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THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention : "COMPOSITIONS FOR RETARDED RELEASE OF ORAL DOSAGE FORMS AND METHOD OF PRODUCING THEM"
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.

Compositions for retarded release of oral dosage forms and method of obtaining them
Technical Field
The present invention relates to a dry ready to use extended release or sustained release dosage formulation composition comprising a mixed matrix of polymers components having plurality of layers thereby providing controlled release rate of one or more therapeutically active agents from the formulation/tablet. Dry composition are applicable to human drug, veterinary and agricultural formulation, it could be applied to the retarded or extended release of fertilizers, insecticides or specific protection agents.
Background or Information on Art
It is well known in pharmaceutical dosage formulation technology that making an extended release or sustained release formulation for drugs having higher solubility is difficult task. Further if drug has shorter half-life and higher dosage content then it becomes very tedious to develop formulation having extended properties. It is to be noted that drug having higher solubility quickly dissolve in gastric juice, providing immediate increase of drug in blood. Therefore in contrast of drugs having less solubility it is often difficult to prepare a highly gastric soluble drug in solid oral dosage formulations having retarded release profile, especially when the drug dosage is higher.
It is noted that when drug of higher solubility in gastric fluid is administered it looses its activity due to quick metabolism. Thus it remains in circulation only for a short period of time. Moreover the bio-availability of drug is high immediately after its administration followed by a quick decline. Thus there is a transient over dosage of the drug which is sometimes dangerous, resulting in uneven drug levels in the blood circulation. Further multiple dosage results in more side effect of drug product. Therefore it becomes mandatory to take drug at predefined intervals to make continuous availability of drug in blood circulation. Multiple daily dosing reduces patient acceptability and uneven administration due to improper timing. An extended or retarded release drug formulation

certainly helps in controlling dosing frequency to once in a day or as much as required without affecting its intended use.
Extended or retarded release formulation have been used in past to obtain solid oral substrates to release drug at desired site of absorption. Coating compositions have been used to release of drug in stomach or small intestine etc. Some examples of coating previously used to get modified release are US2809918, PVA and ethyl cellulose US3835221, methacrylic acid esters US4728512, US4794001, hydroxyl propyl methyl cellulose phthalate (HPMCP) US5225202.
EP1063973 discloses a matrix tablet especially designed for highly soluble drugs such as metformin, comprising matrix tablet a drug which has high water solubility, and an extended release material, hydrophobic polymers.
One of basic method to get retarded release of drug was provided by Kim cherng in W09626718, wherein drug was mixed with polymeric matrix to form a tablet for oral administration. Polymer was water absorbing and dissolved slowly in gastric fluid, further polymer and drug proportions were chosen to facilitate good extended release property. However Kim cherng doesn't disclose that drug having high water solubility can be released by high molecular weight polymer.
Certain prior art discloses controlled release compositions for anti-inflammatory drugs. US4968505 discloses a long acting composition comprising diclofenac sodium wherein the sustained release activity of the drug is obtained by coating the dosage form with a sustained release coating comprises components selected from polyvinylpyrrolidone, ethylcellulose, acrylic acid copolymer and other auxiliary ingredients. Similarly US4948581 also discloses such compositions where the active drug is diclofenac sodium and is coated with an enteric coating that provides the controlled release profile for the drug.
US2002051817 discloses a once a day sustained release composition comprising diclofenac sodium or its pharmaceutically acceptable salt. Composition comprises hydroxyl-ethyl

cellulose, Lactose, Polyvinylpyrrolidone and other auxiliary ingredients. The compositions are aimed at release of not more than 10% of active ingredient at a pH of less than 4.5 and more than 50% at a pH of more than 6.5.
US patent application US2004115267 provide delayed release composition comprising a combined dosage form of Diclofenac and Tramadol. Composition comprises microcrystalline cellulose, substituted hydroxypropylcellulose, Dibutyl sebacate, lactose and other auxiliary ingredients. Additionally these compositions use sustained release formulation for obtaining delayed release properties.
In yet another US patent application US2012183611 discloses preparations of diclofenac potassium comprising an immediate release and a sustained release portion that are compressed to form a single dosage form. Composition comprises sodium starch glycolate, microcrystalline cellulose, HPMC and other auxiliary ingredients.
Furthermore, it is seen that NSAIDs can cause stomach irritation and sometimes peptic ulceration and gastrointestinal bleeding; it would thus be desirable to have a drug delivery system that is capable of providing the controlled delivery of NSAIDs or their pharmaceutically acceptable salts in a predictable manner over a long period of time.
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 or coating methods. Accordingly invention solves the problem of non-availability of robust compositions for drugs highly solubility in organism. Invention provides composition having broad range of application and therefore suitable for large class of drugs i.e. anti-histaminic, anti-diabetic, NSAID and like. Further invention tries to solve problem of time consuming process of dosage formulation of drugs i.e, anti-histaminic, anti-diabetic, NSAID and like by providing ready extended release compositions that when mixed with the drug provide the required release profile with reproducible results.

An object of the present invention is to provide ready to use dry compositions providing extended release profile of drug, in a manner that confines their delivery to the stomach and upper small intestine. Slow, continuous delivery from a gastric retentive system assures that both drug delivery and drug absorption are confined to the upper gastro-intestinal tract.
Another object of present invention is to provide compositions for the class of drugs that are affected by exposure to gastric juices. The polymer matrix of the present invention protects drug during the 4 to 24 hour delivery period during which the drug is continuously released while the dosage form is retained in the Gastro intestinal tract.
Summary of Invention
In accordance with the above-mentioned objectives, the present invention provides a ready-to-use, stable modified release composition (s) comprising a blended matrix of cellulosic polymers components having plurality of layers thereby providing controlled release rate of anti-diabetic drugs or their pharmaceutically acceptable salts forms and prepared oral formulation/tablet thereof.
According to main aspect ready to use composition comprising water soluble cellulosic polymer hydroxypropyl methyl cellulose (HPMC) and like with a viscosity modifier, glidant, lubricant and drug. Moreover the compositions are applicable to a wide range of drugs. The compositions may also provide extended release profiles for less soluble drugs.
Present invention provides dry ready to use extended/retarded release composition comprising, a water soluble cellulosic polymer hydroxypropyl methyl cellulose (HPMC) and like with other polymer having thickening role, and optionally glidant, lubricant and combination of other excipients.
In accordance with the above-mentioned objectives, the present invention provides a ready-to-use, stable modified release composition comprising a blended matrix of cellulosic polymers components having plurality of layers thereby providing controlled release rate of

Non-steroidal anti-inflammatory drugs (NSAIDs) or their pharmaceutically acceptable salts forms and prepared oral formulation/tablet thereof.
In accordance with the above-mentioned objectives, the present invention provides a ready-to-use, stable modified release composition comprising a blended matrix of cellulosic polymers components having plurality of layers for Diclofenac or diclofenac-Na.
In another aspect, present inventive composition optionally further comprises other pharmaceutically acceptable excipients, bulking agents, flavoring agents, coloring agents, additional lubricants and like.
In yet another aspect method are provided for method for modified release oral dosage form. In which ready to use composition(s) are used in specified manner to achieve cost effective industrially applicable dosage form.
In further aspect, present invention provides a ready-to-use, stable modified release composition which is relatively inexpensive to manufacture for Non-steroidal anti-inflammatory drugs (NSAIDs) or anti-diabetic drugs.
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
To describe the invention, certain terms are defined herein specifically as follows. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.
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 ilfustration rather than limitation of the invention as set forth the appended claims.
The term 'Polymer' of the present invention comprises low molecular weight, high molecular weight, highly branched, un-branched, high viscosity, low viscosity polymers. Low molecular weight polymers include polymers with molecular weight in the range from about 1-250 K Da, including but are not limited to Hydroxy-propyl-methyl-cellulose, some of its grades like HPMC(K4M), HPMC(K100M), HPMC(K15M), Carboxy-methyl-cellulose and derivatives, sodium carboxymethyl cellulose, starch, gelatin, ethyl cellulose, cellulose acetate, vinyl acetate/vinyl chloride copolymers, acrylate/methacrylate copolymers, polyethylene oxide, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, stearyl alcohol and cetyl alcohol. High molecular weight polymers include polymers with molecular weight in the range from about 250-1200 KDa including but not limited to carrageenan, alginic acid and salts thereof, xanthan gum, karaya gum, acacia gum, tragacanth gum, locust bean gum, guar gum, beeswax, carnauba wax, hydrogenated vegetable oils, and combinations thereof.
Polymer act as viscosity increasing agent and surrounds the drug components, thereby retarding the rate of dissolution in gastrointestinal tract. Alternatively polymer also acts as half-life increasing agent and slowly releasing drug according to predefined rate. Some of the polymer can act as thickening agent. It is desired that polymer release drug substances with zero order kinetics i.e. drug is released at a constant velocity through time and for a programmable time period. Therefore polymer providing similar zero order kinetics release are included in scope of invention.
'Glidant' are finely divide powders that are added to the formulations to improve their flow properties. Unless otherwise stated the glidant in accordance with some of the embodiment comprise talc, colloidal silicon dioxide (e.g. Aerosil 200), starch and the like.
'Lubricant' are 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. Lubricants of the present in some of the embodiment comprise magnesium stearate, stearic acid, calcium stearate, glyceryl behenate, hydrogenated vegetable oils and the like.
The term 'Solvent' in the context of the present invention, is taken to mean ingredient that facilitate mixing of components in wet granulation process. Solvent can be used in present invention includes but not limited to Acetone, ethanol, methylene di chloride, isopropy! alcohol, water or their mixture thereof.
Granulation is a particle design process whereby small particles are brought together to form physically strong agglomerates. This helps the powdery particles to improve appearance, flow properties and mixed-ness, reduce dustiness and, in general, produce engineered particles with superior attributes. Agglomeration in wet granulation is achieved by introducing a "solvent" fluid onto a shearing mass of fine powders.
The 'drug' or 'active ingredient' of the present invention comprises an active drug having curative effect as anti-diabetic like Metformin, Buformin, Phenformin, and other insulin sensitizers and derivatives thereof, anti-hypertension, analgesic like Non-steroidal anti-inflammatory drugs (NSAlDs) selected from group consisting of ibuprofen, flurbiprofen, diclofenac, aceclofenac, naproxen, ketoprofen and their pharmaceutically acceptable salts, exemplified NSAIDs is diclofenac-Sodium., anti-arthritic, antianxiety, anticonvulsant, antidepressant, anti-manic, anti-obsessional, antipsychotic, sedative-hypnotic, stimulant and the like.
Anti-diabetic drug are comprise about 50% to 75%, by weight of the total weight of final tablet, acceptable ranges of the active substances are 55% to 70%, 57% to 67% of the total weight of final tablet. In one of the exemplified herein use metformin as active ingredient in range of 50% to 75%, by weight of the total weight of final tablet, acceptable ranges of the active substances are 55% to 70%, 57% to 67% of the total weight of final tablet.
The term "ready-to-use", in the context of the present invention, is taken to mean that, the composition according to the invention can 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 'sustained release', 'controlled release', 'modified release', 'extended release', 'retarded release' were used synonymously in the context of the present invention as meaning drug release is slower and its content of drug is released in longer duration, and respective term have their standard meaning as specified in technology.
The term 'filler' in the context of the present invention, is taken to mean ingredient that facilitate weight gain. Filler can be used in present invention includes but not limited to lactose, lactose monohydrate, dibasic calcium phosphate (anhydrous), Micro-crystalline cellulose, and further may includes calcium sulphate, cellulose, kaolin, mannitol, sodium chloride, powdered sugar, dry starch and like.
Unexpectedly, inventors have found that when Non-steroidal anti-inflammatory drugs (NSAIDs) are formulated with a mixed matrix of cellulosic polymers components having plurality of layers have advantageous sustained release properties. Further inventors also observed that when anti-diabetic drugs are formulated with a mixed matrix of cellulosic polymers components having plurality of layers have advantageous sustained release properties. In yet another embodiment cellulosic polymer is mixed with different viscosity grades of the same orva riant cellulosic polymer.
Cellulosic polymer are polymer of glucose subunits having p(l→4)-glycosidic bonds. Some of the cellulosic polymer were chemically modified to provide additional abilities like stability, charge neutralization includes but not limited to ether, derivatives (like Alkyl, hydroxyalkyl, carboxy alkyl etc.) organic and inorganic esters. Cellulosic polymer according to invention includes but not limited to derivative cellulose, ethyl cellulose, methyl cellulose, ethyl methyl cellulose, Hydroxyethyl cellulose, hydroxyproply cellulose, hydroxy propyl methyl cellulose, hydroxyethyl methyl cellulose, ethyl hydroxyethyl cellulose, and like.

These cellulosic derivative polymers has an average molecular weight of about few hundreds to thousands (e.g. HPMC 25,000-300,000 Da). Cellulosic polymers having higher molecular weights known to have wide range of fluid resistance parameters known as viscosity (100-10,000 mPa).
Upon administration of dosage form in patient present inventive formulation comprising a mix of cellulosic polymers, and active ingredient reaches in gastric juices the cellulosic polymer portion of the formulation absorbs the moisture and creates a gel like substances. In accordance with present invention mixture of lower viscosity grade polymer is mixed with higher viscosity grade polymer.
It is well known in state of art that active component of the drug disperse in body through erosion. It was surprisingly observed that due to increased moisture absorbing affinity of higher viscosity grade cellulosic polymer and lower moisture absorbing affinity of lower viscosity grade cellulosic polymer create physical tension in drug covering layer. In accordance with this observation one can achieve numerous combination of cellulosic polymeric mixture. Upon absorbing moisture polymer forms a gel like substance but due to absorbing differences of varying viscosity grade prolonged drug release is achieved. Therefore due to this physical barrier active ingredient is release in sustained delivery manner,
Dry ready to use composition comprises combination of polymer(s) prepared by blending in a suitable blender. In yet another aspect dry ready to use composition comprises combination of polymer(s) prepared by blending in a suitable blender. Further dry ready to use composition optionally comprises lubricant, glidant, flavoring agent, lake or natural colors.
The amount of cellulosic polymer employed in ready to use composition for NSAIDs drugs is from 30 to 50% by weight of the ready to use composition. Advantageously according to one of the embodiment the cellulosic polymer comprising a major proportion of HPMC in range

of 32- 48 %, particularly 35-45%, by weight of the ready to use composition for NSAIDs drugs.
The amount of cellulosic polymer employed in ready to use composition for NSAIDs drugs further comprise lower and higher viscosity grade cellulosic polymer, wherein higher viscosity grade polymer is from 20 to 31% more preferably 21 to 30% by weight of the ready to use composition. Further lower viscosity grade polymer is from 10 to 20% more preferably 11 to 19% by weight of the ready to use composition.
Alternatively in one of the aspect of present invention ready to use composition for NSAIDs drugs is obtained addition of one more fillers with cellulosic polymer. Therefore optionally if desired, a proportion of the cellulosic may be replaced by filler.
The amount of filler employed in a formulation according to the invention is from 50 to 75% by weight of the ready to use composition for NSAIDs drugs. Advantageously according to one of the embodiment filler comprises 59-65%, by weight of the ready to use composition for NSAIDs drugs.
The ready to use composition for NSAIDs drugs comprise cellulosic polymer with filler. In one of the embodiment cellulosic polymer is selected from pool of cellulosic polymer having variable viscosity strength, molecular weight. In accordance with objective different cellulosic polymer could be combined to achieve ready-to-use composition for NSAIDs drugs.
According to one of the embodiment ready to use composition for anti-diabetic drugs comprise mixture of polymers, wherein combination of polymer is in ratio of 15:1 to 3:1 for first phase ready to use composition and 4:1 to 1:1 for second phase ready to use composition.
According to one of the embodiment ready to use composition for anti-diabetic drugs comprise mixture of cellulosic polymer, wherein combination of cellulosic polymer is in ratio

of 15:1 to 3:1 for first phase ready to use composition and 4:1 to 1:1 for second phase ready to use composition.
According to one of the embodiment ready to use composition for anti-diabetic drugs comprise mixture of HPMC and carboxy methyl cellulose, wherein combination of HPMC and carboxy methyl cellulose is in ratio of 15:1 to 3:1 for first phase ready to use composition and 4:1 to 1:1 for second phase ready to use composition.
In accordance of one of the embodiment ready to use composition is mixed with anti-diabetic active ingredient to get final dosage formulation. Additionally in some of the embodiments ready to use composition it added in two phases namely first phase ready to use composition before granulation step and second phase ready to use composition after
granulation step.
In accordance of one of the embodiment ready to use composition is mixed with active ingredient to get final dosage formulation. Additionally in some of the embodiments ready to use composition it added in two phases as in before granulation step and after granulation step followed by final tablet compression.
In one of the embodiment to get ready to use composition polymer is in amount of about 25 to 50% w/w of the total weight of final tablet. The anti-diabetic drug or active pharmaceutical ingredient is added to ready to use composition in about 50-75% w/w of the total weight of final tablet.
In one of the embodiment to get ready to use composition polymer is in amount of about 25 to 50% w/w, or 26 to 45% w/w, or 28 to 42% w/w of the total weight of final tablet. The anti-diabetic drug or active pharmaceutical ingredient is added to ready to use composition in about 50-75% w/w, or 55% to 70% w/w, or 57% to 67% w/w of the total weight of final tablet.

In yet another aspect of ready to use composition is generated by taking polymer in amount of 25 to 50% w/w of the total weight of final tablet. These types of compositions are useful in generating placebo tablets having absence of active pharmaceutical ingredient.
The amount of lubricant employed in a formulation according to the invention is from 0.1 to 5% by weight of the formulation. Advantageously according to one of the embodiment lubricant comprises 0.2 - 3 %, particularly 0.5-2%, by weight of the formulation.
The amount of glidant employed in a formulation according to the invention is from 0.1 to 5% by weight of the formulation. Advantageously according to one of the embodiment glidant comprises 0.2 - 3 %, particularly 0.5-2%, by weight of the formulation.
In a formulation the active ingredient is blended with the inventive ready to use composition and the mixture is compressed to produce a solid formulation. Preferably the ingredients are blended to form a uniform powder and then compressed with means generally known to skilled in the art. Optionally a lubricant, glidant can be added to facilitate compression of tablets. 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.
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, polyethyleneglycol and like; lactose, sucrose, alginic acid and like. The pharmaceutically acceptable excipients may be applicable recognized by those skilled in the art are listed in Wade, A. and P. J. Welter (1994). Handbook of pharmaceutical excipients, Pharmaceutical press incorporated herein for reference only. Quantity of such

pharmaceutically acceptable excipient 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 5% and more preferably up to 2% by weight of the total composition.
According to present invention dosage form of Non-steroidal anti-inflammatory drugs {NSAIDs) is greater than 10 mg, in some of the non-limiting embodiment of present invention NSAIDs is exemplified with diclofenac-Na. In particular NSAIDs are used in ratio of about 30-40 % of final formulated dosage formulation.
Preferred formulations according to the invention are obtained when the compositions comprise Non-steroidal anti-inflammatory drugs (NSAIDs) about 30-40 % and inventive ready to use composition comprising cellulosic polymer about 58-70% by weight of final formulated dosage form. In accordance with one of the embodiment preferred formulations comprise Non-steroidal anti-inflammatory drugs (NSAIDs) about 32-38 % and inventive ready to use composition comprising cellulosic polymer about 59-69% by weight of final formulated dosage form.
Preferred formulations according to the invention are obtained when the compositions comprise diclofenac-Na about 30-40 % and inventive ready to use composition comprising cellulosic polymer about 58-70% by weight of final formulated dosage form. In accordance with one of the embodiment preferred formulations comprise diclofenac-Na about 32-38 % and inventive ready to use composition comprising cellulosic polymer about 59-69% by weight of final formulated dosage form.
It is well known in the art that controlled release formulation solid dosage form can 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.
The ready to use composition or final compositions give properties of the barrier layer to drug substances. Eventually composition provides retarded or extended release of drug for a time period that strictly depends on its composition, which can vary from 1 hour to approx. 20-24 hours or more.
According to yet another aspect ready to use composition and purified drug in dry form are individually sifted to get homogenous powders. According to one of the embodiment polymer(s) and purified drug in dry form are individually sifted to get homogenous powders.
Sieving or Sifting is required to reduce chances of lumps, uneven mixing, remove any other solid impurity etc. for the purpose of present invention upto 40 mesh size sieve can be used.
Sieved material could be mixed in variety of method or steps to facilitate homogenized powder. In one of the embodiment two or more sifted polymers are mixed to get working polymer mixture. Alternatively polymer could be.mixed with one or more glidant to get working polymer glidant mixture. Similarly depending on drug dosage and composition two or more sifted dry drug powder could be mixed to get working drug mixture.
Inventive formulation can be prepared by blending anti-diabetic drugs, their derivatives or combination thereof along with inventive composition. Therefore inventive formulation for anti-diabetic drugs preparation comprise steps as
1. Blending of polymer(s) to get first ready to use composition;
2. Optionally shifting first ready to use composition;
3. Mixing of first ready to use composition with anti-diabetic drug;
4. Optionally shifting blended mix;
5. Mixing with solvent and wet granulation;

6. Drying of granulated wet mass to get first dry-mix composition
7. Mixing with second ready to use composition;
8. Optionally addition of glidant and lubricant;
9. Final tablet compression
Accordingly ready to use composition for anti-diabetic drugs is prepared by mixing combination of polymer(s), wherein combination of polymer is in ratio of 15:1 to 3:1 for first phase ready to use composition and 4:1 to 1:1 for second phase ready to use composition, blending is done with blender and later shifted to get homogenized powder.
After getting homogenized sifted first ready to use composition and drug composition such as anti-diabetic drugs are mixed together using standard dry blending or mixing techniques known to those of ordinary skill. A preferred process mixing is by conventional blending apparatus like in a food processor, blender or "V-blender" or a similar device. The ingredients are individually weighed, added to high-speed mixer, blended for a sufficient time until a substantially uniform mixture of the ingredients is obtained. The time required to achieve such substantial uniformity will, depend upon the batch size. In one of the embodiment time taken for mixing is about 20-30 minutes. This mixture is then passed through a 40 mm sieve to get 'Blended Mix'. Alternatively in one of the embodiment 'Blended Mix' can also have glidant in 0.1-5% w/w of the total weight of final tablet.
Further 'Blended Mix' is granulated using standard techniques known to those of ordinary skill. In one of the embodiment wet granulation process is performed by taking 'Blended Mix' with solvent to make wet mass. In one of the embodiment of invention granulating solution is water in sufficient quantity to generate 'wet mass'. Accordingly 'wet mass' is sifted and dried using standard techniques known to those of ordinary skill followed by milling to generate granules. In one of the embodiment wet mass is sifted through appropriate sieve (e.g. 8-40) and dried at 50-70°C and subsequently milled. Alternatively if drug substance is heat sensitive other methods can be used wherein dry temperature is lower.

Further granules are sifted through fine sieves (16-20 mesh) depending upon requirements of tableting procedures. According to one of the embodiment dried composition is sifted through 20 mesh sieves to get 'first dry-mix composition'.
Accordingly 'first dry-mix composition' is mixed with glidant and subsequently with lubricant to get 'ready-mixed composition'. In one of the embodiment 'first dry-mix composition' is mixed with glidant at about 0.1-15% w/w of the total weight of final tablet weight, subsequently with lubricant at about 0.1-15% w/w of the total weight of final tablet weight to get 'ready-mixed formulation'.
According to another aspect of present invention inventive 'first dry-mix composition' is further layered with second ready to use composition, glidant and subsequently with lubricant to get 'ready-mixed formulation'. In one of the embodiment inventive 'first dry-mix composition' is further layered with second ready to use composition, glidant at about 0.1-5% w/w of the total weight of final tablet weight, subsequently with lubricant at about 0.1-5% w/w of the total weight of final tablet weight to get 'ready-mixed formulation'.
According to yet another aspect of present invention inventive 'first dry-mix composition' is further layered with second ready to use composition having secondary drug, glidant and subsequently with lubricant to get 'ready-mixed formulation'.
Inventive formulation may be prepared by blending Non-steroidal anti-inflammatory drugs (NSAIDs), their derivatives or combination thereof along with inventive composition. Therefore inventive formulation for NSAIDs preparation comprise steps as
1. Blending of cellulosic polymer(s) and filler
2. Thorough mixing to form dry powder
3. Wet granulation with NSAIDs and solvent
4. Sieving through appropriate size
5. Tray drying or fluidized bed drying
6. Optionally addition of lubricant

7. Final tablet compression
Initially inventive ready to use composition for NSAIDs is prepared by blending desired quantity of cellulosic polymer(s) along with filler to form 'ready to use powder' 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 Non-steroidal anti-inflammatory drugs (NSAIDs) along with inventive ready to use composition. Further NSAIDs are blended with 'ready to use powder' using solvent through wet granulation or a similar wet mixing method to generate dosage formulation. Dosage formulation is further tray dried, sieved and compressed optionally with addition of lubricant to form oral dosage form.
In one of the embodiment of present invention, inventive dosage formulations are prepared by blending NSAIDs along with inventive ready to use composition. Initially celluiosic polymers having different viscosity strength and filler are blended to form 'ready to use composition' preferred process of mixing is by conventional dry blending in a food processor or "V-blender" or a similar function device. Upon dry blending composition is sieved to get fine particles (e.g. 40 mesh). Further NSAIDs are blended with 'ready to use composition' with dry mixing method followed by mixing with appropriate quantity of solvent and wet granulating of blended dosage formulation. Dosage formulation is further tray dried at 40-45°C to make it dry. Generated dry powder sieved to get fine particles (e.g. 20 mesh). Inventors observed that sieving quality and fineness of blended dosage formulation 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 blended biend is essential. Obtained sieved blend is then uniformly mixed with premeasured amount of the lubricant 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 solvent used for wet granulation can comprise uniform mixture of two or more solvents. The ratio of solvent is in range of 70:30 to 90:10, preferably 75:25 to 85:15 more preferably 80:20. In one of the embodiment solvent used are isopropyl alcohol and water in range of 75:25 more preferably 80:20.
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 or 20 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 NSAIDs are formulated in oral dosage form for controlled release delivery. In an exemplary inventive formulation in accordance with invention have pharmacologically active ingredient is diclofenac-Na. Inventive composition may be comprising 50 to 100 mg of diclofenac-Na in plurality of dosage formulations. Controlled release formulation can 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.
In accordance of present invention NSAIDs formulation produced are suitable for once a day administration, more preferably once a day administration.
It has been surprisingly found that inventive 'ready to use composition' and respective method of preparation of oral dosage form is applicable to formulation of drugs having anti¬diabetic, anti-hypertension, analgesic, anti-arthritic, antianxiety, anticonvulsant, antidepressant, anti-manic, anti-obsessional, antipsychotic, sedative-hypnotic, stimulant like activities. Further suitable APIs that can be used with the present invention include, but are not limited to: andrenergic blocking agent; acetyl-cholin-esterase inhibitor; analgesic or antipyretics; angiotensin modulator; anthelmintic agents; anti-anxiety agent; antibacterial;

antibiotic; anticoagulant; anticonvulsant; antidepressant; antifungal; antihistamine; antimalarial; antimicrobial agent; antipsychotic agent; Antiviral agents; blood glucose lowering drug; calcium channel modulator; diuretic; erectile dysfunction; gastric acid secretion inhibitor; histamine H2-receptor antagonist; inhibitor of steroid Type II 5[alpha] -reductase including; lipid regulating agents; selective H|- receptor antagonist; vasodilator; vitamins.
According to one of the embodiment inventive 'ready to use composition' provides extended release or retarded formulation for heat labile drugs as well as drugs affected by gastric juices. Further 'ready to use composition' is suitable for formulation and extended release of drugs having short half-life in organism circulation system. In continuation 'ready to use composition' can be used in formulation of various drugs to get wherein extended or retarded release is expected / desired.
Following examples are offered to more fully illustrate the invention embodiments, it is to be noted examples are not to be construed as limiting the scope thereof. Further examples their respective embodiment could be combined in any order to perform oral dosage preparation.
Example 1
In accordance with forgoing objectives first ready to use composition is prepared by taking table components, Hypromellose (hydroxypropyl methylcellulose or HPMC) 76.51% (w/w of dry weight composition), weighing appropriate quantity and sieving through 40 mesh screen. Subsequently Carboxymethyl cellulose sodium 22.29% (w/w of dry weight composition) is weighed and sieved through 40 mesh screen followed by Colloidal silicon dioxide 1,20% (w/w of dry weight composition) weighing and sieving through 40 mesh screen. All components duly sieved are combined together in blender for 20 minutes (e.g. octagonal blender). In order to get homogenized ready to use powder final blend from blender is optionally sifted through 40 mesh screen. Dry powder thus prepared is stable for storage and reusable in batches of operations.

Table 1
SN Ingredients Amount in percent (w/w) Weight (mg)
1 Hypromellose (HPMC) (100,000 cps) 76.51 127
2 Carboxymethylcellulose sodium 22.29 37
3 Colloidal silicon dioxide (Aerosil 100) 1.20 2
Tota 100 166
First ready to use composition is stable for appropriate storage period and could be further mixed with appropriate active ingredient to get ready mixed formulation suitable for oral dosage preparation.
Example 2
Second ready to use composition is prepared by taking table components, Hypromellose (hydroxypropyl methylcellulose or HPMC) 50% (w/w of dry weight composition), weighing appropriate quantity and sieving through 40 mesh screen. Subsequently Carboxymethyl

cellulose sodium 50% (w/w of dry weight composition) is weighed and sieved through 40 mesh screen. Both components are duly sieved and combined together in blender for 20 minutes (e.g. octagonal blender). In order to get homogenized ready to use powder final blend from blender is optionally sifted through 40 mesh screen. Dry powder thus prepared is stable for storage and reusable in batches of operations.

Table 2
SN ingredients Amount in percent (w/w) Weight (mg)
1 Hypromellose (HPMC) (100,000 cps) 50 63
2 Carboxymethylcellulose sodium 50 63
Total 100 126
Second ready to use composition is stable for appropriate storage period and, mixed with active ingredient composition already processed with first ready to use composition, to get ready mixed formulation suitable for oral dosage preparation.

Example 3
First ready to use composition as prepared is further mixed with active ingredient in suitable blender having capacity to blend powder in homogenized manner. In order to prepare dosage formulation for Metformin hydrochloride of 800 mg (2,500 tablets for 2.0 KG batch) an exemplary anti-diabetic drug is used wherein Metformin hydrochloride is taken in quantity of about 62.5% (w/w of dry weight of final tablet) and weighed accordingly 1250.0grams, subsequently sieved to get uniformly granulated powder through 40 mesh screen. Further 415.0 grams of first ready to use composition (Table 1 composition) with processed drug powder are taken and granulated for 20 minutes to generate blended mix. The 'Blended Mix' is then granulated with sufficient quantity of water as granulating solvent to required consistency. The speed of the Rapid mixer granulator (RMG) is adjusted at low to medium for 10 minutes, after then the speed is increased for 5 minutes to generate 'Wet Mass'.
The 'Wet Mass' thus obtained is again sieved using a #12 mesh sieve and subsequently dried at about 60°C to 65°C , and keep Loss on drying is maintained at 1-2% (at 105 °C for 10 minutes).

Table 3 - Final formulation
SN Formulation ingredients % w/w mg/ tablet For 2 Kg Btach
1 Metformin hydrochloride 62.5 500 1250.0
2 Table 1 composition 20.75 166 415.0
3 Water q.s q.s
4 Table 2 composition 15.75 126 315.0
5 Magnesium stearate 0.63 5 12.5
6 Colloidal silicon dioxide 0.38 3 7.5
Total 100.00 800.00 2500 Tablets
The dried granules are again sieved through a size #20 mesh sieve to get 'first dry-mixed formulation'. This is further mixed with 315.0 grams of 'Table 2' second ready to use composition for 10 min in octagonal blender. Subsequently mixture of 12,5 grams of magnesium stearate and 7.5 grams of Colloidal silicon dioxide is sifted through #40 mesh

sieve and mixed with the granules obtained from the above steps in octagonal blender to get 'ready-mix formulation'.
Finally the 'ready-mix formulation' is compressed on a compression machine (for e.g 500 mg strength at 800 mg average weight) in circular, biconcave punches. The oral dosage forms thus obtained has 500 mg active ingredient at 800 mg total weight.
Example 4
Additional First ready to use composition were prepared, as described in Example 1 by weighing equivalent quantities from table Respective examples,unless otherwise stated all ingredients are stated in weight percent (w/w).

Table 4
SN Ingredients Example 5 Example 6 Example 7 Example 8 Example 9 Example 10
1 HypromeHose 89.74 92.11 89.29 90.00 86.94 82.77
2 Carboxymethyl cellulose sodium 7.69 6.58 8.93 8.00 11.21 15.54
3 Colloidal silicon dioxide (Aerosil 100) 2.56 1.32 1.79 2.00 1.85 1.69
Tota 100 100 100 100 100 100
Additionally Second ready to use compositions were prepared, as described in Example 2 by weighing equivalent quantities from table 5respective examples,unless otherwise stated all ingredients are stated in weight percent (w/w).

Table 5
SN Ingredients Example 5 Example 6 Example 7 Example 8 Example 9 Example 10
1 Hypromellose 56.34 55 72.92 50 50 50
2 Carboxymethyl cellulose sodium 43.66 45 27.08 50 50 50
3 Colloidal silicon dioxide (Aerosil 100) 2.56 1.32 1.79 2.00 1.85 1.69
Total 100 100 100 100 100 100

Additionally final oral dosage formulations were prepared, as described in Example 3 by weighing equivalent quantities from table 6respective examples, unless otherwise stated all ingredients are stated in weight percent (w/w).

Table 6
SN Ingredients Example 5 Example 6 Example 7 Example S Example 9 Example 10
1 Metformin hydrochloride 62.50 58.14 58.14 66.67 66.67 66.67
2 First ready to use composition 9.75 17.67 13.02 19.33 20.93 23.60
3 Second ready to use composition 26.63 23.26 27.91 12.93 11.33 8.67
4 Water q.s. q.s. q.s. q.s. q.s. q.s.
5 Magnesium stearate 0.63' 0.58 0.58 0.67 0.67 0.67
6 Colloidal silicon dioxide 0.50 0.35 0.35 0.40 0.40 0.40
Tota 100 100 100 100 100 100
Finally the 'ready-mix formulation' is compressed on a tablet preparation compression machine in circular, biconcave punches of respective final tablet weight and drug strength. The oral dosage forms thus respectively obtained has 500 mg, as active ingredient, and have 800 mg, 860 mg total tablet weight. Further oral dosage forms respectively obtained can have 1000 mg active ingredient and 1500 mg total tablet weight.
Example 11
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 for present invention is standardized for sustained release profile is as per table 7:-

Table 7
Time (Hour) Limit
1 20%-40%
2 35 % - 55 %
3 45% -65%
6 65 % - 85 %
10 NLT85%
Dissolution study was performed on Electrolab dissolution test apparatus Type 2 with experimental parameters as rpm of 100, and 1000 ml of 0.05 M Phosphate buffer at pH 6.8 as dissolution medium. Time intervals for dissolution evaluation are set as 1, 2, 3, 6 and 10 hour. For the purpose of analysis active ingredient standard was prepared by dissolving 25 mg of Metformin hydrochloride in 25 ml volumetric flask with phosphate buffer of pH 6.8. Active ingredient absorbance was checked at 233 nm on UV-VIS Spectrophotometer (UV 2700-Thermo Fisher Scientific).
Solid oral dosage forms prepared are subjected to dissolution in type 2 dissolution apparatus at 50 rpm for 1, 2, 3, 6 and 10 hours of time intervals. Absorbance of solution is recorded at 233 nm on spectrophotometer. At a given time a definite amount of dissolution (1 ml) solution was taken and the content of active ingredient remaining was determined. Solution withdrawn is taken in volumetric flask and volume is made up to 100 ml with phosphate buffer pH 6.8. Dissolution results for example batches of Metformin hydrochloride ER tablets are given in the following table 8

Table 8
Time (Hour) Limit Oral dosage form of Example

Example 3 E.g. 5 E.g. 6 E.g. 7 E.g. 8 E.g. 9 E.g. 10
1 20%-40% 31.96 27.25 29.02 29.08 24.07 24.86 24.74
2 35 % - 55 % 48.92 43.09 44.00 40.40 38.60 36.20 41.80
3 45% -65% 63.59 55.63 55.71 52.61 48.33 46.16 48.91
6 65 % - 85 % - 80.96 81.36 80.62 74.49 71.37 -
10 NLT85% - 99.03 - - 102.33 - -

Example 12
First ready to use composition is prepared by taking Hypromellose 100,000 cps 89.3% (w/w of dry weight composition) weighing appropriate quantity and sieving through 40 mesh screen. Subsequently Carboxymethyl cellulose sodium 8.9% (w/w of dry weight composition) is weighed and sieved through 40 mesh screen followed by Colloidal silicon dioxide 1.8% (w/w of dry weight composition) weighing and sieving through 40 mesh screen. All components duly sieved are combined 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 9
SN Ingredients Amount in percent
1 Hypromellose (HPMC) (100,000 cps) 89.3
2 Carboxymethylcellulose sodium 8.9
3 Colloidal silicon dioxide 1.8
Total 100
In order to prepare dosage formulation for Metformin hydrochloride an exemplary anti-diabetic drug is used wherein Metformin hydrochloride is 1650 grams and weighed accordingly, subsequently sieved to get uniformly granulated powder through 40 mesh screen. To generate blended mix 369.6 grams of first ready to use composition (Table 9 composition) with processed anti-diabetic drug powder are taken and granulated for 20 minutes, The 'Blended Mix' is then granulated with around 750 grams of water as granulating solvent. The speed of the Rapid mixer granulator (RMG) is adjusted at low to medium for 10 minutes, after then the speed is increased for 5 minutes to generate 'Wet Mass',
The 'Wet Mass' thus obtained is again sieved using a #12 mesh sieve and subsequently dried at about 60°C to 65°C , and keep Loss on drying is maintained at 1-2% (at 105 °C for 10 minutes).

Table 10- second ready to use composition
SN Ingredients Amount in percent
1 HPMC(100000cps) 50
2 Carboxymethylcellulose sodium 50
Total 100
The dried granules are again sieved through a size #20 mesh sieve to get 'first dry-mix composition'. Further 'first dry-mix composition' is mixed with 594 grams of 'Table 10' second ready to use composition for 10 min in octagonal blender.
Subsequently mixture of 16.5 grams of magnesium stearate and 10 grams of Colloidal silicon dioxide is sifted through #40 mesh sieve and mixed with the granules obtained from the above steps in octagonal blender to get 'ready-mix composition'.

Table 11- Final composition
SN Formulation ingredients % w/w mg/ tablet
1 Metformin hydrochloride 62.5 500
2 Table 1A composition 14 112
3 Water q.s q-s
4 Table IB composition 22.5 180
5 Magnesium stearate 0.63 5
6 Colloidal silicon dioxide 0.37 3
Total 100
Finally the 'ready-mix composition' are compressed on a compression machine (for 500 mg strength at 800 mg average weight) circular, biconcave punches. The oral dosage forms thus obtained has 500 mg active ingredient at 800 mg total weight.Dissolution results for example batches of Metformin hydrochloride was evaluated as described in example 12 and results are given in the following table 12.

Table 12
Time (Hour) Limit Example 12
1 20%-40% 28.92
2 35 % - 55 % 43.44
3 45% -65% 57.24
6 65 % - 85 % 79.64
10 NLT85% 112.96

Example 13
To evaluate composition synergy following experiments were conducted, methods were used as described in Example 1 by weighing equivalent quantities from table 13respective examples,unless otherwise stated all ingredients are stated in weight percent (w/w).

Table 13
SN Ingredients Example 14 Example 15
1 Hypromellose 79.93 100
2 Ethyl-cellulose 12.64 -
3 PVPK-30 7.43 -
Tota 100 100
Additional composition was prepared, as described in Example 2 by weighing equivalent quantities from table 14 respective examples,unless otherwise stated all ingredients are stated in weight percent (w/w).

Table 14
SIM Ingredients Example 14 Example 15
1 Hypromellose - 52.63
2 Carboxymethyl cellulose sodium - 47.37
Total 100 100
Additionally final oral dosage formulations was prepared, as described in Example 3 by weighing equivalent quantities from table 15 respective examples,unless otherwise stated all ingredients are stated in weight percent (w/w}.

Table 15
SN Ingredients Example 14 Example 15
1 Metformin hydrochloride 64.51 62.5
2 First ready to use composition 34.71 12.5
3 Second ready to use composition 0 23.75
4 Water q.s. q.s.
5 Magnesium stearate 0.97 0.63
6 Colloidal silicon dioxide - 0.63
Final Tablet Weight (mg) 775 800

It was observed that both formulations were not passing monographed extended or retarded release profile in consistent batches, therefore deemed to be non-industrially acceptable batches.
Example 16
Ready to use composition for NSAIDs is prepared by taking Hypromellose high viscosity (HPMC) 26% (w/w of dry weight composition) and Hypromellose low viscosity 13% (w/w of dry weight composition) weighing appropriate quantity and sieving through 40 mesh screen. Subsequently filler Lactose monohydrate 61% (w/w of dry weight composition) is weighed and sieved 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 16
SN Ingredients w/w Percent(%) Grams
1 Hypromellose (HPMCK15M) USP 26 260.0
2 Hypromellose (HPMCK4M) USP 13 130.0
3 Lactose monohydrate USP 61 610.0
Total 100 1000.0
Example 17
Sustained release solid oral dosage formulation of Diclofenac Sodium (for 100 mg strength at 300 mg average weight) is prepared using ready to use composition of example 1'.

Table 17
SN Ingredients % w/w of total dry weight
1 Diclofenac sodium 33
2 Ready to use composition 66.00
3 Solvent (IPA:water El 80:20) q.s.
4 Magnesium stearate 1.00
Tota 100
In order to get dosage formulation for Diclofenac Sodium exemplary Table 17 composition is used wherein Diclofenac Sodium is 33 % (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 Diclofenac Sodium is blended with 66% {w/w of dry weight composition) of ready to use composition in blender for 20 minutes (e.g. RMG granulator). Solvent system of IPA and Water is prepared for wet granulation procedure, wherein IPA is mixed with water in 80:20 ratio and poured in RMG granulator in low to medium speed in the duration of 10 minutes followed by 5 minutes of high speed. Generated we mass is sieved using 12 mesh screen dried in tray drier (or Fluidized bed dryer) at 60 to 65°C keeping loss on drying ar 1-2% (at 105oC for 10 minutes). Dry granules/powder are further sieved through 20 mesh screen after though tray drying process. To promote efficient tablet punching further 0.83% % (w/w of dry weight composition) of magnesium stearate sieved through 40 mesh screen is added to above dried blended formulation in blender for subsequent 5 minutes. Granules mixed with lubricant have bulk density of about 0.35 (g/ml) and tapped density of about 0.4 (g/ml). Final screened granules are compressed using 10 mm (for 100 mg strength at 300 mg average weight) circular, biconcave punches at hardness not less than 12 kg/cm2, thickness about 3-4 mm, friability about Not more than 1 {%).
Example 18
Additional ready to use composition for NSAIDs were prepared, as described in Example 16 by weighing equivalent quantities from table 18respective examples,unless otherwise stated all ingredients are stated in weight percent (w/w).

Table 18
SN ingredients Example 19 Example 20 Example 21
1 Hypromellose (HPMCK15M) 21 30 40
2 Hypromellose(HPMCK4M) 19 11 30
3 Lactose 60 59 30
Tota 100 100 100
Additional final oral dosage formulations were prepared, as described in Example 17 by weighing equivalent quantities from table 19respective examples,unless otherwise stated all ingredients are stated in weight percent (w/w).

Table 19
SIM Ingredients Example 19 Example 20 Example 21
1 Diclofenac sodium 30 40 33.33
2 Ready to use composition 69 59 65.67
3 Solvent (!PA:water HI 80:20) q.s. q.s. q.s.
4 Magnesium stearate 1.00 1.00 1
Fina Tablet Weight (mg) 300 300 300
Finally the 'ready-mix formulation' is compressed on a tablet preparation compression machine in circular, biconcave punches of respective final tablet weight and drug strength. The oral dosage forms thus obtained has 100 mg as active ingredient, and have 300 mg total tablet weight.
Example 22
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 for present invention is standardized for sustained release profile is as per table 20:-

Table 20
Time (Hour) Limit
1 15% - 28%
2 20% - 40%
4 35% - 55%
5 45% - 65%
6 50% - 80%
8 52% - 82%
10 65% - 85%
16 75% - 95%
24 NLT 85%
Dissolution study was performed on Electrolab dissolution test apparatus Type 2 with experimental parameters as rpm of 50, and 900 ml of 0.05 M Phosphate buffer at pH 7.5 as dissolution medium. Time intervals for dissolution evaluation are set as 1, 5, 10, 16 and 24

hours with additional time points: 2, 4, 6 and 8 hours. For the purpose of analysis active ingredient standard was prepared by dissolving 25 mg of Dicofenac Sodium in 25 ml volumetric flask with 0.05 M phosphate buffer of pH 7.5 (100 ppm) and dilutions of 10, 15, 20 ppm was prepared with phosphate buffer of pH 7.5. Active ingredient absorbance was checked at 276 nm.
Solid oral dosage forms prepared are subjected to dissolution in type 2 dissolution apparatus at 50 rpm for 1, 2, 4, 6 and 10 hours of time intervals. Absorbance of solution is recorded at 276 nm on spectrophotometer. At a given time a definite amount of dissolution (5ml) solution was taken and the content of active ingredient remaining was determined. Solution withdrawn is taken in volumetric flask and volume is made up to 25 ml with 0.05 M phosphate buffer pH 7.5. Dissolution results for example batches of Diclofenac Sodium ER 100 mg tablets are given in the following table 21

Table 21
Time (Hour) Limit Example 17 Example 19 Example 20 Example 21
01 NMT 28% 19.56 18.40% 18.73% 17.04
02 20% - 40% 28.66 25.21% 26.63% 30.24
04 35% - 60% 42.44 51.69% 50.79% 46.71
06 50% - 80% 63.12 65.22% 57.97% 55.27
10 NLT 85% 81.12 87.65% 85.79% 76.08
Example 23:
To evaluate composition synergy following experiments were conducted, methods were used as described in Example 16 by weighing equivalent quantities from table 22unless otherwise stated all ingredients are stated in weight percent (w/w).

Table 22
SN Ingredients Example 24 Example 25
1 Hypromellose (HPMCK100M) 50% -
2 Hypromellose (HPMCK4M) - 32%
3 Micro crystalline cellulose 34% 34%
4 Lactose 16% 34%
Total 100 100

Additionally final oral dosage formulations were prepared, as described in Example 17 by weighing equivalent quantities from table 23unless otherwise stated all ingredients are stated in weight percent (w/w). Further to make to try two phase composition prepared in table 21 was added in two phase to judge enhanced modified release.

Tabl e23
SN Ingredients Example 24 Example 25
1 Diclofenac Na 33.36 32.79
2 Table 21 composition first phase 43.30 31.15
3 Table 21 composition second phase 20.01 31.15
4 PVPK 30 1.33 1.31
5 Mag stearate 1.00 0.98
6 Aerosil 200 0.98
7 Talc 1.00
Final Tablet Weight (mg) 300 300
It was observed that both formulations were not passing monographed extended or retarded release profile in consistent batches, therefore deemed to be non-industrially acceptable batches.

We claim,
1. A dry ready to use modified release composition comprising, combination of cellulosic polymer(s) of different viscosities and filler for non-steroidal anti-inflammatory drugs {NSAID's).
2. A modified release composition of claim 1 wherein, the cellulosic polymer comprises cellulose, ethyl cellulose, methyl cellulose, ethyl methyl cellulose, Hydroxyethyl cellulose, hydroxyproply cellulose, hydroxypropyl methyl cellulose, hydroxyethyl methyl cellulose and ethyl hydroxyethyl cellulose, their salts, chemical derivatives and combinations thereof.
3. A modified release composition of claim 1 wherein, the filler comprises lactose, lactose monohydrate, dibasic calcium phosphate (anhydrous), Micro-crystalline cellulose and their salts or derivatives and combinations thereof.
4. A modified release composition of claim 1 wherein, the cellulosic polymer is present in the range from 30% to 50% by weight of the modified release composition.
5. A modified release composition of claim 1 wherein, the filler is present in the range from 50% to 75% by weight of the modified release composition.
6. A modified release pharmaceutical solid dosage form comprising, non-steroidal anti¬inflammatory drugs (NSAID's) and dry ready to use modified release composition comprising combination of cellulosic polymer(s) of different viscosities, glidant and lubricant; wherein ready to use composition is added in one step.
7. A modified release pharmaceutical solid dosage form of claim 6 wherein, the active

ingredient comprises 30% to 40% of the total weight of the pharmaceutical solid dosage form.
8. A method of making pharmaceutical solid dosage forms containing the ready to use
composition comprising steps of-
a. wet granulation of the dry ready to use modified release composition with
active ingredient and granulating solvent;
b. sieving the granules through a sieve of appropriate size;
c. drying the granules;

d. optional addition of lubricant;
e. final compression to form solid dosage form.
9. A dry ready to use modified release composition comprising, cellulosic polymer(s) of different viscosities for anti-diabetic drug.
10. A modified release composition of claim 10 wherein, the cellulosic polymer comprises cellulose, hydroxypropyl methyl cellulose, hydroxyproply cellulose, carboxymethyl cellulose, ethyl cellulose, methyl cellulose, ethyl methyl cellulose, Hydroxyethyl cellulose, hydroxyethyl methyl cellulose and ethyl hydroxyethyl cellulose, their salts, chemical derivatives and combinations thereof.
11. A modified release composition of claim 10 wherein ready to use composition is added in two phases of oral dosage preparation.
12. A modified release composition of claim 10 wherein, combination cellulosic polymer is in ratio of 15:1 to 3:1 for first phase ready to use composition and 4:1 to 1:1 for second phase ready to use composition.
13. A modified release composition of claim 10 wherein, the polymer is present in the range from 25% to 50% by weight of the modified release composition.
14. A modified release pharmaceutical solid dosage form comprising, an anti-diabetic drug and dry ready to use modified release composition comprising combination of cellulosic polymer(s) of different viscosities, glidant and lubricant; wherein ready to use composition is added in one or two step.
15. A modified release pharmaceutical solid dosage form of claim 15 wherein, anti-diabetic drug comprises 50% to 75% of the total weight of the pharmaceutical solid dosage form.
16. A method of making pharmaceutical solid dosage forms containing the ready to use composition comprising steps of-
a. blending of polymer(s) to get first ready to use composition;
b. optionally Shifting first ready to use composition;
c. mixing of first ready to use composition with anti-diabetic drug;
d. optionally shifting blended mix;

e. mixing with solvent and wet granulation;
f. drying of granulated wet mass to get first dry-mix composition
g. mixing with second ready to use composition;
h. optionally addition of glidant and lubricant;
i. final tablet compression
17. A dry ready to use modified release composition of claim 9 further comprising a glidant selected from group of talc, colloidal silicon dioxide (Aerosil 200), starch and the like
18. A dry ready to use modified release composition as claimed in claim 17 wherein glidant comprise about 0.1-5% by weight of the formulation.
19. A dry ready to use modified release composition of claim 1 & 9 further comprising a lubricant comprises magnesium stearate, stearic acid, calcium stearate, glyceryl behenate, hydrogenated vegetable oils and the like.
20. A dry extended release composition as claimed in claim 19 wherein lubricant comprise about 1-15% by weight of the dry composition.