FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
PHARMACEUTICAL COMPOSITION COMPRISING DIACEREIN OR
SALTS THEREOF
2. APRlTCANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D-4, MIDC, Chikalthana,
Aurangabad (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a pharmaceutical composition comprising rhein or diacerein or salts thereof adsorbed on a pharmaceutically acceptable adsorbent, optionally with one or more pharmaceutically acceptable excipients.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. Description
The present invention provides a pharmaceutical composition comprising rhein or diacerein or salt thereof adsorbed on a pharmaceutically acceptable adsorbent, optionally with one or more pharmaceutically acceptable excipients.
Rhein, (Formula I), is chemically 9,10-dihydro-4, 5-dihydroxy-9, 10-dioxo-2-anthracene carboxylic acid and diacerein, (Formula II), is chemically 4,5-bis (acetyloxy) 9,10-dihydro-4, 5-dihydroxy-9, 10-dioxo-2-anthracenecarboxylic acid. Diacerein is used particularly in the treatment of osteoarthritis. Diacerein has a unique mode of action that differentiates it from non-steroidal anti-inflammatory drugs (NSAIDs) and other conventional forms of drug therapy. It has a melting point of 217-218°C. It has a molecular weight of 368.29 and molecular formula is C19H12O8.
O H 0 O H
Formula-I
H,C^ .0 O O. . CH.
' T T
o o


Diacerein is practically insoluble in the solvents compatible with a pharmaceutical use, such as water, alcohols, acetone, dichloromethane and chloroform. Further, diacerein can be administered by oral route but it cannot be completely absorbed by the digestive tract, and this incomplete absorption may result in undesirable side effects such as laxatives effects.
In order to overcome these problems, various derivatives, pharmaceutical compositions and specific galenic forms have been proposed in the literature. For example, European patent EP 243,968 describes a diacerein potassium salt, which is water-soluble and can be used in the preparation of compositions for parenteral administration.
Besides, it is known that the solubility and/or wettability of a substance can be improved by treatment with a surface-active agent, which results in promoting the bioavailability of the active principle.
It is also known that the grinding of active principles in the presence of certain water-soluble polymers improves the solubility and the bioavailability of the product (Yamamoto et al., J. Pharm. Sci. (1976) 65, p. 1484-88).
There are various patents/applications, which describe pharmaceutical compositions of diacerein. For example, EP243968B1 provides parenteral preparations of diacerein salts.
US Patent No 6,124,358 and European Patent No EP904060B1 provides pharmaceutical composition comprising co-micronized rhein or diacerein, with sodium lauryl sulfate.
Although it is possible to improve the bioavailability of diacerein by comicronization, as described in EP 904061B1; US 6,124,358, it is still desirable to develop new formulations or new compositions likely to further improve the

bioavailability, and it might be possible to use the dissolution kinetics of diacerein.
US Patent No 5,149,542 (EP263083B1), 4,861,599 (EP 264989B1) and 5,275,824 (EP 446753B1) provides controlled release or delayed release compositions.
US Patent No 5,225,192 (EP 364944B1) and 5,569,469 describe different poorly soluble medicaments supported on polymer substances.
US Patent No 5,952,383 and European Patent No EP 862423B1 provides pharmaceutical compositions of diacerein, rhein and their salts along with excipients.
The present inventors while working on diacerein formulation have noticed that when diacerein is adsorbed on a pharmaceutically acceptable adsorbent that provides large exposed surface area, it results in increased solubility of diacerein which in turn leads to significant increase in percent drug release of diacerein as compared to Art 50 (Marketed formulation of diacerein). Art 50 releases about 14% of diacerein in 60 minutes, whereas pharmaceutical composition of the present invention releases 100% diacerein in 45 minutes. This may lead to increased bioavailability. The increased bioavailability may further lead to reduction in side effects i.e. soft stools.
One of the aspects of the present invention provides a pharmaceutical composition comprising rhein or diacerein, or salts thereof adsorbed on a pharmaceutically acceptable adsorbent, optionally with one or more pharmaceutically acceptable excipients.
Suitable pharmaceutically acceptable adsorbents may include one or more of colloidal silicon dioxide, lactose, saccharides, calcium silicate, magnesium aluminum silicate, porous ceramics, polypropylene foams, cellulose, cellulose

derivatives, polyols, starches, pre-gelatinized starches, starch derivatives, modified starches, dextrins, maltodextrins, polydextroses, dextroses, calcium carbonate, calcium phosphate, calcium sulfate and the like.
In yet another aspect of the invention there is provided a process of preparing a pharmaceutical composition comprising rhein or diacerein, or salts thereof, which process comprises of:
a) providing slurry or solution of rhein or diacerein, optionally with one or more pharmaceutically acceptable excipients in suitable solvent,
b) adding pharmaceutically acceptable adsorbent to slurry or solution of step a) or vice versa,
c) recovering rhein or diacerein, or salts thereof adsorbed on a pharmaceutically acceptable adsorbent from slurry or solution of step b) thereof.
Slurry or solution of rhein or diacerein, or salts thereof may be microfluidized through microfluidizer in order to reduce the particle size of rhein or diacerein.
Suitable solvents in the process of the present invention are those known to ordinary skilled in the art and include but not limited to one or more of water, methanol, ethanol, butanol, isopropyl alcohol, acetone, chloroform, dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), methylene chloride and the like.
Adsorption can be also carried out by fluidized bed processor, glatt, spray dryer or by any other suitable coating techniques known in the art.
In the process of the present invention the rhein or diacerein, or salts thereof adsorbed on a pharmaceutically acceptable adsorbent can be recovered from the suspension by any suitable means, such as removal of the solvent. Removal of the solvent can be carried out by means of drying the mixture with or without

vacuum, freeze-drying, or lyophilization, fluidized bed processor. Drying further includes evaporation and/or distillation or any other means known to skilled artisan for removal of solvent from mixture.
In yet another aspect of the present invention there is provided a pharmaceutical composition, which comprises of rhein or diacerein, or salts thereof adsorbed on a pharmaceutically acceptable adsorbent optionally with one or more pharmaceutically acceptable excipients; and wherein the formulation exhibits a dissolution profile such that within 20 minutes more than 85% of diacerein is released, wherein the release rate is measured in Apparatus 2 (USP, Dissolution, paddle, 75 rpm) using 1000 ml of pH 5.7 phosphate buffer at 37 °C ± 0.5°C.
The pharmaceutical composition of the present invention can be present in the form of tablet, capsule, powder, disc, caplet, granules, pellets, granules in capsule, minitablets, minitablets in capsule, pellets in capsule, sachet and other dosage forms suitable for oral administration.
The pharmaceutical composition comprises of pharmaceutically acceptable excipients wherein excipients may include fillers, binders, surface-active agents, lubricants, disintegrants, and glidants.
Suitable filler may be one or more of, microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar and the like.
Suitable binder may be one or more of, povidone, starch, stearic acid, gums, hydroxypropylmethyl cellulose and the like.
Suitable surface-active agents may be one or more of, sodium lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or another ester of polyoxyethylene sorbitane, sodium dioctylsulfosuccinate (DOSS), lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil,


polyoxyethylene fatty acid glycerides, poloxamer, cremophore RH 40 and the like.
Suitable lubricant may be one or more of, magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl behenate and the like.
Suitable glidant may be one or more of, colloidal silicon dioxide, talc or cornstarch and the like.
Suitable disintegrant may be one or more of, starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
The pharmaceutical composition of the present invention can be prepared by dispersing diacerein along with pharmaceutically acceptable excipients in water and adding an adsorbent to diacerein slurry. Mixture thus obtained can be dried, blended with other pharmaceutically acceptable excipients and converted into suitable dosage form.
The pharmaceutical composition of the present invention can be prepared by dispersing diacerein along with other pharmaceutically acceptable excipients in water and spraying slurry thus obtained in on pharmaceutically acceptable adsorbent. Mixture thus obtained can be dried, blended with other pharmaceutically acceptable excipients and converted into suitable dosage form.
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 intended to be included within the scope of the present invention.


Example-I
Table-1 Composition of Diacerein Capsules (50mg)

S.No. Ingredients %w/w
Part-I
1 Diacerein 10-60
2 Microcrystalline cellulose 5-70
3 Sodium docusate 1-20
4 Sodium lauryl sulfate 1-20
5 Povidone 5-40
6 Water Part-ll .9-S-

7 8 Silicified microcrystallinecelluloseStarch 5-70 10-50
9 Croscarmellose sodium 1-15
10 Magnesium stearate 0.1-3
Procedure: Diacerein along with sodium docusate, sodium lauryl sulfate, povidone is dispersed in sufficient quantity of water to get slurry. Slurry is microfluidized through microfluidizer and the resultant microfluidized slurry is sprayed on microcrystalline cellulose using glatt. Dried mass is sieved and blended with silicified microcrystalline cellulose, starch, croscarmellose sodium, lubricated with magnesium stearate and lubricated blend is filled into hard gelatin capsules of suitable size.


Table 2: Comparative dissolution data of ART 50 vs Diacerein Tablets prepared as per example I

Time (min) % drug released (Art 50) % drug released (Example-I)
5 3 45
10 4 78
15 5 r 89
20 7 95
30 9 98
45 11 100
60 14 100
Table 2 provides the dissolution data for diacerein capsules (50mg) prepared as per the formula given in Table 1. For determination of drug release rate, USP Type 2 Apparatus (rpm 75) was used wherein 1000 ml of pH 5.7 phosphate buffer at 37 °C ± 0.5°C was used as medium.

Example-II
Table-3 Composition of Diacerein Capsules (50mg)

S.No. Ingredients %w/w
Part-I
1 Diacerein 10-60
2 Microcrystalline cellulose 5-70
3 Sodium docusate 1-20
4 Sodium lauryl sulfate 1-20
5 Povidone 5-40
6 Water .4A. _
Part-ll
7 8 Silicified microcrystallinecelluloseStarch 5-70 10-50
9 Croscarmellose sodium 1-15
10 Magnesium stearate 0.1-3
Procedure: Diacerein along with sodium docusate, sodium lauryl sulfate, povidone is dispersed in sufficient quantity of water to get slurry. Microcrystalline cellulose is added to the slurry under stirring. Wet mass thus obtained is tray dried overnight in an oven at 35-40°C. Dried mass is sieved and blended with silicified microcrystalline cellulose, starch, croscarmellose sodium, lubricated with magnesium stearate and lubricated blend is filled into hard gelatin capsules of suitable size.

WE CLAIM:
1) A pharmaceutical composition comprising rhein or diacerein, or salts thereof adsorbed on a pharmaceutical^ acceptable adsorbent, optionally with one or more pharmaceutically acceptable excipients.
2) The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable adsorbent comprises one or more of colloidal silicon dioxide, lactose, saccharides, calcium silicate, magnesium aluminum meta silicate, porous ceramics, polypropylene foams, cellulose, cellulose derivatives, polyols, starches, pre-gelatinized starches, starch derivatives, modified starches, dextrins, maltodextrins, polydextroses, dextroses, calcium carbonate, calcium phosphate, calcium sulfate.
3) A process of preparing a pharmaceutical composition comprising rhein or
diacerein, or salts thereof, which process comprises of:
a) providing slurry or solution of rhein or diacerein, optionally with one or more pharmaceutically acceptable excipients in suitable solvent,
b) adding pharmaceutically acceptable adsorbent to slurry or solution of step a) or vice versa,
c) recovering rhein or diacerein, or salts thereof adsorbed on a pharmaceutically acceptable adsorbent from slurry or solution of step b) thereof.
4) The process according to claim 3, wherein suitable solvent comprises one
or more of water, methanol, ethanol, butanol, isopropyl alcohol, acetone, chloroform, dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), methylene chloride and the like.
5) A pharmaceutical composition, which comprises of rhein or diacerein, or
salts thereof adsorbed on a pharmaceutically acceptable adsorbent,

optionally with one or more pharmaceutically acceptable excipients; and wherein the formulation exhibits a dissolution profile such that within 20 minutes more than 85% of diacerein is released, wherein the release rate is measured in Apparatus 2 (USP, Dissolution, paddle, 75 rpm) using 1000 ml of pH 5.7 phosphate buffer at 37 °C ± 0.5°C.
6) The pharmaceutical composition of claim 1, 3 and 5 comprises one or more of a tablet, capsule, powder, disc, caplet, granules, pellets, granules in capsule, minitablets, minitablets in capsule, pellets in capsule, sachet and other dosage forms suitable for oral administration.
7) The pharmaceutical composition of claim 1, 3 and 5 wherein pharmaceutical!;/ acceptable excipients comprises one or more of fillers, lubricants, disintegrants, and glidants.

ABSTRACT
The present invention provides a pharmaceutical composition comprising rhein or diacerein or salts thereof adsorbed on a pharmaceutically acceptable adsorbent optionally with one or more pharmaceutically acceptable excipients. The invention also relates to processes for the preparation of such compositions. The composition of the present invention may exhibit improved bioavailability along with reduced undesirable side effects.