Technical field of the invention
The present invention relates to dispersible pharmaceutical compositions comprising aceclofenac and processes for the preparation thereof.
Background
Solid dosage forms which are swallowed, such as tablets and capsules, provide accurate dosage and avoid taste problems; but since they have to disintegrate in the gastrointestinal tract and the medicament has then to dissolve before it can be absorbed, absorption tends to be slower than from a suspension, and may be less than complete. Also, some patients have difficulty swallowing tablets and capsules, and there is a practical limit to the size, and therefore the dose, that can be swallowed.
Aceclofenac, a phenylacetic acid derivative (2-{(2,6-dichlorophenyl)amino} Phenylacetooxyacetic acid), is a novel NSAID indicated for the symptomatic treatment of pain and inflammation.
From the point of view of bioavailability, the preferred form of administration of sparingly soluble medicaments such as aceclofenac is often an aqueous suspension. However, there are problems associated with this form of administration. For example, such preparations in multidose form may have a limited shelf life; and usual methods of dose measurement lack accuracy. Suspensions are refrigerated to prevent the loss of potency and therefore are inconvenient while traveling. Further, skills for precise measurement of dose of the correct dose are required. The bitter taste of many such medicaments is also a drawback.
Existing marketed formulations of aceclofenac are film coated tablets that provide immediate release of the active ingredients once the tablet reaches the stomach.
Single dose powders for reconstitution in sachet form, and dispersible tablets, offer the advantages of suspensions without the problems of instability, measurement inaccuracy, difficulty in swallowing, or size limitation. In general, dispersible tablets

are advantageous in that they combine the accuracy of dosage associated with tablets, with the optimum bioavailability of suspensions. They may also accommodate larger doses than swallow tablets or capsules.
One of the important requirements of dispersible tablets is that they should disperse in an aqueous solution within a short period of time, for example, less than one minute, to form a smooth suspension without any coarse lumps.
Dispersible tablets of a few non-steroidal anti-inflammatory agents have been prepared. The US patent No. 5,256,699, assigned to Ciba Geigy describes a dispersible formulation of diclofenac in the free acid form, comprising a super disintegrant and a diluent.
EP 599767 filed by Quimicos Farmaceuticos describes dispersible diclofenac tablets and process of preparing the tablets, in which compression process is carried out in 3 phases.
US Patent No. 5,837,292; 4,886,669 and 5,698,226 also describe fast disintegrating and fast dissolving compositions.
Various processes are used for preparing dispersible tablets. However, a need exists for a cost effective, rapid operation process for producing dispersible pharmaceutical compositions comprising aceclofenac, which provide for ease of oral administration and result in a suspension which has a smooth mouth feel without any gritty particles.
Summary
In one general aspect there is provided a water dispersible tablet comprising aceclofenac, a disintegrant and pharmaceutically acceptable excipients wherein the disintegrant is used both intragranularly as well as extragranularly.
The intragranular disintegrant and the extragranular disintegrant each constitute from about 0.5% to about 10% w/w based on the total weight of the tablet.

According to another embodiment, the intragranular and extragranular disintegrants are similar or different.
Examples of disintegrant comprise starches, celluloses, algins, gums, cross-linked polymers and clays. Particularly sodium starch glycolate, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose etc. are used.
In another embodiment the pharmaceutically acceptable excipients are selected from one or more of diluents, lubricants, glidants, colorants and flavoring agents.
In yet another embodiment the water-dispersible tablet further comprises a sweetener.
In yet another embodiment the sweetener is used both intragranularly as well as extragranularly.
Sweetening agents comprise water soluble sweetening agents, water-soluble artificial sweeteners, dipeptide based sweetening agents and mixtures thereof.
Examples of water soluble sweetening agents comprise monosaccharides, disaccharides and polysaccharides, such as xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, corn syrup and sugar alcohols such as sorbitol, mannitol, xylitol, and mixtures thereof.
Examples of water soluble artificial sweetening agents comprise free acid form of saccharine and its soluble salts such as sodium or calcium saccharine salts, cyclamate salts, acesulfame, aspartame and mixtures thereof.
In another embodiment the water-dispersible tablet is prepared by a process comprising the steps of:
(A) granulating aceclofenac and a sweetener with an aqueous solution of intragranular disintegrant,

(B) mixing the granules with extragranular disintegrant, diluents,
sweeteners, flavors and lubricants.
(C) compressing the blend of step (B) into tablets.
The water dispersible tablet may further contain surfactants or wetting agents.
In yet another embodiment the water dispersible tablet comprises one or more of the following features. For example, the water dispersible tablet may disperse to form a solution, or non-gritty suspension or slurry, in less than about three minutes.
In another embodiment the water dispersible tablet may be compressed using suitable tooling to produce a scored tablet. Scored tablets may be easily divided into smaller pieces to provide a lower dose. In particular, the tablet may be scored through its center so that it can be easily divided into two equal halves.
It is one of the aspects to provide a process for preparing a water dispersible tablet, the process comprising the steps of:
(A) granulating a blend comprising aceclofenac, a sweetener and an
intragranular disintegrant with water,
(B) drying the granulated mixture,
(C) mixing the dried granules with extragranular disintegrant, diluents,
sweeteners, flavors and lubricants.
It is another aspect to provide a process for preparing a water dispersible tablet, the process comprising the steps of:
(A) granulating aceclofenac and a sweetener with an aqueous solution of
intragranular disintegrant,
(B) drying the granulated mixture,
(C) mixing the dried granules with extragranular disintegrant, diluents,
sweeteners, flavors and lubricants,
(D) compressing the blend of step (C) into tablets.
In another aspect there is provided a method of treating pain and inflammation in osteoarthritis, rheumatoid arthritis and ankylosing spondylitis comprising

administering a dispersible pharmaceutical composition comprising aceclofenac, disintegrant and other pharmaceutically acceptable excipients.
Embodiments include that a portion of the sweetener is added intragranularly along with aceclofenac.
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 present invention relates to orally disintegrating pharmaceutical compositions comprising aceclofenac, disintegrants and pharmaceutically acceptable excipients and processes for the preparation thereof.
Disintegrants may be used both in the intragranular portion as well as in the extragranular portion. The extragranular disintegrant aids in quick disintegration of the dispersible tablet into granules, and the intragranular disintegrant aids into disintegration into individual particles. The intragranular disintegrant is associated intimately with the active by the wet granulation process. This process of wet granulation is suitable for the preparation of dispersible tablets, as it results in the formation of softer, more porous granules which can disintegrate in aqueous solution to give a smooth suspension, avoiding the presence of coarse lumps. Particularly, good dispersibility is achieved if the active is granulated with a dispersion, solution or suspension of the disintegrant. Through this process, the disintegrant gets uniformly dispersed with the active. Use of an excessively great amount of disintegrant may make the tablet extremely moisture sensitive, and fragile. On the other hand lower amounts of disintegrant may delay complete disintegrations. Selection of an optimum amount is therefore desired. If the disintegrant is used as an intragranular disintegrant, about 0.5% to about 10% w/w can be used. Similarly, if the disintegrant is used as an extragranular disintegrant, about 0.5% to about 10% w/w can be used.

Disintegrant may be selected from a wide range of materials such as starches, celluloses, aligns, gums, cross-linked polymers and clays. Particularly sodium starch glycolate, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose etc. are used.
Suitable sweetening agents may be selected from a wide range of materials such as water soluble sweetening agents, water-soluble artificial sweeteners, dipeptide based sweetening agents and mixtures thereof.
Water soluble sweetening agents encompass monosaccharides, disaccharides and polysaccharides, such as xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, corn syrup and sugar alcohols such as sorbitol, mannitol, xylitol, and mixtures thereof.
Water soluble artificial sweetening agents encompass free acid form of saccharine and its soluble salts such as sodium or calcium saccharine salts, cyclamate salts, acesulfame, aspartame and mixtures thereof.
A portion of the sweetener may be used both in the intragranular portion as well as in the extragranular portion. The presence of the sweetener, particularly in the intragranular portion efficiently masks the bitter taste of the drug, since the sweetener gets evenly dispersed along with the drug.
The term 'pharmaceutically acceptable excipient' as used herein includes all physiologically acceptable excipients used in the pharmaceutical art of dispensing.
Examples include diluents, lubricants, glidants, colorants and flavoring agents. These excipients may be present intragranularly, extragranularly or both.
Suitable diluents include one or more of lactose, starch, sugar alcohols, sucrose, calcium carbonate, dicalcium phosphate and mixtures thereof.
Suitable lubricants and glidants include, but are not limited to, colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor

oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax and white beeswax.
The coloring agents and flavoring agents of the present invention may be selected from any FDA approved colors and flavors for oral use.
Suitable flavoring agents include synthetic and natural flavors such as spearmint, peppermint, lemon, orange, grape, lime, grapefruit, apple, cherry, pineapple, cocoa and chocolate.
The water dispersible tablet formulation may further contain surfactants or wetting agents.
Surfactants/wetting agents include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical compositions. These include polyethoxylated fatty acids and its derivatives, for example polyethylene glycol 400 distearate, polyethylene glycol - 20 dioleate, polyethylene glycol 4 -150 mono dilaurate, polyethylene glycol -20 glyceryl stearate; alpohol - oil transesterification products, for example polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example propylene glycol monocaprylate; mono and diglycerides, for example glyceryl ricinoleate; sterol and sterol derivatives, for example sitosterol; sorbitan fatty acid esters and its derivatives, for example polyethylene glycol - 20 sorbitan monooleate, sorbitan monolaurate; polyethylene glycol 8 alkyl ether or phenols, for example polyethylene glycol - 20 cetyl ether, polyethylene glycol 10 - 100 nonyl phenol; sugar esters, for example sucrose monopalmitate; polyoxyethylene polyoxypropylene block copolymers known as "poloxamer"; ionic surfactants, for example sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl filmarate, propylene glycol alginate, octyl sulfosuccinate disodium, palmitoyl carnitine; and mixtures thereof.
The ingredients discussed above may be formed into tablets by conventional techniques, for example either by direct compression, or first slugging some of the ingredients, milling the slugs, blending with the remaining ingredients and then

compressing as appropriate. Dispersible tablets may also be prepared using wet granulation techniques.
In particular wet granulation methods may be used which help to achieve soft and porous granules which disintegrate readily to form a solution or smooth suspension or slurry free of lumps in the mouth.
The process may further include drying the granules prior to compressing into tablets. The process may further include sizing the compacts prior to compressing into tablets. The solvent used in forming the granules may be one or more of water, ethanol, methanol, isopropyl alcohol, dichloromethane, and acetone.
The pharmaceutical composition of the invention may be packaged in unit dose, rolls, bulk bottles, blister packs and combinations thereof without limitation.
Preferably the composition is in unit dose form. The amount of medicament in a unit dose will depend on the condition to be treated and the assay of the medicament. The unit dose will be repeated according to the usual regime of the medicament.
A method of treating pain and inflammation in osteoarthritis, rheumatoid arthritis and ankylosing spondylitis is provided comprising administering a dispersible pharmaceutical composition comprising aceclofenac, disintegrant and other pharmaceutically acceptable excipients.
The following example illustrates various aspects of the present invention. This example is for illustration only and should not be construed as limiting the scope of the invention.

EXAMPLE
Table 1

(Table Removed)
Process:
1. Aceclofenac and aspartame were mixed in a rapid mixer granulator for 10
minutes.
2. Croscarmellose sodium was dispersed in purified water.
3. Material of step (1) was wet granulated using the dispersion of step (2) in the
rapid mixer granulator.
4. Granules of step (3) were dry granulated at 60°C in a fluid bed drier.
5. Dried granules of step (4) were sieved and milled in a multi mill.
6. Remaining portion of Croscarmellose sodium, magnesium stearate, colloidal
anhydrous silica, microcrystalline cellulose, flavor peppermint and aspartame
were blended together.
7. Granules of step (5) and the blend of step (6) were loaded in a double cone
blender and mixed.
8. Magnesium stearate was added into the blend of step (7) and mixed.
9. The above blend was compressed using specific tooling.
The chemical and physical stability of aceclofenac in the water-dispersible tablet prepared according to Example given above in Table 1 under accelerated stability conditions of 40°±2°C and 75±5% relative humidity, were evaluated on the basis of assay, disintegration time and in vitro dissolution measured between initial and 3-month time points. The in vitro dissolution was carried out in 900 ml of 0.1 N HCL at 50 rpm under 37°C using USP II apparatus. The stability results for three months (M) at 40°C/75%RH are given below in the tables 2, 3 and 4.
Table 2

(Table Removed)
Table 3

(Table Removed)
Table 4

(Table Removed)
It will be apparent to those skilled in the art that various modifications and variations can be made in the water-dispersible tablet of the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents. Accordingly, the invention is not limited by the embodiments described above which are presented as examples only but can be modified in various ways within the scope of the protection defined by the appended patent claims.

WE CLAIM:
1. A water-dispersible tablet comprising aceclofenac, a disintegrant and
pharmaceutically acceptable excipients wherein the disintegrant is used both
intragranularly as well as extragranularly.
2. The water-dispersible tablet of claim 1 further comprising a sweetener
selected from water soluble sweetening agents, water-soluble artificial
sweeteners and dipeptide based sweetening agents wherein the sweetener is
used both intragranularly as well as extragranularly.
3. The water-dispersible tablet of claims 1 or 2, wherein the intragranular and
extragranular disintegrant each constitute from about 0.5% to about 10% w/w
of the tablet.
4. The water-dispersible tablet of claims 1 or 2, wherein the disintegrant is
selected from starches, celluloses, aligns, gums, cross-linked polymers and
clays.
5. The water-dispersible tablet of claims 1 or 2, wherein the pharmaceutically
acceptable excipients are selected from one or more of diluents, lubricants,
glidants, colorants and flavoring agents.
6. A water-dispersible tablet of the preceding claims prepared by a process
comprising the steps of:

(A) granulating aceclofenac and a sweetener with an aqueous solution of
intragranular disintegrant,
(B) mixing the granules with extragranular disintegrant, diluents,
sweeteners, flavors and lubricants.
(C) compressing the blend of step (B) into tablets.

7. A process for preparing a water dispersible tablet of claims 1-5, the process
comprising the steps of:
(A) granulating a blend comprising aceclofenac, a sweetener and an
intragranular disintegrant with water,
(B) drying the granulated mixture,
(C)mixing the dried granules with extragranular disintegrant, diluents, sweeteners, flavors and lubricants.
8. A process for preparing a water dispersible tablet of claims 1-5, the process
comprising the steps of:
(A) granulating aceclofenac and a sweetener with an aqueous solution of
intragranular disintegrant,
(B) drying the granulated mixture,
(C)mixing the dried granules with extragranular disintegrant, diluents,
sweeteners, flavors and lubricants, (D) compressing the blend of step (C) into tablets.
9. The water-dispersible tablet of the preceding claims, wherein the tablet may
disperse to form a solution, or non-gritty suspension or slurry, in less than
about three minutes.
10. A water-dispersible tablet comprising aceclofenac and process of preparation
thereof substantially as described herein.