F0RM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
{See section 10; rule 13)
1. Title of the invention : "Ready to use compositions for Non-steroidal antiinflammatory drugs (NSAIDs)"
2. Applicant(s)

(a) NAME : IDEAL CURES PVT. LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS : A-223-229,2nd floor, Virwani Industrial Estate, Off. Western Express Highway, Goregaon (East), Mumbai -400 063. E-mail- patent@idealcures.co.in
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Ready to use compositions for P-blockers
Technical Field
The present invention relates to a dry ready to use modified release dosage formulation composition comprising a mixed matrix of natural gums components having plurality of layers thereby providing controlled release rate of p-blockers or beta-adrenergic blocking agents from the formulation/tablet. Dry composition are applicable to drug, veterinary and agricultural formulation, it could be applied to the retarded release of fertilizers, insecticides or specific protection agents. Present ready-to-use modified release compositions is capable of regulating release of p-blockers or beta-adrenergic blocking agents at various dosage strength, a process for production thereof and also use thereof as formulated pharmaceutical compositions.
Background or Information on Art
It is well known in the art that p-blockers or beta-adrenergic blocking agents, are a class of drugs used for various cardiac arrhythmias, heart protection after myocardial infarction (heart-attack), and hypertension. As beta adrenergic receptor antagonists, they diminish the effects of stress hormones. This class of drug is represented by many pharmaceutical drugs namely propranolol, pronethalol, Bisoprolol, carvedilol, metoprolol etc. Generally chemical drugs of this class have one or more isomers and termed as racemic mixtures. One of widely studied p-blockers Metropolol is a mixture of optical isomers, called enantiomers.
In practice drugs are formulated as low concentration dosage to avoid toxicity and other adverse side-effects medical complications, but sometimes it is essential to maintain certain level of medications in blood stream. This can either achieved by repeated dose after every 3-4 hours or administration of a modified release formulated medication. Later is also termed as sustained release dosage and it offers numerous advantages to patients besides maintaining drug quantity in body through one dose.

Several modified release systems are known in the art providing sustained or modified release profile to medication.
In one of the basic method for solid oral pharmaceutical products was prepared with protracted active ingredient release e.g. US4199560 described method where-in tablet internal phase is composed of a hydrophobic component and a hydrophilic component.
Subsequently later tablets release was modified with matrix systems e.g. US4252786 with use of rupturable film, in which water was permeable and film was substantially insoluble in water, comprising a combination of hydrophobic and hydrophilic polymers.
Another method for modified release was presented in EPQ092060, displaying protective barrier method. System comprised a core of rigid polymer matrix of biodegradable polymer with drug further coated by filmogenic polymer allowing drug diffusion across polymer coating and lastly protective film coat which does not allow leaching of filmogenic polymer.
Certain NSAID like Ibuprofen release was modified in US5415871 which describes a controlled release pharmaceutical formulation containing xanthan gum, dimethylsiloxane, silicic acid, mannans or galactans, micronized seaweed.
Metoprolol was formulated with water insoluble inert cores like silicon dioxide, glass, or plastic resin particles in US4927640 for preparing controlled release dosage forms. One of the limitations of invention was that it can only be practiced to water insoluble materials, for the reason that the water soluble material will absorb water in large quantity and eventually burst thereby delivering entire drug content immediately instead of controlled release. Carboxylic acid based polymers like polymethacrylate plastics were used in US4351825 to obtain matrix-type tablets with delayed release preparation process comprising granulation.
In yet another formulation of Metoprolol as disclosed in US4942040 it was used as coating beads with a water insoluble polymeric membrane, dihyrdopyridine and dihydrophilic. Upon

absorbing water gel matrix is formed which restricts rapid release of the drug. Drug coated with polymer further restricts its rapid dissolution thereby enhancing its delayed release time. It was observed that use of swollen gel matrix results in big tablet size which is difficult to consume and moreover contains small amount of active ingredient.
Other methods such as buoyant controlled release formulation (e.g. US5169638); use of Sodium alginate with binder (e.g. US4792452); beads of metoprolol with polymeric membrane coating (e.g. US4957745); acrylic polymer used with anionic polymer (e.g. US5081154) are known in the art for producing controlled release formulations but most of them are directed towards coating of polymer and additional method to delay the release which may require use of harmful organic solvent or low drug dosage thereby not suitable for industrial application and prolonged use.
Baichwal et al. US5399358 discloses formulation of metoprolol in gum based formulation, preferably using xanthan gum and locust bean gum. However, these gum based formulation are susceptible to microbiological growth contamination and thereby requiring a complicated and expensive process to manufacture, sophisticated machinery and skilled workers.
Although many methods and formulation has been derived in prior art but it has become desirable to provide ready-to-use formulation composition for modified release profiles, an objective not contemplated in other prior art as most of them requiring lengthy step by step procedures to prepare final formulation. Superior advantages of modified release formulation are well known in industry and it also significantly improves patient acceptability by reducing dosage regimen.
It is therefore an object of the present invention to provide a ready-to-use, stable modified release composition which can be used for a wide variety of therapeutically active substances.

It is an object of the present invention to provide a ready-to-use, stable modified release composition for β-blockers or beta-adrenergic blocking agents.
It is another object of the present invention to provide a ready-to-use, stable modified release composition having the properties set forth above which can be used with both relatively soluble and relatively insoluble therapeutically active substances.
It is a further object of the present invention to provide a free-flowing directly compressible a ready-to-use, stable modified release composition which is relatively inexpensive to manufacture.
Summary of Invention
In accordance with the above-mentioned objectives, the present invention provides a ready-to-use, stable modified release composition comprising natural gum with cellulosic polymer and polymer having pH dependent solubility for β-blockers or beta-adrenergic blocking agents or its pharmaceutically acceptable salts.
In one of the embodiment invention also provides a ready-to-use, stable modified release composition comprising natural gum with cellulosic polymer and polymer having pH dependent solubility for which may be used with both relatively soluble and relatively insoluble therapeutically active substances.
In accordance with the above-mentioned objectives, in one of the embodiment invention also provides a ready-to-use, stable modified release composition comprising natural gum with cellulosic polymer and polymer having pH dependent solubility for Metoprolol.
In another aspect, present inventive composition optionally further comprises other pharmaceutically acceptable excipients, bulking agents, flavoring agents, coloring agents, additional lubricants and like.

In further aspect, inventive compositions are free-flowing directly compressible a ready-to-use, stable modified release composition which is relatively inexpensive to manufacture for β-blockers or beta-adrenergic blocking agents.
The details of one or more embodiments in the practice of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the appended examples and claims.
Detailed description
Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present invention, the preferred methods and materials are described. To describe the invention, certain terms are defined herein specifically as follows.
Unless stated to the contrary, any of the words "having" "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims.
The term "ready-to-use", in the context of the present invention, is taken to mean that, the composition according to the invention may be used directly without further processing for its purposes by the user as simply mixing inventive composition in required quantity of active ingredient.

The term "active ingredient", in the context of the present invention, is taken to mean β-blockers or beta-adrenergic blocking agents or their pharmaceutically acceptable salts or combination thereof.
The term 'lubricant' in the context of the present invention, is taken to mean that a ingredient added to prevent the adhesion of tablet materials to the punches and dies, reduce inter-particle friction and facilitate the ejection of oral dosage forms from the die cavity, also to facilitate the flow of material.
The term 'sustained release', 'controlled release', 'modified release', 'extended release' were used synonymously in the context of the present invention, and have their standard meaning as specified in technology.
Unexpectedly, inventors have found that when β-blockers or beta-adrenergic blocking agents are formulated with natural gum(s) polymer in combination with cellulosic polymers have advantageous sustained release properties.
Natural gums are carbohydrate polymers (sugars) of natural origin. These have ability of increasing viscosity of the solution even at small quantity or concentration. In the food industry they are used as thickening agents, gelling agents, emulsifying agents, and stabilizers. Natural gum according to present invention is having property to delay the release of active ingredient. Natural gum in accordance with present invention could be selected from Agar, Alginic acid, Carrageenan, Gum Arabic, Gum ghatti, Gum tragacanth, Karaya gum, Guar gum, Locust bean gum, Beta-glucan, Chicle gum, Dammar gum, Glucomannan, Mastic gum, Spruce gum, Tara gum, Gellan gum, Xanthan gum or like etc.
In one of the embodiment of present invention natural gum is Xanthan gum which is a high molecular weight natural carbohydrate produced in a pure culture fermentation process by the xanthomonas campestris microorganism. According to general production process by fermentation xanthomonas campestris is cultured in aerobic conditioned medium containing glucose, nitrogen source, di-potassium hydrogen phosphate and trace elements (general fermentation process could be followed to achieve xanthan gum as explained on

Pace, G. W.; Righelato, R. C. Production of Extracellular Microbial Polysaccharides. In Advances in Biochemical Engineering; Fiechter, A., Ed.; Springer-Verlag: New York, 1980; Vol. 15, pp 41-70.) Xanthan gum is of unvarying chemical structure and has uniform chemical and physical properties.
Upon administration of dosage form in patient present inventive formulation comprising natural gum, and active ingredient reaches in gastric juices the natural gum portion of the formulation absorbs the moisture and creates a gel like substances. In one of the embodiment invention is natural gum like Xanthan gum, displays a good swelling action on contact with an aqueous medium.
It is believed that erosion plays a part in the release of active ingredient from the solid composition, however, the gel formed is of sufficient thickness and abrasion resistance to allow diffusion to be the principle form by which the active ingredient is released into the body whether from the intact dose form or from sma\ler portions of drug containing gel that are eroded from it
The amount of natural gum employed in a formulation according to the invention is from 20 to 50% by weight of the formulation. Advantageously according to one of the embodiment the natural gum comprising a major proportion of xanthan gum comprises 22- 44 %, particularly 22-40%, by weight of the formulation.
The natural gum according to present invention allows the release of the (3-blockers or beta-adrenergic blocking agents from the formulation over a period of time greater than that expected from a conventional immediate release tablet. In yet another embodiment of the present invention natural gum is mixed with different viscosity grades of the same or variant natural gum.
The natural gum according to one of the main embodiment of present invention is xanthan gum allow the release of the (i-blockers or beta-adrenergic blocking agents from the formulation over a period of time greater than that expected from a conventional immediate release tablet. In yet another embodiment of the present invention Xanthan gum

is mixed with different viscosity grades of the xanthan gum or synthetic variant of natural gum.
Alternatively in one of the aspect of present invention is to get delayed release composition which is obtained by addition of one more cellulosic additional polymer with natural gum and polymer with pH dependent solubility having more solubility in aqueous solution than natural gum. Therefore if desired, a proportion of the natural gum may be replaced by cellulosic additional polymer(s), or polymer(s) with pH dependent solubility.
In yet another aspect of present invention is to get delayed release composition which is obtained by addition of one more cellulosic additional polymer with natural gum and polymer with pH dependent solubility having more solubility in aqueous solution than natural gum and optionally a lubricant.
Cellulosic additional polymers have sugar subunits with ability of increased solubility in aqueous solutions. Some of the cellulosic additional polymers includes but not limited to purified cellulose; microcrystalline cellulose; and alkyl celluloses and their derivatives and salts (e.g., methylcellulose, carboxymethylcellulose and the like).
The amount of cellulosic polymer employed in a formulation according to the invention is from 25 to 50% by weight of the formulation. Advantageously according to one of the embodiment cellulosic polymer comprises 28-46%, by weight of the formulation.
In accordance with objective of present invention polymer used are having pH-dependent solubility include but not limited to methacrylic acid copolymers, non- neutralized or partially-neutralized poly(methacrylic acid, ethyl acrylate) and poly(methacrylic acid, methyl methacrylate) additional polymers also found useful are polyvinylacetate phthalate (PVAP), PVAP coprocessed with titanium dioxide (PVAP-T), cellulose acetate phthalate (CAP), hydroxypropylmethyl cellulose acetate succinate (HPMC-AS) and hydroxypropylmethyl cellulose phthalate (HPMC-P).

The amount of polymer with pH-dependent solubility employed in a formulation according to the invention is from 25 to 40% by weight of the formulation. Advantageously according to one of the embodiment the polymer with pH-dependent solubility comprises 28- 38 %, particularly 30-35%, by weight of the formulation.
The ready to use composition in accordance with present invention comprise natural gum with cellulosic polymer and polymer having pH dependent solubility. In one of the embodiment of present invention natural polymer is xanthan gum and cellulosic polymer is hydroxypropyl methyl cellulose having variable viscosity strength, molecular weight. In accordance with present invention different natural gum and cellulosic polymer could be combined to polymer having pH dependent solubility achieve ready-to-use free flow composition.
Lubricants of the present invention comprise silica or silicon dioxide, magnesium stearate, stearic acid, calcium stearate, glyceryl behanate, hydrogenated vegetable oils and the like. The amount of lubricant employed in a formulation according to the invention is from 2 to 10% by weight of the formulation.
In a preferred formulation according to the invention the pharmacologically active ingredient comprises β-blockers or beta-adrenergic blocking agents. Particularly suitable active ingredients for a formulation according to the invention are propranolol, pronethalol, Bisoprolol, carvedilol, metoprolol etc. and their pharmaceutically acceptable salts. Especially advantageous sustained release properties are obtained when metoprolol is combined with Natural gum comprising a major proportion of xanthan gum in a formulation according to the invention.
In a formulation according to the invention the pharmacologically active ingredient is blended with the inventive composition and the mixture is compressed to produce a solid formulation. Preferably the ingredients are blended to form a uniform powder and them compressed with means generally known to skilled in the art. Appropriately the inventive composition and pharmacologically active ingredient are blended substantially throughout

the whole solid formulation. Solid formulation thus prepared could be further coated with other means for shiny look, palatability, taste masking, pigmentation, distinguishing marking, grooves and like.
In particular, when formulations comprise metoprolol and a composition according to the present invention, the formulations thereby achieved are therapeutically effective and exhibit desired bioavailability characteristics. Furthermore, the controlled release formulation achieved with inventive composition with Metoprolol it is observed that active drug molecules retains upto 24 hours or even more in accordance with some of the embodiment of invention. In standards of pharmacological drug delivery such formulation which delivers drug upto 24 hours or more could be termed as once a day formulation, providing a patient compliance and one dose per day regfmen.
Accordingly other pharmaceutically acceptable excipients may be combined to produce modified release formulation. It is anticipated that such excipients may be added to further modify rate of drug availability in body or may support other property which assist successful tablet manufacturing. Pharmaceutically acceptable excipient may be added in sufficient and appropriate quantities for successful dosage composition include, but are not limited to fatty acid and derivatives e.g. stearic acid, metallic stearates, stearyl alcohol, hydrogenated cotton seed oil and like; lactose, sucrose and tablet disintegrants for example corn starch and alginic acid and like; dibasic calcium phosphate and like etc. The pharmaceutically acceptable excipients may be applicable recognized by those skilled in the art are listed in Wade, A. and P. J. Wetler (1994). Handbook of pharmaceutical excipients, Pharmaceutical press incorporated herein for reference only. Quantity of such pharmaceutically acceptable excipients varies according, to their role and quality/grades. In one of the embodiment of present invention the quantity of pharmaceutically acceptable excipients used is suitably up to 10%, preferably up to 8% and more preferably up to 6% by weight of the total composition.
According to present invention dosage form of β-blockers or beta-adrenergic blocking agents is greater than 10 mg, in some of the non-limiting embodiment of present invention

β-blocker is exemplified with Metoprolol succinate with 25, 50 and 100 mg. In particular β-blockers or beta-adrenergic blocking agents comprise about 15-22%, preferably 16-20% w/w of final formulated dosage form.
Preferred formulations according to the invention are obtained when the compositions comprise β-blockers or beta-adrenergic blocking agents about 16-20% and inventive composition comprising xanthan gum about 65-84% by weight of final formulated dosage form. In accordance with one of the embodiment preferred formulations comprise β-blockers or beta-adrenergic blocking agents about 17-18% and inventive composition comprising xanthan gum about 68-82% by weight of final formulated dosage form.
Preferred formulations according to the invention are obtained when the compositions comprise metoprolol about 16-20% and inventive composition comprising xanthan gum about 65-84% by weight of final formulated dosage form. In accordance with one of the embodiment preferred formulations comprise metoprolol about 17-18% and inventive composition comprising xanthan gum about 68-82% by weight of final formulated dosage form.
It is well known in the art that controlled release formulation solid dosage form may be provided in standard pharmacologically accepted form. In accordance with present invention some of the solid dosage form prepared include but not limited too, capsules, tablets, various suppositories, pessary, lozenges or implants, skin patches or like etc. According to one of the main embodiment of present invention preferably tablet formulations are prepared and intended to release the drug molecules slowly after predetermined controlled release within alimentary canal of organism including oesophagus, stomach, intestine and respective organ cavities. Optionally produced dosage form may be further coated with suitable coating composition to improve taste-masking, delivery, sweetening, flavor etc.
According to one of the main embodiment of present invention solid dosage formulation is prepared through conventional dosage preparation methods listed in Swarbrick, J. and J. C.

Boylan (2001), Encyclopedia of pharmaceutical technology; Association, A. P. (1986) "Handbook of pharmaceutical excipients" incorporated herein by reference only. Preferably one of the embodiments uses combination of method like slugging and tablet compression to generate final dosage formulation. Accordingly inventive composition is prepared by combining cellulosic polymer and natural gum in blender with pharmaceutically acceptable excipients.
Inventive formulation may be prepared by blending p-blockers or beta-adrenergic blocking agents, their derivatives or combination thereof along with inventive composition. Therefore inventive formulation preparation comprise steps as
1. Blending of polymer(s) and natural gum
2. Dry Granulation or slugging
3. Moderate hardness tablet compression
4. De-slugging and breaking tablets
5. Sieving through appropriate size
6. Optionally addition of lubricant
7. Final tablet compression
Initially inventive composition is prepared by blending desired quantity of cellulosic polymer along with natural gum to form 'ready to use composition' preferred process blending is performed by conventional dry blender or a food processor or "V-blender" or a similar function device. According to one of the embodiment inventive formulations are prepared by blending p-blockers along with inventive composition. Further P-blockers are blended with ready to use composition by dry granulation or slugging or a similar method to generate inventive formulation. Inventive formulation is further compressed to form oral dosage form with addition of lubricant.
In yet another words inventive formulations are prepared by blending p-blockers along with inventive composition. Initially cellulosic polymer along with xanthan gum and pH dependent solubility polymer are blended to form 'ready to use composition' preferred process blending is performed by conventional dry blender or a food processor or "V blender" or a similar function device. Further P-blockers are blended with ready to use

composition by dry granulation or slugging or a similar method to generate inventive formulation. Inventive formulation is further compressed to form oral dosage form with addition of lubricant.
In one of the embodiment of present invention, inventive formulations are prepared by blending β-blockers along with inventive composition. Initially celiulosic polymer along with xanthan gum and pH dependent solubility polymer are blended to form 'ready to use composition' preferred process mixing is by conventional dry blending in a food processor or "V-blender" or a similar function device. Further (3-blockers are blended with ready to use composition with dry granulation or slugging or a similar method to generate inventive formulation. In another embodiment when concentration of p-blocker is lower than wet granulation using isopropyl alcohol with water in 80:20 ratio could be performed with subsequent drying and slugging. Inventive formulation is further compressed to form intermediate solid form then compressed solid form is broken into small granules and sieved to get fine particles (e.g. 18-20 mesh). Prepared solid form may be milled or crushed using standard milling technique thereby reducing them to granules. Inventors observed that sieving quality and fineness of blended blend provide excellent compression and desired controlled release function. Therefore it is recommended that in any formulation to produce consistent controlled release formulation uniform size of the mixed blend is essentia!. Obtained sieved blend is then uniformly mixed with premeasured amount of the lubricant and/or glidant to improve industrial acceptability and oral dosage compression quality. Subsequently uniform mixed inventive formulation is compressed in standard pharmacopoeial equipment to get a controlled release oral dosage formulation of the correct desired weight and strength.
The controlled release oral dosage formulation according to invention may be compressed to get adequate hardness to prevent premature inflowing of the aqueous medium into oral dosage form. According to one of the main embodiment wherein hardness of tablets produced is in range of 5 Kg/cm2 to 10 Kg/cm2 or 15 Kg/cm2. Oral dosage forms produced by inventive composition having human administrable active ingredient is suitable of human

use. Alternatively drug suitable for veterinary purpose formulated in accordance with present composition will be suitable for veterinary use.
According to the objective of present invention β-blockers are formulated in oral dosage form for controlled release delivery. In an exemplary inventive formulation in accordance with invention have pharmacologically active ingredient is Metoprolol. Inventive composition may be comprising 20-500 mg, more preferably 25-200 mg in plurality of dosage formulations. Controlled release formulation may have more drug content than normal delivery dosages because it does not delivery all content of drug immediately thereby reducing toxic effect or other related problems. Therefore in accordance of present inventive formulation suitably comprise at least 50% by weight of β-blockers, preferably at least 60-95%, more preferably 75-88%.
In accordance of present invention p-blockers formulation produced are suitable for once a day administration, more preferably once a day administration.
Following examples are offered to more fully illustrate the invention, but are not to be construed as limiting the scope thereof.
Examples
Example 1.
Ready to use composition is prepared by taking xanthan gum 35% (w/w of dry weight composition) weighing appropriate quantity and sieving through 40 mesh screen. Subsequently hyperomllose 30% (w/w of dry weight composition) is weighed and sieved through 40 mesh screen followed by Methacrylic acid copolymer type C 35% (w/w of dry weight composition) weighing and sieving through 40 mesh screen. All components duly sieved are blended together in blender for 20 minutes (e.g. octagonal blender). Dry powder thus prepared is stable for storage and reusable in batches of operations.

Table 1

Sr. No. Ingredients % w/w of total dry weight
1. Hypromellose(KlOOM) 30
2. Xanthan Gum 35
3. Methacrylic acid copolymer type C (Ecopol SlOO) 35
Total = 100
Example 2.
Another Ready to use composition is prepared by taking xanthan gum 34% (w/w of dry weight composition) weighing appropriate quantity and sieving through 40 mesh screen. Subsequently hyperomllose 29% (w/w of dry weight composition) is weighed and sieved through 40 mesh screen followed by Methacrylic acid copolymer 37% (w/w of dry weight composition) weighing and sieving through 40 mesh screen. All components duly sieved are blended together in blender for 20 minutes (e.g. octagonal blender). Dry powder thus prepared is stable for storage and reusable in batches of operations.
Table 2

Sr. No. Ingredients % w/w of total dry weight
1. Hypromellose(KlOOM) 29
2. Xanthan Gum 34
3. Methacrylic acid copolymer 37
Total = 100
Example 3.
Another Ready to use composition is prepared by taking xanthan gum 22.88% (w/w of dry weight composition) weighing appropriate quantity and sieving through 40 mesh screen. Subsequently hyperomllose 46.27% (w/w of dry weight composition) is weighed and sieved through 40 mesh screen followed by Methacrylic acid copolymer 30.85% (w/w of dry weight composition) weighing and sieving through 40 mesh screen. All components duly sieved are

blended together in blender for 20 minutes (e.g. octagonal blender). Dry powder thus prepared is stable for storage and reusable in batches of operations.
Table 3

Sr. No. Ingredients % w/w of total dry weight
1. Hypromellose(KlOOM) 46.27
2. Xanthan Gum 22.88
3. Methacrylic acid copolymer 30.85
Total = 100
Example 4
Sustained release solid oral dosage formulation of metoprolol (for 50 mg strength at 300 mg average weight) is prepared using ready to use composition of example 1.
Table 4

Sr. No. Ingredients % w/w of total dry weight
1. Metoprolol succinate 15.83
2. Ready to use composition 80.83
j. Colloidal silicon dioxide 1.67
4. Magnesium stearate 1.67
Total = 100
In order to prepare dosage formulation for metoprolol succinate exemplary Table 4 composition is used wherein metoprolol succinate is 15.83% (w/w of dry weight composition) and weighed accordingly, subsequently sieved to get uniformly granulated powder through 40 mesh screen. It is noted that other size screen could be used to get similar results. Sieved metoprolol succinate is blended with 80% (w/w of dry weight composition) of ready to use composition in blender for 20 minutes (e.g. octagonal blender). To promote efficient tablet punching further 0.83% % (w/w of dry weight composition) of magnesium stearate along with 0.83 %% (w/w of dry weight composition) of colloidal silicon dioxide are sieved through 40 mesh screen and added to above blended formulation in blender for subsequent 5 minutes. Resultant blend is subjected to slugging by compressing

on 18x7.5 mm of capsule shaped punches at 700 mg of average weight and of moderate hardness (e.g. 7 kg/cm2). Prepared tablets are further milled or crushed using standard milling technique thereby reducing them to granules (e.g. Milti mill at 2500 rpm), Generated granules are further sieved through 20 mesh screen. To further promote efficient tablet punching 0.83% (w/w of dry weight composition) of magnesium stearate along with 0.83% % (w/w of dry weight composition) of coloidal silicon dioxide are sieved through 40 mesh screen and then added to above screened granules. Granules mixed with lubricant have bulk density of about 0.500 - 0.520 (g/ml) and tapped density of about 0.570-0.600 (g/ml). Final screened granules are compressed using 10mm (for 50mg strength at 300 mg average weight) circular, biconcave punches at hardness not less than 10 kg/cm2, thickness about 4.0-4.2mm, friability about 0.042-0.055(%).
Example 5
Dissolution Profile Evaluation
A dissolution study was performed to evaluate the effect of ready to use composition with active ingredient. Drug dissolution profiles of tablet prepared are measured by USP 35 dissolution test of rotating basket method <711>. It is evident from standard state of the art that active ingredient may have its own dissolution testing parameters which can be found in their respective monographs. The active ingredient content standardized for sustained release profile is as per table 5:-
Table 5

Time (Hour) Limit
01 NMT 25%
04 20% - 40%
08 40% - 60%
20 NLT 80%

Dissolution study was performed on Electrolab dissolution test apparatus (Type 2) with experimental parameters as rpm of 50, and 500 ml of Phosphate buffer at pH 6.8 as dissolution medium. For the purpose of analysis active ingredient standard was prepared by dissolving Metoprolol succinate in 100 ml volumetric flask with phosphate buffer of pH 6.8 (100 ppm) and dilutions of 8,12,16, 20, 24,28 ppm was prepared with phosphate buffer of pH 6.8. Active ingredient absorbance was checked at 222.5 nm.
Solid oral dosage forms prepared are subjected to dissolution in type 2 dissolution apparatus at 50 rpm for 1, 4, 6 and 20 hours of time intervals. Absorbance of solution is recorded at 222.5 nm on spectrophotometer. At a given time a definite amount of dissolution (e.g. 5 ml) solution was taken and the content of active ingredient remaining was determined. Dissolution results for example batches of metoprolol succinate ER 50 mg tablets are given in the following table 8
Table 6

Time (Hour) Limit Test Product Example 4
01 NMT 25% 14.18
04 20% - 40% 31.54
08 40% - 60% 47.05
20 NLT 80% 89.42
Example 6
Ready to use formulation is prepared according to procedures as described in example 1 and solid oral dosage formulation of metoprolol succinate is prepared with ingredients as specified in table 9.
Table 7

Sr. No. Ingredients % w/w of total dry weight

1. Metoprolol succinate 16.96
2. Ready to use composition 79.46
3. Colloidal silicon dioxide 1.79
4. Magnesium stearate 1.79
Total = 100
Granules for tablet preparation are prepared as specified in Example 4 and further compressed in machine using 18 mm x 7.5 mm capsule shaped, biconcave punches at hardness NLT 12 Kg/cm2 (for 100 mg strength at 560 mg average weight). Tablets were evaluated for dissolution test time though method as illustrated in Example 7 and outcome results are stated in table 10.
Table 8

Time (Hour) Limit Example
01 NMT 25% 13.8
04 20% - 40% 26.59
08 40% - 60% 48.62
20 NLT 80% 95.1
Example 7
Ready to use formulation is prepared according to procedures as described in example 1 and solid oral dosage formulation of metoprolol succinate is prepared with ingredients as specified in tabie 9.
Table 9

Sr. No. Ingredients % w/w of total dry weight
1. Metoprolol succinate 19
2. Ready to use composition 77
3. Colloidal silicon dioxide 2
4. Magnesium stearate 2

Total = 100
Granules for tablet preparation are prepared as specified in Example 4 and further compressed in machine using 22.5 mm x 10.5 mm capsule shaped, biconcave punches at hardness NLT 12 Kg/cm2 (for 200 mg strength at 1000 mg average weight). Tablets were evaluated for dissolution test though method as illustrated in example 7 and outcome results are stated in table 10.
Table 10

Time (Hour) Limit Example
01 NMT 25% 12.66
04 20% - 40% 26.94
08 40% - 60% 46.67
20 NLT 80% 93.59
Example 8
Solid oral dosage formulation is prepared by mixing ingredient of table-11 composition, it is to be noted that no qualities of dry blend was observed with present composition.
Table 11

Sr. No. Ingredients % w/w of total dry weight
1. Hypromellose(KlOOM) 33.3
2. Xanthan Gum 40.8
Further solid oral dosage formulation of metoprolol succinate is prepared with ingredients as specified in table 12.
Table 12

Sr. No. | Ingredients % w/w of total dry weight

1. Metoprolol succinate 15.83
2. Table 11 composition 80.83
3. Colloidal silicon dioxide 1.67
4. Magnesium stearate 1,67
Total - 100
Granules for tablet preparation are prepared as specified in Example 4 and further compressed in machine using 22.5 mm x 10.5 mm capsule shaped, biconcave punches at hardness NLT 12 Kg/cm2 (for 100 mg strength at 1000 mg average weight). Tablets were evaluated for dissolution test though method as illustrated in example 7 and outcome results are stated in table 13.
Table 13

Time (Hour) Limit Example
01 NMT 25% 15.49
04 20% - 40% 51.29
08 40% - 60% 87.64
20 NLT 80%
It was observed that present composition was not showing standard sustained release properties hence does not complies for pharmacopoeial monographs.

We Claim,
1. A ready-to-use, stable modified release composition comprising natural gum with cellulosic polymer and polymer having pH dependent solubility for β-blockers or beta-adrenergic blocking agents or its pharmaceutically acceptable salts thereof.
2. A ready-to-use, stable modified release composition comprising
a. natural gum;
b. cellulosic polymer;
c. polymer having pH dependent solubility,
3. A stable modified release formulation comprising ready to use composition of claim 2 and β-blocker.
4. A stable modified release formulation comprising ready to use composition of claim 2, p-blockerand other pharmaceutical ingreditents.
5. A stable modified release formulation according to claim 3 wherein p-blocker is in range of about 15-22% of weight by weight of formulation.
6. A stable modified release formulation comprising
a. natural gum;
b. cellulosic polymer;
c. polymer having pH dependent solubility; and
d. β-blockers or beta-adrenergic blocking agents or its pharmaceutically
acceptable salts thereof.
7. A stable modified release formulation comprising
a. natural gum in range of 20-50% w/w);
b. cellulosic polymer in range of 25-50% w/w);
c. polymer having pH dependent solubility in range of 25-40% w/w); and
d. β-blockers or beta-adrenergic blocking agents in range of 15-22%).

8. A process for preparing a stable composition ready for use according to preceding
claims comprising steps of-
a. Pre-coalescing of polymer(s) and natural gum
b. Dry Granulation or slugging with β-blockers
c. Moderate hardness compression and micronization
d. Sieving through appropriate size
e. Optionally addition of lubricant
f. Final compression
9. The ready to use composition of the process of Claim 5.
10. The ready-to-use composition according to claim 2, wherein natural gum is selected from Agar, Alginic acid, Carrageenan, Gum Arabic, Gum ghatti, Gum tragacanth, Karaya gum, Guar gum, Locust bean gum, Beta-glucan, Chicle gum, Dammar gum, Gtucomannan, Mastic gum, Spruce gum, Tara gum, Gellan gum, Xanthan gum or combination thereof.
11. The ready-to-use composition according to claim 2, wherein natural gum is in range of 20% to 50% of weight by weight of ready to use composition.
12. The ready-to-use composition according to claim 2, wherein cellulosic polymer is selected from purified cellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, alkyl celluloses derivatives or salts, or combination thereof.
13. The ready-to-use composition according to claim 2, wherein cellulosic polymer is in range of 25% to 50% of weight by weight of ready to use composition.
14. The ready-to-use composition according to claim 2, wherein polymer having pH dependent solubility is selected from methacrylic acid copolymers, non- neutralized or partially-neutralized poly(methacrylic acid, ethyl acrylate) and poly(methacrylic acid, methyl methacrylate), polyvinylacetate phthalate (PVAP), PVAP co-processed with titanium dioxide (PVAP-T), cellulose acetate phthalate (CAP), hydroxypropylmethyl cellulose acetate

succinate (HPMC-AS) and hydroxypropy!methyl cellulose phthalate (HPMC-P) or combination thereof.
15, The ready-to-use composition according to claim 2, wherein polymer having pH
dependent solubility is in range of 25% to 40% of weight by weight of ready to use
composition.
16. A stable modified release formulation comprising ready to use composition in range
of 58-70 % of weight by weight of formulation.