TECHNICAL FIELD OF THE INVENTION
The present invention relates to wet granulated controlled release compositions comprising aceclofenac and one or more hydrophilic polymers.
BACKGROUND
Aceclofenac, also named 2- [2- [2- [ (2, 6- dichlorophenyl) amino] phenyl] acetyl] oxyacetic acid is a nonsteroidal anti-inflammatory agent, with remarkable antiinflammatory, analgesic and antipyretic properties. The usual dosage of aceclofenac, normally presented in its acid form, is of two daily doses of 100 mg.
Acelofenac is absorbed rapidly in the gastrointestinal tract upon oral administration, and distributed in kidneys, vesica, liver, thyroid gland and the like at high concentration but distributed in eye, brain, and fat tissues and the like at low concentration. Upon oral administration, aceclofenac shows an onset time shorter man 30 minutes, a time to maximum blood concentration (Tmax) of about 1.5-2. 5 hours and a duration time of about 12 hours. It is known that, upon oral administration, about 66.8% of the administered aceclofenac is eliminated in urine arid about 18% is eliminated in faeces, and aceclofenac has an elimination half-life of about 4 hours. Since it has a shorter plasma half life (about 4 hours), in practice aceclofenac is given twice or thrice a day in order to ensure relatively constant plasma levels.
PCT Application WO 2003004060A1 filed by Pharm. Tech. Res. INC. discloses compositions and preparation methods for oral aceclofenac dosage forms comprising a polymeric base and a surfactant. The preparation is formulated into a solid powder by a complex spray drying process whereby the dissolution is faster.
WO 0217877A2 filed by University Gent discloses a controlled release pharmaceutical pellet composition comprising a drug having low solubility under acidic conditions, the said composition providing a release of at least 75 % of the said drug within 45 minutes in phosphate buffer pH 6.8, further comprising a microcrystalline cellulose and a swellable polymer.

WO 9912524A1 filed by Nycomed Denmark discloses oral pharmaceutical modified release multiple-units composition of an NSAID substance to obtain both a relatively fast or quick onset of the therapeutic effect and the maintenance of a therapeutically active plasma concentration for a relatively long period of time. The modified release multiple-units composition comprises at least two fractions of multiple units such as a first and a second fraction. The first fraction comprises individual units to quickly release the drug substance. The second fraction comprises individual units coated with a combination of hydroxypropylmethyl cellulose and eudragit which are designed to slowly release the drug substance to enable a delayed and extended release of the drug substance.
Indian Application 189/MUM/2005 filed by Ipca discloses controlled release pharmaceutical compositions of aceclofenac comprising a combination of hydrophilic and hydrophobic polymers. Hydroxypropylmethyl cellulose and ethyl cellulose are present in a specified ratio of 3:1 in the formulation.
Marketed controlled release formulations of aceclofenac include ZERODOL-CR® and HIFENAC-MR® manufactured by Ipca Laboratories Ltd. and Intas Pharmaceuticals Ltd. respectively. These formulations although meant for once-a-day administration were found to release about 80% of the drug in vitro within two hours in phosphate
buffer, thereby raising toxicity issues.
Unintended, rapid drug release in a short period of time of the entire amount or a significant fraction of the drug contained in a controlled release dosage form is often referred to as "dose dumping" and is particularly delicate and critical. Depending on the therapeutic indication and the therapeutic index of a drug, dose-dumping can pose a significant risk to patients, either due to safety issues or diminished efficacy or both. Generally dose-dumping is observed due to a compromise of the release-rate-controlling mechanism.
Formulations using hydrophilic polymers alone typically provide outstanding controlled-release performance by themselves, eliminating the potential performance
variations that may arise in multipolymer systems using a combination of hydrophilic and hydrophobic polymers.
Further, hydrophilic polymers are very versatile release agents. They are nonionic, so they minimize interaction problems when used in acidic, basic, or other electrolytic systems. Hydrophilic polymers work well with soluble and insoluble drugs and at high and low dosage levels. They are tolerant of many variables in other ingredients and production methods.
Hydrophilic polymers are widely used in oral controlled drug delivery because of their flexibility to obtain a desirable drug release profile, cost-effectiveness, and broad regulatory acceptance. The ability of the hydrophilic polymers to release an entrapped drug in aqueous medium and to regulate the release of such drug by control of swelling and cross-linking makes them particularly suitable for controlled-reiease applications.
A research article, "Preparation, In vitro, Preclinical and Clinical Evaluations of Once Daily Sustained Release Tablets of Aceclofenac", published in Archives of Pharmaceutical Research, 2007, discloses controlled release formulations of aceclofenac prepared by direct compression using hydrophilic polymer.
The main limitation of direct compression is that the technique depends on the major components of the formulation having appropriate flow and compaction properties. While it is impossible to modify the properties of drug substance by particle engineering, this is usually outside the scope of the formulator, and the formulation must be designed to accommodate the limitation imposed by the drug substance. i ui low dose drugs, it is usually possible to overcome such limitation through careful selection of excipients, but for a controlled release dosage form at high dose levels, it becomes impractical to produce a tablet of acceptable size.
Direct compression has a negative influence on the bulk properties of the drug substance, e.g., flow properties and bulk density. The compression behavior of the drug substance may also be poor, leading to weak interparticulate bonds and polymorphism changes under pressure. Therefore, direct compression is not a

feasible option for routine production because of, e.g., the high hygroscopicity, the poor flowability with resulting processability problems and dose uniformity problems.
Further, direct compression places greater demands on the excipients, particularly the fillers. This has resulted in the introduction of a number of expensive excipients designed specifically for use in direct compression formulations.
In light of the above background, it will be appreciated by those versed in the pharmaceutical dispensing art that a need exists for a controlled release pharmaceutical composition using hydrophilic polymers that can deliver aceclofenac in a controlled, extended form. At the same time, the composition must be capable of being formulated by employing a simple process that involves fewer steps.
SUMMARY
In one general aspect there is provided a wet granulated controlled release composition comprising aceclofenac, one or more hydrophilic polymers and one or more pharmaceutically acceptable excipients.
In another embodiment there is provided a wet granulated controlled release composition comprising aceclofenac, one or more hydrophilic polymers and one or more pharmaceutically acceptable excipients, wherein the in vitro release of aceclofenac in phosphate buffer at phi 6.8 is not less than about 80% after 16 hours.
Preferably, the in vitro release of aceclofenac in phosphate buffer at pH 6.8 is from about 35% to about 55% after 4 hours and not less than about 10% after 1 hour.
In another embodiment there is provided a wet granulated controlled release composition comprising aceclofenac, one or more hydrophilic polymers and one or more pharmaceutically acceptable excipients, wherein the composition exhibits better dissolution parameters in vitro in phosphate buffer at pH 6.8 than commercially available HIFENAC-MR® tablets (Aceclofenac modified release tablets, Intas Pharmaceuticals Ltd.) & ZERODOL-CR® (Aceclofenac controlled release tablets, Ipca Laboratories Ltd.).

Examples of hydrophilic polymers comprise starch, gums, alginates, polysaccharides, polyvinylprrolidone, polyethylene glycol, acrylic acid derivatives, gelatin, polyvinyl alcohol, cellulose derivatives or mixtures thereof.
Cellulose derivatives comprise hydroxypropyl cellulose, hydroxypropyl
methylcellulose, hydroxyethylcellulose, hydroxymethylcellulose,
carboxymethylcellulose, .methylcellulose, sodium carboxy methylcellulose or
mixtures thereof,
In yet another embodiment there is provided a wet granulated controlled release composition comprising aceclofenac, one or more hydrophilic polymers selected from one or more of starch, gums, alginates, polysaccharides, polyvinylprrolidone, polyethylene glycol, acrylic acid derivatives, cellulose derivatives or mixtures thereof and one or more pharmaceutically acceptable excipients.
Particularly, hydrophilic polymer is cellulose derivative, polyvinylpyrrolidone or mixture of both.
The controlled release composition may further comprise one or more pharmaceutically acceptable excipients.
The pharmaceutically acceptable excipients are those known to the skilled in the art and may be selected from binders, fillers, disintegrants, lubricants, glidants, oil or wax-like material as plasticizers, coloring agents and flavoring agents.
In another aspect there is provided a process for preparing a wet granulated controlled release composition comprising the steps of:
(a) granulating a mixture of aceclofenac and one or more hydrophilic polymers with a solvent;
(b) mixing/blending the granules of step (a) with one or more pharmaceutically acceptable excipients;
(c) compressing the blend of step (b) into tablets or filling into capsules.

In yet another aspect there is provided a process for preparing a wet granulated controlled release composition comprising the steps of:
(a) granulating aceclofenac with a solution of one or more hydrophilic polymers in a solvent;
(b) mixing/blending the granules of step (a) with one or more pharmaceutically acceptable excipients;
(c) compressing the blend of step (b) into tablets or filling into capsules.
Example of solvents used for granulation comprise methylene chloride, isopropyl
alcohol, acetone, methanol, ethanol, water or mixtures thereof.
The capsules may contain pellets, beads, granules, multiparticulates, tablets or
powder.
In one embodiment the wet granulated controlled release composition may be present in a single unit dosage form such as a monolithic tablet.
in another embodiment the wet granulated controlled release composition may be formulated as a bilayered tablet.
In another aspect there is provided a process for preparing a wet granulated controlled release composition comprising:
(a) preparing an immediate release portion comprising aceclofenac and one or more pharmaceutically acceptable excipients;
(b) preparing a controlled release portion comprising aceclofenac and one or more hydrophilic polymers;
(c) forming an immediate release layer and a controlled release layer and combining the layers in a single tablet to form a layered tablet.
In another embodiment, the wet granulated controlled release composition may comprise an inner and an outer portion. The inner portion may be surrounded by the outer portion in such a manner that only one surface of the inner portion is exposed, i. e., a tablet within a tablet or in-lay tablet.

In yet another embodiment, the dosage forms may be prepared as reservoir- type formulations in which the active is admixed with pharmaceutical^ acceptable excipients to form a core. This core is then surrounded by polymeric coatings.
In yet another embodiment, the composition is optionally coated with one or more layers comprising film forming agents and/or pharmaceutical^ acceptable excipients.
The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and claims.
DESCRIPTION
The inventors have now developed controlled release compositions comprising aceclofenac and one or more hydrophilic polymers prepared by wet granulation.
The advantages of the wet granulation process are well established and include:
(a) Permits mechanical handling of powders without loss of mix quality;
(b) Improves the flow of powder without loss of mix quality;
(c) Increases and improves the uniformity of powder density;
(d) Improves cohesion during and after compaction;
(e) Reduces air entrapment;
(f) Reduces the level of dust and cross-contamination;
(g) Allows for the addition of a liquid phase to powder (wet process only); and (h) Makes hydrophobic surfaces hydrophilic.
The term "controlled-release", as used herein, includes any type of controlled-release including prolonged release, sustained release, modified release and extended release.
The pharmaceutical compositions of the present invention can be administered orally in the form of tablets, such as monolithic tablets, tablet in a tablet, bilayered or multilayered tablets. The composition may also be in the form of capsules containing pellets, beads, granules, multiparticulates, tablets, powder or osmotic

dosage forms comprising a core covered with a semipermeable membrane containing one or more additional immediate release layers, and various other controlled release compositions known to a person skilled in the art.
The controlled release compositions of the present invention allow for highly reproducible release in vivo as the entire dosage form hydrates uniformly on contacting the gastrointestinal fluids. The controlled release compositions can be tailored to prolong or extend the release and absorption of the pharmaceutical active ingredient for up to about 2 hours to about 24 hours.
Preferably the in vitro release of the aceclofenac in phosphate buffer at pH 6.8 is not less than about 80% after 16 hours; from about 35 to about 55% after 4 hours and not less than about 10% after 1 hour.
Examples of' hydrophilic polymers include but are not limited to starch, gums, alginates, polysaccharides, polyvinylprrolidone, polyethylene glycol, acrylic acid derivatives, gelatin, polyvinyl alcohol, cellulose derivatives or mixtures thereof.
Cellulose derivatives comprise hydroxypropyl cellulose, hydroxypropyl
methylcellulose, hydroxyethylcellulose, hydroxymethylcellulose,
carboxymethylcellulose, methylcellulose, sodium carboxy methylcellulose or
mixtures thereof.
Preferably, hydrophilic polymer is cellulose derivative, polyvinylpyrrolidone or mixture
of both.
The hydrophilic polymers may comprise about 5 to about 90% by weight of the formulation. The hydrophilic polymers in accordance with this invention may also act as binder and may be added as such or dissolved or dispersed in an appropriate solvent system and the resulting solution or dispersion is then used to granulate the
active agent.
Suitable solvents used for granulation include, but are not limited to methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water or mixtures thereof.


The wet granulation solvent addition can be carried out using any technique known in the art. For example, the liquid can be added in single or multiple rapid additions, sprayed onto a stirring powder bed, pumped directly onto the powder or introduced into fluidizing gas. Mixing times with the liquid are generally optimized such that the majority of fine particles are bound in granules, yet the granules themselves are not over-hardened.
The controlled release composition further comprises one or more pharmaceutically acceptable excipients.
The pharmaceutically acceptable excipients are those known to the skilled in the art and may be selected from binders, fillers, disintegrants, lubricants, glidants, oil or wax-like material as plasticizers, coloring agents and flavoring agents.
Examples of binders include, but are not limited to, microcrystalline cellulose, tnethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, polyvinyl alcohol, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol or mixtures thereof.
Examples of fillers include, but are not limited to, corn starch, lactose, white sugar, sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, starch, starch pregelatinized or mixtures thereof.
Examples of disintegrants include, but are not limited to, starch, cross-linked carboxy methyl cellulose sodium, cross-linked polyvinyl pyrrolidone, sodium starch glycolate, low substituted hydroxy propyl cellulose or mixtures thereof.
Examples of lubricants and glidants include, but are not limited to, glyceryl palmitostearate, colloidal anhydrous silica, stearic acid, magnesium stearate,

calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax or mixtures thereof.
Examples of oil or wax-like materials useful in the present invention include, but are not limited to, fatty acids such as stearic acid; long chain fatty alcohols such as, stearyl alcohol, cetyl alcohol, carnuba wax, beeswax, white wax and mixtures thereof. Examples of oils include vegetable oil, glycerides of C6-C-18 fatty acids or
mineral oil or mixtures thereof.
The coloring agents and flavoring agents of the present invention may be selected from any FDA approved colors and flavors for oral use.
The process for preparing a wet granulated controlled release composition according to the present invention comprises granulating a mixture of aceclofenac and one or more hydrophilic polymers with a solvent. Alternatively the wet granulated controlled release composition can be prepared by granulating aceclofenac with a solution of one or more hydrophilic polymers in a solvent.
Non-limiting examples of wet granulation processes include high shear wet granulations, fluid-bed granulations, extrusion granulations and low shear wet granulations. The process may be carried out using stirrers, mixers and blenders,
including bin blenders.
The controlled release composition of the present invention can be compressed into tablets or alternatively filled into capsules.
The tablet may be a single monolithic matrix, bilayered, core coated or tablet in a tablet and the capsules may contain pellets, beads, granules, multiparticulates, tablets or powder.
The term "monolithic" may encompass tablets that do not require multiple layers, special shapes, osmotic compartments and/or specialized coatings, typically without joints or seams.

The term "bilayered or multilayered" may encompass dosage forms where there are two separate drug layers, one on top of the other with only one surface in mutual contact or with an inert layer in between.
These may also be prepared by compression granulation of the immediate release portion of the drug on a previously compressed granulation of the sustained release portion, or alternatively by feeding previously compressed tablets of the sustained leiease portion into a machine and compressing granulation layer of the immediate release portion on the preformed tablets.
The dosage forms may be multiple-compression tablets comprising an inner core and an outer coat of the active, and may be prepared such that one surface of the inner core is exposed. These types of tablets are also referred to as inlay or bull's-eye tablets and these are similar to compression-coated tablets except that one surface of the coating is eliminated.
The controlled release composition of the present invention can optionally be coated with one or more layers comprising film forming agents and/or pharmaceutically acceptable excipients.
Coating may be performed by applying one or more film forming polymers with or without other pharmaceutically inert excipients. This may be done as a solution or suspension using any conventional coating technique known in the prior art, such as spray coating in a conventional coating pan or fluidized bed processor, or dip
coating.
Suitable film forming polymers include one or more of ethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, waxes, methacrylic acid polymers such as Eudragit® RL and RS, and mixtures thereof. The coating can also be performed using any commercially available ready TO coat preparations such as opadry-AMB, opadry-white, opadry-clear, etc.

4

Suitable solvents used for making a solution/suspension of film forming polymer include one or more of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water or mixtures thereof.
The in vitro drug release of the wet granulated controlled release compositions of aceclofenac prepared according to the present invention was compared with marketed controlled release formulations of aceclofenac ZERODOL-CR® and HIFENAC-MR® manufactured by Ipca Laboratories Ltd. and Intas Pharmaceuticals Ltd. respectively. The marketed formulations were found to release almost 80% of aceclofenac within 2 hours in phosphate buffer at pH 6.8.
The controlled release compositions of the present invention released from about 35% to about 55% of aceclofenac after 4 hours in phosphate buffer at pH 6.8. Further the in vitro release was found to be not less than about 80% after 16 hours and not less than about 10% after 1 hour in phosphate buffer at pH 6.8.
Ffom the in vitro dissolution profile in phosphate buffer at pH 6.8 it was evident that the composition of the present invention provided substantially zero order release of aceclofenac in comparison to the marketed formulations. The present invention provided a constant, linear, continuous, sustained and controlled release rate of the aceclofenac from the hydrophilic polymer layers prepared by wet granulation.
In addition, the pharmacokinetic data showed that the once daily controlled release formulations prepared as per the present invention was comparable with two doses of Preservex® 100 mg tablets (immediate release tablets containing aceclofenac 100 mg) administered twice daily.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.

EXAMPLE 1 Controlled release monolithic tablets of aceclofenac
(Table Removed)
Process:
1. Aceclofenac, Microcrystalline cellulose and Hydroxypropylmethyl cellulose were blended and granulated with a solution of Polyvinylpyrrolidone in purified water.
2 Dried granules of step 1 were blended with Glyceryl palmitostearate.
3. Material of step 2 was compressed into tablets.
EXAMPLE 2 Controlled release capsules of aceclofenac
(Table Removed)
Process;
Preparation of immediate release tablets
1. Aceclofenac, Microcrystalline cellulose and Croscarmeliose sodium were
blended and granulated with a solution of Polyvinylpyrrolidone in purified
water.
2. Dried Granules of step 1 were blended with Glyceryl palmitostearate.
3 Material of step 2 was compressed into tablets followed by coating using opadry dispersion Preparation of sustained release tablets
1. Aceclofenac, Microcrystalline cellulose and Hydroxypropylmethyl cellulose were blended and granulated with a solution of Polyvinylpyrrolidone in purified water.
2. Dried Granules of step 1 were blended with Glyceryl palmitostearate.
3. Material of step 2 was compressed into tablets followed by coating using opadry dispersion
The immediate release tablets and sustained release tablets were filled into
capsules.
EXAMPLE 3 Controlled release bilayered tablets of aceclofenac
I Percent (%) w/w (total
(Table Removed)
Process:
Preparation of immediate release blend
1. Aceclofenac, Macrocrystalline cellulose and Croscarmellose sodium were
blended and granulated with a solution of Polyvinylpyrrolidone in purified water.
2. Granules of step 1 were blended with Glyceryl palmitostearate.
3. Material of step 2 was compressed into tablets. Preparation of sustained release blend

1. Aceclofenac, Microcrystalline cellulose and Hydroxypropylmethyl cellulose were blended and granulated with a solution of Polyvinylpyrrolidone in purified water.
2. Granules of step 1 were blended with Glyceryl palmitostearate.
The immediate release blend and sustained release blend were compressed into bilayered tablets.
Table 1: Drug Release of Aceclofenac controlled release formulations prepared as per Examples 1 & 2 and comparative marketed controlled release formulations HIFENAC-MR® (Intas Pharmaceuticals Ltd.) & ZERODOL-CR® (Ipca Laboratories Ltd.) in Phosphate buffer pH 6.8, 900 ml, USP II at 50 rpm.
(Table Removed)
In vivo bioequivalence study
In vivo performance of a single dose of aceclofenac controlled release formulations repared as per Examples 1 & 2, administered once daily were evaluated with respect to two doses of Preservex 100 mg tablets (Immediate release product of aceclofenac) administered twice daily in healthy male volunteers. Pharmacokinetic parameters AUC 0-24 (Area under the plasma concentration vs. time curve from 0 hours to 24 hours); AUC inf-0bs (Area under the plasma concentration vs. time curve tram 0 hours to infinity) and AUC iast (Area under the plasma concentration vs. time curve from 0 hours to the time of last sample collected) were calculated from the data obtained. Statistical analysis was carried out at 90% interval using "SAS" software package. The results of the study are given in Table 2.
Table 2: Pharmacokinetic data for controlled release formulations prepared as per Examples 1 & 2 once daily vs. two doses of Preservex 100 mg tablets containing aceclofenac 100 mg) administered twice daily:
(Table Removed)
While mere has been shown and described what are the preferred embodiments of ilie invention, one skilled in the pharmaceutical formulation art will appreciate that vanous modifications in the formulations and process can be made with out .1-1 ,, ting from the scope of the invention as it is defined by the appended claims.

WE CLAIM:
1. A wet granulated controlled release composition comprising aceclofenac, one or more hydrophilic polymers and one or more pharmaceuticaily acceptable excipients.
2. The composition according to claim 1, wherein the in vitro release of aceclofenac in phosphate buffer at pH 6.8 is not less than about 80% after 16 hours.
3. The composition according to claim 1, wherein the in vitro release of aceclofenac in phosphate buffer at pH 6.8 is from about 35 to about 55% after 4 hours.
4. The composition according to claim 1, wherein the in vitro release of aceclofenac in phosphate buffer at pH 6.8 is not less than about 10% after 1
hour.
5. The composition according to claim 1 wherein the hydrophilic polymer is selected from the group consisting of starch, gums, alginates, polysaccharides, polyvinylprrolidone, polyethylene glycol, acrylic acid derivatives, gelatin, polyvinyl alcohol, cellulose derivatives like hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, carboxymethylcellulose, methylcellulose, sodium carboxy methylcellulose or mixtures thereof.
6. The composition according to claim 1, wherein the composition further comprises pharmaceuticaily acceptable excipients selected from one or more of binders, diluents, lubricants, glidants, colorants and flavoring agents.
7 A process for preparing a wet granulated controlled release composition according to claim 1 comprising the steps of;
(a) granulating a mixture of aceclofenac and one or more hydrophilic polymers with a solvent;
(b) mixing/blending the granules of step (a) with one or more pharmaceutically acceptable excipients;
(c) compressing the blend of step (b) into tablets or filling into capsules.
8. A process for preparing a wet granulated controlled release composition
according to claim 1 comprising the steps of:
(a) granulating aceclofenac with a solution of one or more hydrophilic polymers in a solvent;
(b) mixing/blending the granules of step (a) with one or more pharmaceuticatly acceptable excipients;
(c) compressing the blend of step (b) into tablets or filling into capsules.

9. The process according to claims 7 and 8 wherein the tablet is a single monolithic matrix, bilayered, core coated or tablet in a tablet and the capsules contain pellets, beads, granules, multiparticulates, tablets or powder.
10. A wet granulated controlled release composition comprising aceclofenac substantially as described herein.