FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule!3)
1. TITLE OF THE INVENTION:
EXTENDED RELEASE COMPOSITIONS OF METOPROLOL SUCCINATE
2. APPLICANT (S)
(a) NAME: WOCKHARDT LIMITED (b)NATIONALITY:
(d) ADDRESS: Wockhardt Towers,
Bandra-Kurla Complex, Bandra East, Mumbai -400051.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.
ATTACHED HEREWITH.

1084
MUM - 6 SEP 2005

EXTENDED RELEASE COMPOSITIONS OF METOPROLOL SUCCINATE
The present invention relates to a sustained or modified release solid pharmaceutical composition comprising antihypertensives, in particular, Metoprolol succinate or its pharmaceutically acceptable derivatives thereof and a process for preparing such a formulation.
Beta blockers or beta-adrenergic blocking agents are a class of drugs used to treat a variety of cardiovascular conditions and some other diseases. Beta blockers block the action of epinephrine and norepinephrine on the [3-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 are three types of beta receptors: bi-receptors located mainly in the heart, and Pa-receptors located all over the body, but mainly in the lungs, muscles and arterioles. p3-receptors are less well characterised, but have a role in fat metabolism.
Activation of Pi -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.
Drugs that block P2 receptors generally have a calming effect and are prescribed for anxiety, migraine, esophageal varices and alcohol withdrawal syndrome, among others. Many beta blockers affect both type 1 and type 2 receptors; these are termed nonselective blockers. Selective beta blockers primarily affect Pi-receptors.
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The b-adrenergic blockers have an important role in the Pharmacotherapy of ischemic heart disease, heart failure, arrhythmia, and hypertension. The p-adrenergic blockers vary
in their lipid solubility, selectivity for the Pi-adrenergic receptor subtype, presence of partial agonist or intrinsic sympathomimetic activity, and membrane-stabilizing properties. Regardless of these differences, almost all of the P-adrenergic receptor antagonists are also equally effective as antihypertensives agents.
The b-blockers (examples: Atenolol, metoprolol, Propranolol) act as competitive antagonists at the adrenergic Pi receptors. The newer agents tend to be more selective for the cardiac (p-1) receptors which allows for decreased systemic side effects
b-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 antihypertensives 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 p-blockers include Acebutol, Atenolol, Betaxolol, Bisoprolol, Cartelol, Carvedilol, Esmolol, Labetolol, Metoprolol, Nadolol, Penbutolol, Pindolol, Propranolol, Timolol and the like.
Metoprolol is first selective P-adrenergic blocker devoid of intrinsic sympathomimetic activity and at higher plasma concentrations; metoprolol also inhibits b2-adrenoreceptors, chiefly located in the bronchial and vascular musculature. Metoprolol is a potent inhibitor of b-receptor mediated effects mainly involving bi-adrenoreceptors. 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 isoproterenol-induced tachycardia, and (4) reduction of reflex orthostatic tachycardia.
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Metoprolol is a secondary amine and is widely employed in the form of its succinate salt, namely (+) l-(isopropyIamino)-3-[p-(2-methoxyethyl) phenoxy]-2-propanol succinate.
Metoprolol succinate has the following structural formula

CH2COOH
CH2COOH 2
Metoprolol is a basic drug with pKa of 9.6. However it's succinate salt shows a pH 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 P-adrenergic blockers have been reported in the literature, many of which relate to formulations of metoprolol. For example, formulations relating to oral, controlled release and pulse release compositions for metoprolol or its salts and derivatives have been reported. Examples of patents describing such formulations are as follows.
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U.S. 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.
U.S. 4,871,549 assigned to Fujisawa Pharmaceuticals Inc., describes a time controlled explosion system comprising metoprolol, a swelling agent such as a low substituted hydroxypropylcellulose, sodium starch glycolate or carboxymethylcellulose 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.
U.S. patent 4,792,452 assigned to E.R. Squibb Inc. describes controlled release pharmaceutical compositions, which are said to provide pH-independent release for a basic drug such as Verapamil. The formulations include a pH-dependent polymer, which is a salt of alginic acid, a pH-independent hydrocolloid gelling agent and a binder. The salt of the alginic acid is preferably sodium alginate or potassium alginate. The weight ratio of the alginic acid salt to the hydrocolloid gelling agent is all within the range 0.1:1 to 10:1, and the formulation is free of calcium ion and carbon dioxide-producing material.
U.S.5,081,154 assigned to Aktiebolaget Hassle is directed to metoprolol succinate in an oral composition coated with an anionic polymer soluble at pH over 5.5 and a water
insoluble quaternary ammonium substituted acrylic polymer.
Further, U.S. patents 5,399,358 and 5,399,362, both the patents assigned to Edward Mendell Co. Inc., disclose a sustained release oral solid dosage form of metoprolol which includes a sustained release excipient including a gelling agent, an inert pharmaceutical diluent, and a cationic cross-linking agent. The formulation provides release of metoprolol for at least about 24 hours.
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US application 20030228361 (Penwest 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 over coated 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 either of the gums alone, the resultant gel being faster-forming and more rigid.
Yet, the rheological behavior of xanthan gum and locust bean gum systems form weak gels. I.e. These systems give maximum synergistic effect when the ratio of xanthan gum to locust bean gum is 1:1. Also, as the temperature increases, locust bean gum is reported to show downward shift of viscosity values. This direction of change in apparent viscosity may not be readily predictable with presence of other additives or polymers mixed with a gel and hence may affect the long-term stability of the formulation.
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. The 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 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. When hydration and gelation of the gum at the tablet/liquid interface progresses, a viscous gel barrier is
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formed. The drug in this gelated form is thus released at a much slower rate. The release
rate of the drug 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. The solubility of the drug is hence critical for adequate release of the drug from such systems.
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.
To this end, present invention reports modified release composition of metoprolol succinate or its pharmaceutically acceptable derivatives thereof using hydrophilic polymer matrix comprising of at least one hydrocolloid gelling agent and optionally comprising one or more gelling agents along with other suitable excipients to form the core which may optionally be coated with suitable polymers.
SUMMARY OF THE INVENTION
The present invention provides novel sustained 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 its pharmaceutically acceptable derivative thereof along with hydrophilic polymer matrix comprised of at least one hydrocolloid gelling agent optionally with one or more gelling agents such as gums and gum derivatives thereof and other suitable pharmaceutically acceptable excipients. The said composition may optionally be coated with suitable pharmaceutical polymers. The said composition releases the drug over 24 hours.
Accordingly, it is an object of the present invention to provide an oral sustained or modified release pharmaceutical composition and a process for preparing the same for administration of antihypertensives to patients suffering from hypertension and other related disorders.
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Another object of the present invention is a sustained or modified solid pharmaceutical
composition adapted for oral administration.
It is further object of the present invention to provide a oral sustained or modified release formulation of metoprolol succinate or its pharmaceutically acceptable derivatives thereof suitable for once-a-day administration.
It is a further object of the present invention to provide oral sustained release composition which release metoprolol succinate over a time period of at least about 24 hours when exposed to gastrointestinal tract.
Yet another object of the present invention is a sustained or modified metoprolol succinate composition comprised of metoprolol succinate or its pharmaceutical derivatives thereof in a core formed by the drug and hydrophilic polymer matrix comprised of at least one hydrocolloid gelling agent optionally with one or more gelling agents such as gums and gum derivatives thereof.
The present invention, therefore also provides a pharmaceutical sustained or modified release formulation comprising at least one antihypertensive such as metoprolol succinate or its pharmaceutically acceptable derivative thereof along with hydrophilic polymer matrix comprised of at least one hydrocolloid gelling agent optionally with one or more gelling agents such as gums and gum derivatives thereof and other suitable pharmaceutically acceptable excipients. This 'core' may optionally be coated with a suitable coating material.
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 sustained 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 pharmaceutically acceptable derivative thereof with hydrophilic polymer matrix
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comprised of at least one hydrocolloid gelling agent optionally with one or more gelling
agents such as gums and gum derivatives thereof and other suitable pharmaceutically
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.
The present invention is further directed to a sustained release oral solid dosage form for absorption of metoprolol succinate or its pharmaceutically acceptable derivative thereof in the gastrointestinal tract, said drug comprising an effective amount of metoprolol succinate; and a hydrophilic polymer matrix comprising at least one hydrocolloid gelling agent when exposed to gastrointestinal fluid, said dosage form providing a therapeutic effect for about 24 hours after oral administration.
The present invention further provides use of at least one antihypertensive such as metoprolol succinate or its pharmaceutically 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 a sustained 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 pharmaceutically acceptable derivative thereof together with hydrophilic polymer matrix comprised of at least one hydrocolloid gelling agent optionally with one or more gelling agents such as gums and gum derivatives thereof and other suitable pharmaceutically acceptable excipients. This 'core' may optionally be coated with a suitable coating material.
The present invention provides obvious benefits being simple and fast operational process for manufacturing said oral solid sustained release pharmaceutical composition.
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Further aspects and embodiments of the invention may become apparent to those skilled
in the art from a review of the following detailed description, taken in conjunction with
the examples and the claims. It must be understood that that the present disclosure is intended as illustrative, and is not intended to limit the invention to the specific embodiments described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates comparative dissolution profile of Metoprolol succinate from Metoprolol succinate extended release tablets (Example-1-9) in pH 6.8 Phosphate Buffer
DETAILED DESCRIPTION OF THE INVENTION
Before the subject invention is described further, it is to be understood that the invention is not limited to the particular embodiments of the invention described below, as variations of the particular embodiments may be made and still fall within the scope of the appended claims. It is also to be understood that the terminology employed is for the purpose of describing particular embodiments, and is not intended to be limiting. Instead, the scope of the present invention will be established by the appended claims.
In this specification and the appended claims, the singular forms "a", "an" and "the" include plural reference unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs.
Unless defined otherwise, all technical and scientific terms used herein have the same
meaning as commonly understood to one of ordinary skill in the art to which the invention belongs. Although any methods, devices and materials similar or equivalent to
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those described herein can be used in the practice or testing of the invention, the preffered
methods, devices and materials are now described.
All publications mentioned herein are incorporated herein by reference for the purpose of describing and disclosing the subject components of the invention that are described in the publications, which components might be used in connection with the presently described invention.
The information below is not admitted to be prior art to the present invention, but is provided solely to assist the understanding of the reader.
The details of one or more embodiments of the invention are set forth in the description and the examples below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.
The present invention provides novel sustained 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 its pharmaceutically acceptable derivative thereof along with hydrophilic polymer matrix comprised of at least one hydrocolloid gelling agent optionally with one or more gelling agents such as gums and gum derivatives thereof and other suitable pharmaceutically acceptable excipients. The said composition
may optionally be coated with suitable pharmaceutical polymers. The said composition releases the drug over 24 hours.
The term "pharmaceutically acceptable derivative" means various pharmaceutical equivalent isomers, enantiomers, complexes, hydrates, polymorphs, 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, pellets, comprising metoprolol succinate or its pharmaceutically acceptable derivative thereof in a core constituted by drug and hydrophilic polymer matrix comprising at least
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one hydrocolloid gelling agent which may be coated optionally using suitable coating
material.
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.
The term "sustained 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 said medicament according to the present invention comprises a formulation substantially as herein described, and in particular a capsule or a tablet or micro-tablets or granules or pellets filled in capsule formulation, typically a sustained 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 its pharmaceutically acceptable derivative thereof alongwith hydrophilic polymer matrix comprised of at least one hydrocolloid gelling agent optionally with one or more gelling agents such as gums and gum derivatives thereof and other suitable pharmaceutically acceptable excipients and the said core optionally coated with suitable coating material and the process for preparing the same.
In a preferred embodiment of the present invention, a sustained release or modified release formulation comprises a pharmaceutically active agent (metoprolol succinate) alongwith suitable excipients. In particular, the present invention provides sustained 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
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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 therapy, suitably with oral administration. A sustained/modified release is thus achieved by formulation substantially as hereinbefore described.
In a preferred embodiment of the present invention, a sustained 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 gastro-intestinal tract.
The sustained release tablet dosage forms of metoprolol succinate according to the present invention may be formulated by mixing the drug with one or more hydrocolloid gelling agents to form hydrophilic polymer matrix. 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 sustained 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-dependent polymer which preferably is a water soluble salt of alginic acid with a pH-independent hydrocolloid gelling agent forming a hydrophilic polymer matrix along with suitable diluents and other excipients.
Polymers belonging to hydrophilic matrix systems, when exposed to an aqueous medium, does 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.
Therefore, it is theorized that upon oral ingestion of the sustained release tablet of the invention, in an acid aqueous environment, such as the stomach the pH-independent hydrocolloid gelling agent hydrates to form a gel layer at the surface of the tablet. At this low pH environment sodium calcium alginate is formed in situ (formed by calcium carbonate and sodium alginate when added together, sodium alginate forms sodium
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calcium alginate in situ which acts as a pH independent system to release the drug in
controlled manner) and this modifies the gel layer around the tablet. Erosion of the gel
layer gradually exposes more dry matrix that hydrates to replenish the gel layer. Drug dissolves in the gel layer and diffuses out into the surrounding aqueous environments As pH is increased, with passage of the tablet from the stomach down the gastrointestinal tract, the alginic acid salt in the tablet becomes more soluble and the alginic acid formed in the stomach will be reconverted to a more soluble salt, and it will structure the hydrocolloid gelling agent gel layer less. Drug can diffuse more readily through the gel layer now and the ensuing increase in release rate from the matrix compensates for the reducing driving force for dissolution at the elevated pH values in GI tract further. In another embodiment of the present invention, the hydrophilic polymer matrix is incorporated in the matrix along with the drug which matrix provides for the sustained release of metoprolol succinate or its pharmaceutical^ acceptable derivatives thereof. In particular, the present invention provides sustained release tablets comprising a sustained release source comprising hydrophilic polymer matrix comprised of at least one hydrocolloid gelling agent optionally with one or more gelling agents such as gums and gum derivatives thereof and other suitable pharmaceutically acceptable excipients such as diluents, binders, disintegrants, glidents, lubricants and the like.
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, hydroxyethyl cellulose, cellulose alkyl carboxylates such as carboxymethyl cellulose and the like, gums and gum derivatives such as xanthan gum, locust bean gum, vegetable gums such as alginates, gum karaya, pectin, agar, tragacanth, acacia, carrageenan, tragacanth, chitosan, agar, alginic acid, other polysaccharide gums and mixtures thereof and carboxymethylether and propylene glycol esters, carbomers and derivatives thereof, polyvinyl pyrrolidines and derivatives thereof and the like.
Usually, agar, calcium alginate, gelatin and pectin form strong gels. Sodium alginate gels are water-soluble, whereas calcium alginate gels swell in water. Both are used in
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pharmaceutical formulations. Sodium alginate gels have superior emollient properties and are compatible with many pharmaceutical excipients such as starch, sodium
carboxymethylcellulose and the like. Taking advantage of this compatibility and the favorable gel properties, sodium alginate is formulated with sodium carboxymethylcellulose in the non-irritating, water-soluble lubricating gels. The high rigidities of calcium alginate gels make it suitable for preparation of matrix systems for controlled drug delivery.
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 diluent and granulated using suitable granulator with or without the use of suitable binders and using aqueous or nonaqueous or hydro alcoholic solvents. The reultant granules are sized and blended with hydrocolloid gelling agent and optionally one or more gum or gum derivatives along with suitable disintegrants, release modifiers, glidants, lubricants and the like.
Alternatively, second process for preparing the said modified release composition comprises blending of metoprolol succinate or its pharmaceutically acceptable derivative thereof with suitable diluent, disintegrants, release modifiers, polymers, gum or gum derivatives, glidants and lubricants and the like and then compacting/compressing the same using suitable compactor/granulator. The compacts/granules are milled, sized and lubricated and then finally compressed on suitable compression machine. The tablets thus manufactured may optionally be coated to get quality product. More specifically, the present invention suitably the antihypertensive containing formulation core of a pharmaceutical composition according to the present invention may be formulated so as to allow the release of the drug there from in a still sustained or modified release manner, subsequent to the desired release profile provided by the inclusion of hydrophilic polymer matrix.
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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, ethylcellulose, 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, e.g. stearic acid, sodium steryl fumarate, hydrogenated
vegetable oils, calcium and magnesium stearate, solid polyethyl glycols; (c) glidants, e.g. talc, colloidal silicon dioxide; and (d) coatings and protective matrices, e.g. polymeric substances or waxes.
The formulation according to the present invention may also include pharmaceutically 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 steryl fumarate, stearic acid, talc, hydrogenated castor oil, calcium silicate, magnesium silicate 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.
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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. The resultant product may then be granulated and the granules may then be sized and mixed and blended with disintegrants, glidants, release retardants, lubricants and the like. The resultant product may then be compressed and may optionally be coated using suitable polymers.
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.
EXAMPLES
Example -1
Sustained release tablets were prepared using the following materials in the stated quantities:

Sr No. Ingredients Quantity (mg/tablet) Quantity(%w/w)
1. Metoprolol succinate 190 31
2. Methocel KlOOM 300 48
3. Microcrystalline cellulose (Avicel PHI 02) 60 9.7
4. Dicalcium phosphate 50 8
5. Magnesium stearate 6 0.96
6. Talc 14 2.26
7. Purified water q.s q.s
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Procedure: Blend metoprolol succinate, methocel k 100 m, microcrystalline cellulose,
and dicalcium phosphate. The above blend was granulated with water. The resulting granulation was dried, milled and blended with talc and magnesium stearate. The blended material was compressed using suitable compressing machine.
Figure-1 shows the comparative dissolution profiles of the said invented tablet formulation and the reference formulation (Toprol XL Tablets).
Example - 2
Sustained release tablets were prepared using the following materials in the stated quantities:

Sr No. Ingredients Quantity (mg/tablet) Quantity(%w/w)
1. Metoprolol Succinate 190 31
2. Methocel Kl 5 M CR 150 24
3. Hydroxy Propyl cellulose (HPC-LF) 50 9
4. Microcrystalline cellulose (Avicel PHI 02) 15 2.7
5. Sodium Alginate (Keltone HVCR) 80 14
6. Calcium carbonate (Heavy) 56 10
7. Magnesium stearate 5 0.9
8. Talc 9 1.6
9. Purified water q.s q.s
Procedure: Blend metoprolol succinate, methocel k 15 m, hydroxypropyl cellulose- L, microcrystalline cellulose, sodium alginate, calcium carbonate. The above blend was granulated with water. The resulting granulation was dried, milled and talc and magnesium stearate. The blended material was compressed using suitable compressing machine.
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Figure-1 shows the comparative dissolution profiles of the said invented tablet
formulation and the reference formulation (Toprol XL Tablets).
Example - 3
Sustained release tablets were prepared using the following materials in the stated quantities:

Sr No. Ingredients Quantity (mg/tablet) Quantity(%w/w)
1. Metoprolol Succinate 190 29.7
2. Lactose monohydrate 50 7.8
3. MethocelK15MCR 150 23.44
4. Hydroxy Propyl cellulose (HPC-LF) 100 15.63
5. Sodium Alginate (Keltone HVCR) 80 12.5
6. Calcium carbonate (Heavy) 56 8.75
7. Magnesium stearate 5 0.78
8. Talc 9 1.41
9. Purified water q.s q.s
Procedure: Blend metoprolol succinate with lactose monohydrate. The above blend was granulated with water. The resulting granulation was dried, milled and blended with methocel, HPC, calcium carbonate, sodium alginate, talc and magnesium stearate. The blended material was compressed using suitable compressing machine.
Figure-1 shows the comparative dissolution profiles of the said invented tablet formulation and the reference formulation (Toprol XL Tablets).
Example - 4
Sustained release tablets were prepared using the following materials in the stated quantities:
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Sr No. Ingredients Quantity (mg/tablet) Quantity(%w/w)
l. Metoprolol Succinate 190 31.67
2. Lactose monohydrate 60 10
3. MethocelK15MCR 150 25
4. Hydroxy Propyl cellulose (HPC-LH-11) 50 8.33
5. Sodium Alginate (Keltone HVCR) 80 13.33
6. Calcium carbonate (Heavy) 56 9.33
7. Magnesium stearate 5 0.83
8. Talc 9 1.5
9. Purified water q.s q.s
Procedure: Same as mentioned in Example-3.
Figure-1 shows the comparative dissolution profiles of the said invented tablet formulation and the reference formulation (Toprol XL Tablets).
Example - 5
Sustained release tablets were prepared using the following materials in the stated quantities:

Sr No. Ingredients Quantity (mg/tablet) Quantity(%w/w)
1. Metoprolol Succinate 190 29.23
2. Lactose monohydrate 60 9.23
3. MethocelK15MCR 150 23.1
4. Hydroxy Propyl cellulose (HPC-M) 100 15.38
5. Sodium Alginate (Keltone HVCR) 80 12.31
6. Calcium carbonate (Heavy) 56 8.62
7. Magnesium stearate 5 0.77
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8. Talc 9 1.38
9. Purified water q.s q.s
Procedure: Same as mentioned in Example-3.
Figure-1 shows the comparative dissolution profiles of the said invented tablet formulation and the reference formulation (Toprol XL Tablets).
Example - 6
Sustained release tablets were prepared using the following materials in the stated quantities:

Sr No. Ingredients Quantity (mg/tablet) Quantity(%w/w)
1. Metoprolol Succinate 190 28.15
2. Lactose monohydrate 60 8.89
3. MethocelK15MCR 175 25.93
4. Hydroxy Propyl cellulose (HPC-L) 100 14.81
5. Sodium Alginate (Keltone HVCR) 80 11.85
6. Calcium carbonate (Heavy) 56 8.3
7. Magnesium stearate 5 0.74
8. Talc 9 1.33
9. Purified water q.s q.s
Procedure: Same as mentioned in Example-3.
Figure-1 shows the comparative dissolution profiles of the said invented tablet formulation and the reference formulation (Toprol XL Tablets).
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Example - 7
Sustained release tablets were prepared using the following materials in the stated quantities:

Sr No. Ingredients Quantity (mg/tablet) Quantity(%w/w)
1. Metoprolol Succinate 190 27.14
2. Lactose monohydrate 60 8.57
3. MethocelK15MCR 175 25
4. Hydroxy Propyl cellulose (HPC-L) 125 17.86
5. Sodium Alginate (Keltone HVCR) 80 11.43
6. Calcium carbonate (Heavy) 56 8
7. Magnesium stearate 5 0.71
8. Talc 9 1.29
9. Purified water q.s q.s
Procedure: Same as mentioned in Example-3.
Figure-1 shows the comparative dissolution profiles of the said invented tablet formulation and the reference formulation (Toprol XL Tablets).
Example - 8
Sustained release tablets were prepared using the following materials in the stated quantities:

Sr No. Ingredients Quantity (mg/tablet) Quantity(%w/w)
1. Metoprolol Succinate 190 27.14
2. Lactose monohydrate 60 8.57
3. MethocelK15MCR 150 21.43
4. Hydroxy Propyl cellulose (HPC-L) 150 21.43
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5. Sodium Alginate (Keltone HVCR) 80 11.43
6. Calcium carbonate (Heavy) 56 g
7. Magnesium stearate 5 0.71
8. Talc 9 1.29
9. Purified water q.s q.s
Procedure: Same as mentioned in Example-3.
Figure-1 shows the comparative dissolution profiles of the said invented tablet formulation and the reference formulation (Toprol XL Tablets).
Example - 9
Sustained release tablets were prepared using the following materials in the stated quantities:

Sr No. Ingredients Quantity (mg/tablet) Quantity(%w/w)
1. Metoprolol Succinate 190 27.14
2. Lactose monohydrate 60 8.57
3. MethocelK15MCR 150 21.43
4. Hydroxy Propyl cellulose (HPC-M) 82 11.71
5. Sodium Alginate (Keltone HVCR) 120 17.14
6. Calcium carbonate (Heavy) 84 12
7. Magnesium stearate 5 0.71
8. Talc 9 1.29
9. Purified water q.s q.s
Procedure: Same as mentioned in Example-3.
Figure-1 shows the comparative dissolution profiles of the said invented tablet formulation and the reference formulation (Toprol XL Tablets).
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Claim:
1. A sustained or modified release pharmaceutical composition comprising
A. a therapeutically effective amount of metoprolol succinate or its pharmaceutically acceptable derivative thereof comprising
a. a hydrophilic polymer matrix comprising at least one hydrophilic
polymer optionally in combination with gelling agent and
b. pharmaceutically acceptable diluents and other suitable
pharmaceutical excipients thereof
2. A pharmaceutical composition of claim 1, wherein the said composition comprises of metoprolol succinate or its pharmaceutically acceptable derivative thereof and a hydrophilic polymer matrix comprising at least one hydrophilic polymer optionally in combination with gelling agent mixed and compressed together.
3. A pharmaceutical composition of claim 2, wherein the said hydrophilic polymer matrix comprises at least one hydrophilic polymer.
4. A pharmaceutical composition of claim 3, wherein the said hydrophilic polymer is selected from a group comprising cellulose polymers such as cellulose ethers like methylcellulose, cellulose alkyl hydroxylates such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxy ethylcellulose, cellulose alkyl carboxylates such as carboxymethyl cellulose and carboxyethyl cellulose and alkali metal salts of cellulose alkyl carboxylates povidone, vinyl copolymers, polyethylene oxide and derivatives thereof propylene glycol esters, carbomers and derivatives thereof, polyvinyl pyrrolidones and derivatives thereof and the like and the like.
5. A pharmaceutical composition of claim 1, wherein the said pharmaceutically acceptable diluents are selected from the group comprising lactose, mannitol,
sucrose, dextrose, microcrystalline cellulose, powdered cellulose, starches,
sorbitol, dibasic calcium phosphate, calcium carbonate and the like
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6 A pharmaceutical composition of claim 1, wherein the composition is oral
solid dosages form.
7 A pharmaceutical composition of claim 6, wherein the formulation is a
capsule, tablet, granules, pills, granules in capsule, micro-tablets in capsules or combinations thereof.
8 A pharmaceutical composition of claim 1, wherein the formulation is tablet dosages form.
9 A pharmaceutical composition of claim 1, wherein the tablets comprises sustained released metoprolol succinate or its pharmaceutically acceptable derivatives thereof with hydrophilic polymer matrix mixed and compressed together and may optionally be coated with suitable coating materials.
10 The pharmaceutical composition of claim 1, wherein the composition is manufactured comprising the steps of:
(i) mixing and blending metoprolol succinate or its pharmaceutically acceptable derivative thereof with hydrophilic polymer
(ii) granulating the product of step (i) using suitable granulation technique followed by
(iii) compressing the product of step (i) to form tablets comprising metoprolol succinate.
11 The pharmaceutical composition of claim 1, wherein the tablet is manufactured by using wet granulation technique, drying the resultant product and compressing the dried product to form the tablets comprising metoprolol succinate.
12 The pharmaceutical composition of claim 1, wherein the hydrophilic matrix may optionally comprise of gelling agents such as gums and gum derivatives, selected from the group comprising xanthan gum, locust bean gum, vegetable gums such as alginates, gum karaya, pectin, agar, tragacanth, acacia, carrageenan, tragacanth, chitosan, agar, alginic acid, other polysaccharide
gums and mixtures thereof
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13. A process for manufacture of sustained release composition of metoprolol
succinate or its pharmaceutical acceptable derivatives thereof, the process
comprises the steps of
(a) mixing metoprolol succinate or its pharmaceutically acceptable derivative thereof with hydrophilic polymer
(b) granulating the product of step (i) using suitable granulation technique followed by
(c) compressing the product of step I to form tablets comprising metoprolol succinate

14. A pharmaceutical composition in solid dosage form prepared by process of claim 13, wherein the said formulation comprises blending metoprolol succinate or its pharmaceutically acceptable derivative thereof with hydrocolloid agent such as hydroxy propyl cellulose and/or hydroxypropyl methyl cellulose with gelling agents such as sodium alginate and diluents like microcrystalline cellulose, lactose, calcium carbonate and the like and granulating the same using aqueous solvents optionally using binders such as cellulose derivatives, povidone and the like or nonaqueous or hydro alcoholic solvents followed by drying the resultant product and lubricating the same using suitable lubricants and antiadherants such as magnesium stearate and talc and compressing the lubricated granules to form tablets containing metoprolol succinate or its pharmaceutically acceptable derivative thereof.
15. A process of claim 13, wherein the said tablet comprises of metoprolol succinate or its pharmaceutically acceptable derivative thereof and a hydrophilic polymer matrix comprising at least one hydrophilic polymer optionally in combination with gelling agent.
16. A process of claim 13, wherein the said hydrophilic polymer matrix comprises at least one hydrophilic polymer.
17. A process of claim 13, wherein the said hydrophilic polymer is selected from
a group comprising cellulose polymers such as cellulose ethers like
methylcellulose, cellulose alkyl hydroxylates such as hydroxypropyl
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methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxy
ethylcellulose, cellulose alkyl carboxylates such as carboxymethyl cellulose
and carboxyethyl cellulose and alkali metal salts of cellulose alkyl carboxylates povidone, vinyl copolymers, polyethylene oxide and derivatives thereof propylene glycol esters, carbomers and derivatives thereof, polyvinyl pyrrolidones and derivatives thereof and the like and the like.
18. A process of claim 13, wherein the composition is oral solid dosage form.
19. A process of claim 18, wherein the composition is a capsule, tablet, granules, pills, granules in capsule, micro-tablets in capsules or combinations thereof
20. A process of claim 13, wherein the composition is a tablet.
21. A process of claim 13, wherein the hydrophilic matrix may optionally comprise of gelling agents such as gums and gum derivatives, selected from the group comprising xanthan gum, locust bean gum, vegetable gums such as alginates, gum karaya, pectin, agar, tragacanth, acacia, carrageenan, tragacanth, chitosan, agar, alginic acid, other polysaccharide gums and mixtures thereof
22. Use of the pharmaceutical composition of claim 1 in the manufacture of a medicament for treating hypertension and related disorders

Dated September 21, 2005
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ABSTRACT
The present invention relates to sustained release solid pharmaceutical composition comprising antihypertensives, in particular, Metoprolol succinate or its pharmaceutically acceptable derivatives thereof and a process for preparing such a formulation. The present invention is a composition comprising Metoprolol succinate or its pharmaceutically acceptable derivatives thereof and the said composition releases the drug over 24 hours. The composition further comprises hydrophilic polymer matrix based tablets. The present invention describes a sustained release tablet comprising sustained release matrix comprising at least one hydrophilic polymer optionally in combination with gelling agent (like gums and gum derivatives).
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