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:
MODIFIED RELEASE PHARMACEUTICAL COMPOSITIONS OF RHEIN OR
DIACEREIN OR SALTS THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: D-4, M.I.D.C. Area, Chikalthana, Aurangabad - 431210,
(M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
There is provided a modified release pharmaceutical composition comprising rhein or diacerein, or salts or esters or prodrug thereof, wherein the modified release is achieved by functional coating or mixing said rhein or diacerein, or salts or esters or prodrug thereof with one or more pharmaceutically acceptable polymers, or combinations thereof.
The following specification particularly describes the invention and the manner in which it is to be performed.


4. Description
There is provided a modified release pharmaceutical composition comprising rhein or diacerein, or salts or esters or prodrug thereof, wherein the modified release is achieved by functional coating or mixing said rhein or diacerein, or salts or esters or prodrug thereof with one or more pharmaceutically acceptable polymers, or combinations thereof.
Chemically, rhein is 9, 10-dihydro-4, 5-dihydroxy-9, 10-dioxo-2-anthracene carboxylic acid having a structure of Formula I and diacerein is 4, 5-bis (acetyloxy) 9, 10-dihydro-4, 5-dihydroxy-9, 10-dioxo-2-anthracenecarboxylic acid having a structure of Formula II. 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.


Diacerein is practically insoluble in the solvents compatible with a pharmaceutical use, such as water, alcohols, acetone, dichloromethane and chloroform. Although 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 discloses a potassium salt of diacerein, which is water-soluble and can be used in the preparation of compositions for parenteral administration.
EP904060B1 discloses pharmaceutical compositions of rhein or diacerein, wherein rhein or diacerein is co-micronized with sodium lauryl sulfate.
European Patent Nos. EP263083B1; EP 264989B1 and EP 446753B1 disclose controlled release or delayed release compositions like multiplicity of pellets coated witn drug ana coating membrsne or granules or drug coated witn polymers or loading polymeric particles of water swellable cross-linked polymer with drug.
U.S. Patent Nos. 5,225,192 and 5,569,469 describe different poorly soluble medicaments supported on polymeric particles of water swellable cross-linked polymer with drug.
U.S. Patent No. 5,952,383 and European Patent No. EP 862423B1 provide pharmaceutical compositions in capsule dosage form of diacerein, rhein and their salts along with liquid support systems like oils, suspending agents, homogenizing agents and other excipients. This opens up in GIT to release drug.


It was noticed by the inventors while working on the diacerein compositions, when whole portion of rhein or diacerein is present in an immediate release form, rhein or diacerein gets immediately absorbed, resulting in rapid elimination phase and hence decreases area under the plasma time curve (AUC). Additionally, whole of diacerein is also exposed to harsh gastric conditions leading to degradation of diacerein. Inventors have overcome this challenge by providing a modified release pharmaceutical composition comprising rhein or diacerein. The modified release pharmaceutical composition results in prolonged absorption phase and increase in area under the plasma time curve (AUC) leading to increased bioavailability. Further, it prevents the exposure of entire diacerein to harsh gastric conditions, hence preventing its degradation. Additionally, the modified release pharmaceutical composition of the invention is bioequivalent to 50 mg of diacerein formulation commercially marketed under the trade name Art 50®.
In one aspect of the invention, there is provided a modified release pharmaceutical composition comprising rhein or diacerein, or salts or esters or prodrug tnereot, wnerein tne modited release is acnieved by tunctionai coating or mixing said rhein or diacerein, or salts or esters or prodrug thereof with one or more pharmaceutically acceptable polymers, or combinations thereof.
The term 'modified release' as used herein includes extended release or delayed release or combinations thereof with immediate release in any percentage weight ratios. The term extended release may be used interchangeably with prolonged release, controlled release, slow release or sustained release.
The modified release composition of the invention is administered in twice daily dosage regimen.
The modified release in the pharmaceutical composition may further be achieved by attachment of rhein or diacerein to ion exchange resins.
4

In another general aspect, there is provided a modified release pharmaceutical composition comprising rhein or diacerein, or salts or esters or prodrug thereof, wherein the composition exhibits a dissolution profile such that within 60 minutes more than 70% 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.
In yet another aspect of the invention, there is provided a process of preparing a modified release pharmaceutical composition comprising rhein or diacerein, or salts or esters or prodrug thereof, which process comprises of coating or mixing rhein or diacerein, or salts or esters or prodrug thereof with one or more pharmaceutically acceptable polymers, optionally with other pharmaceutical excipients and converting the mixture into suitable dosage form.
In another aspect, there is provided a modified release pharmaceutical composition comprising rhein or diacerein, or salts or esters or prodrug thereof, cnaracterized in tnat tne rate ana/or tne extent OT absorption OT tne rnein or diacerein is equal to or greater than that obtained by a 50 mg diacerein formulation marketed under the trade name Art 50®, wherein the modified release is achieved by coating or mixing rhein or diacerein, or salts or esters or prodrug thereof with a pharmaceutically acceptable polymer or combination thereof
"Bioequivalency" is established by a 90 % confidence interval (CI) of between 0.80 to 1.25 for both Cmax and AUC under USFDA regulatory guidelines, or a 90 % CI for AUC of between 0.80 to 1.25 and a 90 % CI for Cmax of between 0.70 to 1.43 under the European EMEA regulatory guidelines.
The bioequivalence studies were carried out between Art® 50 and the compositions of the invention. The study was monitored in terms of Cmax and


AUC achieved with the test product (compositions of the present invention) and reference product (Art® 50).
The term "confidence interval" as used herein refers to plain meaning known to ordinary skill in the art. Confidence interval refers to a statistical range with a specified probability that a given parameter lies within the range.
The composition of the invention exhibits pharmacokinetic profile characterized by Cmax of about 2.64 to 7.37ug/ml, Tmax of about 4 to 7.0h, AUC of about 15.20 to 35.13 ug.h/ml.
Pharmaceutical^ acceptable polymers may include one or more of rate controlling polymers, or enteric polymers.
Suitable rate controlling polymers may include one or more of polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, a fatty acid, a fatty acid ester, an alkyl alcohol, a wax, shellac, rosin, zein (prolamine from corn), a poly(meth)acrylate, microcrystalline cellulose or poiy(etnyiene oxide), poiyuronic acid sails, ceiiuiose einers, xaninan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan gum locust bean gum, alkali metal salts of alginic acid or pectic acid, sodium alginate, potassium alginate, ammonium alginate, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxyvinyl polymers and the like.
Suitable enteric polymers may include one or more of polymerized gelatin, shellac, methacrylic acid copolymer type C NF, cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propionate phthalate, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethylcellulose (CMEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and acrylic acid polymers and copolymers like methyl acrylate, ethyl acrylate, methyl
6

methacrylate and/or ethyl methacrylate with copolymers of acrylic and methacrylic acid esters (Eudragit NE, Eudragit RL, Eudragit RS) and the like.
The pharmaceutical composition may 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.
Rhein or diacerein or salts or esters or prodrug thereof may be present in the form of powder, granules, pellets, beads, microtablets, minitablets and crystals.
The pharmaceutical composition further comprises pharmaceutical^ acceptable excipients wherein excipients may include surfactants, fillers, lubricants, disintegrants, and glidants.
Suitable surfactants are those known to ordinary skill in the art and include but not limited to one or more of polyoxyethylene glycerol esters of fatty acids, such as i agais; polooxylatea castor on, einyiene glycol esters, sucn as glycol stearate and distearate; propylene glycol esters, such as propylene glycol myristate; glyceryl esters of fatty acids, such as glyceryl stearates and monostearates; sorbitan esters, such as spans and tweens; polyglyceryl esters, such as polyglyceryl 4-oleate; fatty alcohol ethoxylates, such as Brij type emulsifiers; ethoxylated propoxylated block copolymers, such as poloxamers; polyethylene glycol esters of fatty acids, such as Labrafils, Labrafacs, and Labrasols; cremophores; glycerol monocaprylate/caprate, such as Campmul CM 10; Gelucire, Capryol, Captex, Acconon, transcutol, triacetin, TPGS (d-alpha tocopheryl polyethylene glycol succinate) and the like.
Suitable filler may include one or more of, microcrystalline cellulose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar and the like.


Suitable lubricant may include 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 include one or more of colloidal silicon dioxide, talc or cornstarch and the like.
Suitable disintegrant may include one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
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 the invention

Ingredients % w/w
Part-I
Diacerein 5-13
Lactose 10-50
Povidone 5-40
Docusate sodium 1-20
TPGS 5-30
Starch 10-50
Prosolv 5-70
Part-ll
Dried Granules from Part I
Eudragit 7.0
ran HI

Extra granular
Prosolv 5-70
Ac-Di-Sol 1-15
Magnesium Stearate 0.1-3
Procedure: Docusate sodium was dissolved in purified water under stirring. Povidone was added under stirring to above solution of sodium docusate to form clear solution and further diacerein was added to form uniform dispersion. Diacerein dispersion was passed through Dyno mill/Pressure homogenizer/ microfluidizer to get a suitable particle size. Clear solution of TPGS was added to above microparticulate/ nanoparticulate dispersion of diacerein. Diacerein dispersion was sprayed on starch and prosolv by top spray method on glatt. Dried granules thus obtained were coated with Eudragit and further dried and
9

mixed with prosolv, croscarmellose sodium and lubricated with magnesium stearate. Lubricated blend was filled in suitable size capsules.
Table 2: Dissolution data of composition prepared as per example I

Time (min) % drug released (Example-l)
5 26
10 44
15 75
30 97
45 98
60 98
Table 2 provides the dissolution data for diacerein capsules 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-ll
Table 3: Composition of the invention

Ingredients %w/w
Part-I
Diacerein 5-13
Povidone 5-40
Docusate sodium 1-20
TPGS 5-30
Starch 10-50
Prosolv 5-70
Part-ll
Dried Granules from Part 1
Eudragit 4.0
Part III
Extra granular
Prosolv 5-70

Ac-Di-Sol 1-15
Magnesium stearate 0.1-3
Procedure: Docusate sodium was dissolved in purified water under stirring. PVP was added under stirring to above solution of sodium docusate to form clear solution and further diacerein was added to form uniform dispersion. Diacerein dispersion was passed through Dyno mill/Pressure homogenizer/microfluidizer to get a suitable particle size. Clear solution of TPGS was added to above microparticulate/nanoparticulate dispersion of diacerein. Diacerein dispersion was sprayed on starch and prosolv by top spray method on glatt. Dried granules thus obtained were coated with Eudragit and further dried and mixed with


prosolv, croscarmellose sodium and lubricated with magnesium stearate. Lubricated blend was filled in suitable size capsules.
Table 4: Dissolution data of composition prepared as per example II

Time (min) % drug released (Example-II)
5 32
10 56
15 75
30 85
45 90
60 94
Table 4 provides the dissolution data for diacerein capsules prepared as per the formula given in Table 3. 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 -III
Table 5: Composition of the invention

Ingredients %w/w
Part-I
Diacerein 5-13
Povidone 5-40
Docusate sodium 1-20
TPGS 5-30
Sodium lauryl sulfate 1-20
Starch 10-50
Prosolv 5-70
Part-ll
Dried Granules from Part 1
Eudragit 4.0
Part III

Prosolv SMCC 90 5-70
Ac-Di-Sol 1-15
Magnesium Stearate 0.1-3
Procedure: Docusate sodium was dissolved in purified water under stirring. PVP was added under stirring to above solution of docusate sodium to form clear solution and further diacerein was added to form uniform dispersion. Diacerein dispersion was passed through Dyno mill/Pressure homogenizer/microfluidizer to get a suitable particle size. Clear solution of TPGS & sodium lauryl sulfate was added to above microparticulate/nanoparticulate dispersion of diacerein. Diacerein dispersion was sprayed on starch and prosolv by top spray method on glatt. Dried granules thus obtained were coated with Eudragit and further dried


and mixed with prosolv, croscarmellose sodium and lubricated with magnesium stearate. Lubricated blend was filled in suitable size capsules.
Table 6: Bioequivalence data of composition of invention (example I, II and III) against Art 50® with respect to pharmacokinetic parameters.

S.N. Pharmacokinetic parameters. Art 50® Composition of the invention (Ex. 1, II and III)
1 Cmax (µ g/ml) 3.058 5.121
2 Tmax (h) 5.39 5.70
3 AUCo-t (ug.h/ml) 22.688 24.927
4 AUCo-inf (ug.h/ml) 22.816 25.569
Table 7: Bioequivalence data with respect to test (composition of the example I, II and III) to reference (Art 50®) ratios (T/R ratios) at 90 % confidence interval.

S.N. Pharmacokinetic parameters Ratio 90 % C. I. %CV

Lower Upper

1 Cmax 120.17 107.61 134.2 13.33
2 AUCo-t 94.5 91.56 97.3 3.80
3 AUCo-inf 94.55 91.56 97.53 3.86


Example -IV
Table 8: Composition of the invention

Ingredients %w/w
Part-I
Diacerein 5-13
Lactose 10-50
Povidone 5-40
Docusate sodium 1-20
TPGS 5-30
Starch 10-50
Prosolv 5-70
Part-A (Immediate release portion)
Dried Granules (Portion containing 65-85% w/w of total diacerein of part 1)
Part-B (Controlled release portion)

of total diacerein of part 1)
Hydroxypropyl methyl cellulose 3.75
Prosoiv 5-70
Magnesium Stearate 0.1-3
Extra granular
Part A granules
Part B granules
Prosolv 5-70
Ac-Di-Sol 1-15
Magnesium Stearate 0.1-3


Procedure: Docusate sodium was dissolved in purified water under stirring. PVP was added under stirring to above solution of sodium docusate to form clear solution and further diacerein was added to form uniform dispersion. Diacerein dispersion was passed through Dyno mill/Pressure homogenizer/microfluidizerto get a suitable particle size. Clear solution of TPGS was added to above microparticulate/nanoparticulate dispersion of diacerein. Diacerein dispersion was sprayed on starch and prosolv by top spray method on glatt. Dried granules thus obtained were divided into two parts. First part (A) kept as such as an immediate release portion. To second part, hydroxypropyl methylcellulose was added along with prosolv, mixed and lubricated with magnesium stearate. Lubricated granules were compacted through roll compactor and the compacts were granulated through multimill to get granules of uniform size (Part B). Part B granules were mixed with part A granules along with prosolv, ac-di-sol and magnesium stearate and final blend was filled in suitable size capsules.
Table 9 Dissolution data of composition prepared as per example IV.

(min) (Example-IV)
10 45
20 76
30 99
45 100
60 100
90 100
120 100
Table 9 provides the dissolution data for diacerein capsules prepared as per the formula given in Table 8. 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 -V
TablelO: Composition of the invention

Ingredients %w/w
Part-I
Diacerein 5-13
Lactose 10-50
Povidone 5-40
Docusate sodium 1-20
TPGS 5-30
Starch 10-50
Prosolv 5-70
Part-A (Immediate release portion)
Dried Granules (Portion containing 65-85% w/w of total diacerein of part 1)
Part-B (Controlled release Dortion)

Dried Granules (Portion containing 15%-35% w/w of total diacerein of part I)
Hydroxypropyl methyl cellulose 7.5
Prosolv 5-70
Magnesium Stearate 0.1-3
Extra granular
Part A granules
Part B granules
Prosolv 5-70
Ac-Di-Sol 1-15
Magnesium Stearate 0.1-3


Procedure: Docusate sodium was dissolved in purified water under stirring. PVP was added under stirring to above sofution of sodium docusate to form dear solution and further diacerein was added to form uniform dispersion. Diacerein dispersion was passed through Dyno mill/Pressure homogenizer/microfluidizer to get a suitable particle size. Clear solution of TPGS was added to above microparticulate/nanoparticulate dispersion of diacerein. Diacerein dispersion was sprayed on starch and prosolv by top spray method on glatt. Dried granules thus obtained were divided into two parts. First part was (A) kept as such as an immediate release portion. To second part, hydroxypropyl methylcellulose was added along with prosolv, mixed and lubricated with magnesium stearate. Lubricated granules were compacted through roll compactor and the compacts were granulated through multimill to get granules of uniform size (Part B). Part B granules were mixed with part A granules along with prosolv, ac-di-sol and magnesium stearate and final blend was filled in suitable size capsules.
Table 11: Dissolution data of composition prepared as per example V

(min) (Example-V)
10 11
20 24
30 36
45 51
60 72
90 92
120 95
Table 11 provides the dissolution data for diacerein capsules prepared as per the formula given in Table 10. 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 -VI
Table-12: Composition of the invention

Ingredients %w/w
Part-I
Diacerein 5-13
Lactose 10-50
Povidone 5-40
Docusate sodium 1-20
TPGS 5-30
Starch 10-50
Prosolv 5-70
Part-A (Immediate release portion)
Dried Granules (Portion containing 65-85% w/w (of total diacerein of part I)
Part-B (Controlled release portion)
Dried Granules (Portion containing 15%-35% w/w of total diacerein of part I)
Hydroxypropyl methy cellulose 6.25
Prosolv 5-70
Magnesium Stearate 0.1-3
Part-IV (Extra granular)
Part II granules
Part III granules
Prosolv 5-70
Ac-Di-Sol 1-15
Magnesium Stearate 0.1-3


Procedure: Docusate sodium was dissolved in purified water under stirring. PVP was added under stirring to above solution of sodium docusate to form clear solution and further diacerein was added to form uniform dispersion. Diacerein dispersion was passed through Dyno mill/Pressure homogenizer/microfluidizer one or more times to get a suitable particle size. Clear solution of TPGS was added to above microparticulate/nanoparticulate dispersion of diacerein. Diacerein dispersion was sprayed on starch and prosolv by top spray method on glatt. Dried granules thus obtained were divided into two parts/First part (A) was kept as such as an immediate release portion. To second part, hydroxypropyl methylcellulose was added along with prosolv, mixed and lubricated with magnesium stearate. Lubricated granules were compacted through roll compactor and the compacts were granulated through multimill to get granules of uniform size (Part B). Part B granules were mixed with part A granules along with prosolv, ac-di-sol and magnesium stearate and final blend was filled in suitable size capsules.
TABLE 13 Dissolution data OT composition preparea as per example vi.

Time (min) % drug released (Example-VI)
10 24
20 43
30 62
45 80
60 90
90 100
120 100
Table 13 provides the dissolution data for diacerein capsules prepared as per the formula given in Table 12. 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.
Table 14: Bioequivalence data of composition of the invention (examples IV, V and VI) against Art 50® with respect to pharmacokinetic parameters.

S.N. Pharmacokinetic parameters. Art 50® Composition of the examples IV, V and VI.
1 Cmax (µ g/ml)) 3.058 4.773
2 Tmax (h) 5.39 4.44
3 AUCo-t (µ g.h/ml) 22.688 21.651
4 AUCo-inf (µ g.h/ml) 22.816 22.192
Table 15: Bioequivalence data with respect to test (composition of the examples IV, V and VI) to reference (Art 50®) ratios (T/R ratios) at 90 % confidence interval.

S.N. Pharmacokinetic parameters Ratio 90 % C. I. %CV

Lower ! Upper

1 Cmax 122.63 110.76 135.78 11.15
2 AUCo-t 94.89 89.71 100.36 6.13
3 AUCo-inf 94.73 89.34 100.45 6.41


WE CLAIM:
1. A modified release pharmaceutical composition comprising rhein or diacerein, or salts or esters or prodrug thereof, wherein the modified release is achieved by functional coating or mixing said rhein or diacerein, or salts or esters or prodrug thereof with one or more pharmaceutically acceptable polymers, or combinations thereof.
2. The composition as claimed in 1, wherein the said composition exhibits a dissolution profile such that within 60 minutes more than 70% 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.
3. The composition as claimed in 1, wherein the composition comprises one or more of tablet, capsule, powder, disc, caplet, granules, pellets, granules in capsule, minitablets, minitablets in capsule, pellets in capsule and sachet.
4. The composition as claimed in 1, wherein the modified release comprises extended release, delayed release or combinations of both with immediate release.
5. The composition as claimed in 1, wherein the pharmaceutically acceptable polymers comprises one or more of rate controlling polymers and enteric polymers.
6. The composition as claimed in 5, wherein the rate controlling polymers comprises one or more of polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, a fatty acid, a fatty acid ester, an alkyl alcohol, a wax, shellac, rosin, zein (prolamine from corn), a poly (meth) acrylate, microcrystalline cellulose or poly (ethylene oxide), polyuronic acid salts, cellulose ethers, xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan gum locust bean gum, alkali metal salts of alginic acid or pectic acid, sodium alginate,


potassium alginate, ammonium alginate, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and carboxyvinyl polymers.
7. The composition as claimed in 5, wherein the enteric polymers comprises one or more of polymerized gelatin, shellac, methacrylic acid copolymer type C NF, cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propionate phthalate, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethylcellulose (CMEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and acrylic acid polymers and copolymers like methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate with copolymers of acrylic and methacrylic acid esters.
8. The composition as claimed in 1, wherein the said composition exhibits rate and/or extent of absorption of rhein or diacerein or salts or esters or prodrugs thereof equal to or greater than that obtained by 50 mg diacerein
formulation commercially marketed under the trade name Art 50®
9. The composition as claimed in 1 further comprises one or more of pharmaceutically acceptable excipients.
10. A process of preparing a modified release pharmaceutical composition comprising rhein or diacerein, or salts or esters or prodrug thereof, which process comprises of coating or mixing rhein or diacerein, or salts or esters or prodrug thereof with one or more pharmaceutically acceptable polymers, optionally with other pharmaceutical excipients and converting the mixture into suitable dosage form.
Dated this 20™ day of May, 2008 For Wockhardt Limited
(Mandar Kodgule) Authorized Signatory