at least one antihypertensive such as metoprolol succinate or its pharmaceutical^ acceptable derivative thereof together with hydrophilic hydrophobic polymer matrix and other pharmaceutical ly acceptable excipients. This 'matrix core" is coated with an aqueous dispersion of a hydrophobic polymer comprising a release rate controlling hydrophilic polymer.
The present invention provides obvious benefits being simple and fast operational process for manufacturing said oral solid extended release pharmaceutical composition. While the present invention has been described in terms of its specific embodiments.
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certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. Background of the Invention:
The present invention provides novel extended release compositions suitable for oral administration comprising at least one antihypertensive such as metoprolol succinate or its pharmaceutically acceptable derivative thereof. The said composition further comprises metoprolol succinate or pharmaceutically acceptable derivatives thereof along with hydrophilic hydrophobic polymer matrix and other pharmaceutically acceptable excipients. The said composition is coated with an aqueous dispersion of a hydrophobic polymer comprising a release rate controlling hydrophilic polymer. The said composition releases the drug over 24 hours.
The term "pharmaceutically acceptable derivative" means various pharmaceutical equivalent isomers, enantiomers, complexes, hydrates, polymorphs, and etc. of metoprolol succinate.
The term composition includes but not limited to solutions and/or suspensions, dispersions, concentrates, ready mix, powders, granules, tablets, micro-tablets, capsules, and pellets, comprising metoprolol succinate or pharmaceutically acceptable derivatives thereof.
The term "therapeutically effective amount" means an amount of the drug, which is capable of eliciting a physiological response in a human patient. More specifically, the term "therapeutically effective amount" means the amount of drug, which is capable of treating hypertension and related disorders.
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The term "extended release" means that the therapeutically active medicament is released from the composition at a controlled rate such that therapeutically effective blood levels of the medicament are maintained over an extended period of time. e.g. providing a 24 hours therapeutic effect.
The medicament according to the present invention comprises a formulation substantially as herein described, and in particular a capsule, a tablet, micro-tablets, granules or pellets filled in capsule formulation, typically an extended or modified release tablet formulation substantially as hereinafter further described.
Suitably a formulation according to the present invention provides a novel sustained release dosage form, preferably tablets comprising core comprising metoprolol succinate or pharmaceutically acceptable derivatives thereof along with hydrophilic hydrophobic polymer matrix and other pharmaceutically acceptable excipients and the said core is coated with an aqueous dispersion of a hydrophobic polymer comprising a release rate controlling hydrophilic polymer and the process for preparing the same.
In a preferred embodiment of the present invention, an extended release or modified release formulation comprises a pharmaceutically active agent (metoprolol succinate) along with suitable excipients. In particular, the present invention provides extended release tablet formulations comprising a sustained release source of at least one antihypertensive such as metoprolol succinate. As such in a formulation according to the present invention, metoprolol succinate after oral administration can be released over a period of 24 hours. It has been observed that tablets according to the present invention produce relatively uniform blood levels of metoprolol succinate over extended periods of
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therapy, suitably with oral administration. An extended / modified release is thus achieved by formulation substantially as hereinbefore described.
In a preferred embodiment of the present invention, an extended release formulation comprises of at lease one pharmaceutically active agent, which may be formulated so that the release of the drug being held significantly pH-independent throughout the environment of the gastrointestinal tract.
The extended release tablet dosage forms of metoprolol succinate according to the present invention may be formulated by mixing the drug with at least one hydrophilic polymer and a hydrophobic polymer to form a core polymer matrix, which releases the drug over an extended period of time. To achieve further control of the drug from the matrix core the core is further coated with an aqueous dispersion of a hydrophobic polymer comprising a hydrophilic polymer as a release rate-controlling component. In particular, in accordance with the present invention, a controlled release pharmaceutical formulation is provided from which an antihypertensive is released, at a controlled rate relatively independent of the pH of the environment such that in vivo consistent release is achieved throughout the gastrointestinal tract. The extended release pharmaceutical formulation of the invention will preferably be in the form of a tablet and includes an antihypertensive such as metoprolol succinate or its pharmaceutically acceptable derivative thereof; a pH-independent polymer which preferably is a mixture of cellulose derivatives forming the matrix for the core followed by coating with another mixture of pH-independent cellulose polymers to achieve a pH independent release profile along with suitable diluents and other excipients.
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Polymers belonging to hydrophilic matrix systems, when exposed to an aqueous medium,
do not disintegrate, but immediately after hydration develops a highly viscous gelatinous
surface barrier, which controls the drug release from, and the liquid penetration into the
center of the matrix system.
The release of the drug from the composition of the present invention works on two
principles:
1) The Matrix consists of Metoprolol Succinate with combination of polymers known for retarding the drug release like HPMC Of high molecular weight and high viscosity and another such polymer like Hydroxy Propyl Cellulose along with excipients required for tabletting as core for the tablets.
2) Such core being coated with Polymer coating which has property to retard the release rate of the drug.
The compressed matrix has been coated with non-ionic ethyl ether of cellulose (EThyl cellulose) and adding soluble polymer such as HPMC (low viscosity). The release profile is tailored to achieve the desired release profile by adjusting the coating level and by optimizing the HPMC concentration in the coating. Ethyl cellulose coating when in contact with body fluids/dissolution media makes film porous and allows non-swelling, insoluble diffusion barrier coating to achieve sustained release of drug. Ethyl cellulose coating controls the release rate upto 8-12 hours, till the matrix swells to rupture the membrane. Release of drug after 12 hours then takes place directly from the matrix. Schematically the release mechanism can be shown as follows:

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The matrix, when in contact with water, the polymers hydrates rapidly and form a
gelatinous barrier layer around the tablet (matrix). The matrix is a homogeneous
dispersion of solid drug in a polymer mix. Drug in the outside layer, exposed to the
bathing solution is dissolved first and then diffuses out of the matrix, continuously.
The underlying mechanisms of drug release from these systems are complex, involving
up to three moving boundaries, usually termed the swelling, diffusion, and erosion fronts.
The release rate is dependent on the rate of diffusion through the matrix. The polymer
rapidly forms a continuous gel layer at the matrix surface and so prevents initial
dissolution of the surface.
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Since the drug is dispersed in the matrix system, accidental leakage of the total drug component is less likely to occur.
The release rate of drug has been adjusted by inducing desired hydrophobic in matrix by combining the HPMC polymer with Hydroxypropyl cellulose (HPC).
Preferable examples of such hydrophilic polymers without any limitation include,
cellulose polymers, in particular cellulose ethers such as methyl cellulose, cellulose alkyl
hydroxylates such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose,
hydroxymethyl cellulose, hydroxyethyl cellulose, cellulose alkyl carboxylates such as
carboxymethyl cellulose, and alkali metal salts of cellulose alkyl carboxylates, povidone,
vinyl copolymers, polyethylene oxide and derivatives thereof.
Preferable examples of such hydrophobic polymers without any limitation include, cellulose polymers, in particular cellulose ethers such as ethyl cellulose and derivatives thereof.
In general, the present invention provides a process for the manufacture of a pharmaceutical product. The said composition is prepared by using wet granulation or dry granulation technique known in the art.
The process for preparing said composition comprises blending of metoprolol succinate or its pharmaceutically acceptable derivative thereof with suitable diluents, hydrophilic and hydrophobic polymer and other pharmaceutically acceptable excipients. The blend is lubricated and compressed on a suitable compression machine. The tablets thus manufactured are coated with an aqueous dispersion of ethyl cellulose containing Methocel as a release rate-controlling component. Subsequent to this coat a final
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aesthetic coat of HPMC low viscosity grade comprising Titanium dioxide is given to the composition to give it an aesthetic appearance.
Suitable excipients employed in a pharmaceutical composition according to the present invention, may include commonly used pharmaceutical excipients such as pharmaceutically acceptable saccharide, including monosaccharides, disaccharides. polyhydric alcohols and/or mixtures thereof. Examples of suitable diluents include lactose, various forms of lactose, mannitol, sucrose, dextrose, microcrystalline cellulose, powdered cellulose, starches, sorbitol, dibasic calcium phosphate, calcium carbonate, magnesium oxide, and other mineral bases
Other commonly used pharmaceutical excipients would comprise of (a) binders, e.g. acacia, alginic acid, carbomer, carboxymethyl cellulose sodium, ethyl cellulose, guar gum. hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, magnesium aluminum silicate, methyl cellulose, povidone, pregelatinized starch, sodium alginate, starch, dextrin, gelatin, hydrogenated vegetable oils, polymethacrylates. zein and the like; (b) lubricants (c) glidants; and (d) coatings and protective matrices, e.g. polymeric substances or waxes.
The formulation according to the present invention may also include pharmaceutical ly acceptable lubricants and glidants. The artisan can select appropriate lubricants and glidants in order to get good flow to aid in compression of the tablets. Examples of suitable lubricants and glidants include magnesium stearate. calcium stearate, glyceryl behenate, light mineral oil, polyethylene glycol, sodium stearyl fumaratc. stearic acid, talc, hydrogenated castor oil. calcium silicate, magnesium silicate
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and colloidal silicon dioxide. The most preferred pharmaceutical lubricant and glidants are talc and magnesium stearate.
The present invention further comprises a process of preparing a pharmaceutical product, or a pharmaceutical composition, or a medicament substantially as hereinbefore described.
Substantially as hereinbefore described the tablets of the present invention comprise at least one antihypertensive such as metoprolol succinate or its pharmaceutically acceptable derivatives thereof, is prepared by blending metoprolol succinate with suitable diluents, at least one hydrophilic and hydrophobic polymer followed by coating with an aqueous dispersion of a hydrophobic and hydrophilic release rate controlling polymeric component to achieve an extended release over a 24 hour time period..
The present invention will now be illustrated with reference to the following examples. which does not limit the scope of the invention in any way. further different strengths of the formulation may be achieved by proportionately using a dose weight scale-up or scale-down formula. The concentration of the excipients may also be varied or modified to achieve the desired dissolution profile by a skilled artisan. Example 1:
Extended release tablets were prepared using the following excipients in the stated quantities:

Coating: The coating dispersion is prepared by mixing an aqueous dispersion of ethyl
cellulose (Aquacoat KCI) 30) with triacetin and stirring the ingredients for around 10
minutes. To this is added an aqueous solution of HPMC in water (pre mixed for about 30
minutes). After addition of the HPMC solution to the ethyl cellulose dispersion the) are
stirred for around 30 minutes to achieve the final coating suspension.
The tablets obtained after compression are loaded onto an Auto coater and coated with
the aqueous dispersion as prepared above to achieve the desired weight gain. They are
then dried at 60° C, for about 60 minutes.
The dried tablets are further coated with a film coat comprising of an HPMC dispersion
containing polyethylene glycol and titanium dioxide commercially available from
Colorcon as OpadryR to achieve the desired weight gain.
Example 2:
Extended release tablets were prepared using the following excipients in the stated quantities:

Drug release from the formulations: The formulations as prepared in the examples were studied for their drug release over a 24 hour period in pi 1 6.8 phosphate buffer as this was the discriminatory dissolution medium. In addition they were compared for their release with the reference-listed formulation Toprol-XLR. The dissolution was measured as a percentage of drug released over a period of 24 hours, with sampling at various time intervals. The results obtained for percentage of drug release versus time is given for the Examples 1 and 2 in fables 1 and 2 respectively and their comparison with the Innovator product is depicted graphically in Figures 1 and 2 respectively.
In addition the inventors studied the dissolution profiles of the formulation prepared by the said invention in various dissolution media like water, 0.1N hydrochloric acid, pi I 4.5 acetate buffer, pi I 6.8 phosphate buffer and pi I 8.0 phosphate buffer. It was observed that the formulation of the present invention exhibited a pi I independent release profile. The results for the multimedia dissolution depicting a pi I independent release is given in fable 3 and a graphical overlay of the multi-media release profiles in given in Figure 3.
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WE CLAIM:
1. An oral pharmaceutical composition comprising: a therapeutically effective amount of metoprolol succinate or a pharmaceutically acceptable derivative thereof and a hydrophilic hydrophobic polymer matrix, coated with an aqueous dispersion, comprising of a mixture of hydrophobic and hydrophilic polymers and pharmaceutically acceptable excipients thereof, wherein said composition provides an extended or modified release of metoprolol succinate or a pharmaceutically acceptable derivative thereof.
2. The pharmaceutical composition of claim 1. wherein the said composition comprises: (a) metoprolol succinate or a pharmaceutically acceptable derivative thereof and a hydrophilic hydrophobic polymer matrix and pharmaceutically acceptable excipients mixed and compressed together, (b) The compressed mass of (a) is further coated with an aqueous dispersion comprising of a mixture of hydrophobic and hydrophilic polymers and pharmaceutically acceptable excipients and (c) the coated composition of (b) is further coated with a film coat comprising a hydrophilic polymer and pharmaceutically acceptable excipients.
3. The pharmaceutical composition of claim 2, wherein said hydrophilic polymer is selected from a group comprising of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, and hydroxyethyl cellulose and the hydrophobic polymer is selected from a group comprising of cellulose derivatives and is ethylcellulose.
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4. The pharmaceutical composition of claim 1, wherein said pharmaceutically acceptable diluents are selected from the group comprising lactose, microcrystallinc cellulose, powdered cellulose, starches, sorbitol, dibasic calcium phosphate, calcium carbonate and mixtures thereof.
5. The pharmaceutical composition of claim 1, wherein said pharmaceutically acceptable lubricants are selected from the group comprising magnesium stearate, sodium stearyl fumarate, talc and mixtures thereof
6. The pharmaceutical composition of claim 1, wherein the composition is in tablet dosage form.
7. The pharmaceutical composition of claim 1. wherein the composition is manufactured by a process comprising the steps of: (i) mixing and blending metoprolol succinate or a pharmaceutically acceptable derivative thereof with a hydrophilic hydrophobic polymer matrix (ii) coating of the compressed mass obtained in step (i) using an aqueous dispersion of hydrophobic and hydrophilic polymers followed by (iii) film coating the coated mass obtained in step (ii) to form tablets comprising metoprolol succinate.
8. The pharmaceutical composition of claim 1, which gives a pi I independent dissolution release profile over a 24-hour period.
9. A method of treating hypertension and related cardiac disorders in a subject in
need of said treatment, which method comprises administering to the subject a
pharmaceutical product or formulation according to claim 1.

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