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 COMPOSITIONS OF DIACEREIN OR SALTS THEREOF FOR TREATMENT OF OSTEOARTHRITIS
2. APPLICAT(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 along with water-soluble cyclodextrins or derivatives thereof 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 salts thereof along with water-soluble cyclodextrins or its derivatives thereof 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.








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 the diacerein formulation have surprisingly found when diacerein is present along with water-soluble cyclodextrins, either as physical mixture or in form of any sort of complex or any other physical or chemical association, it results in significant increase in solubility of diacerein and 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 90-100% diacerein in 60 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 along with water-soluble cyclodextrins or its derivatives thereof optionally with one or more pharmaceutically acceptable excipients.
In another aspect of the present invention there is provided a pharmaceutical composition comprising rhein or diacerein, or salts thereof along with water-soluble cyclodextrins or its derivatives thereof optionally with one or more


pharmaceutically acceptable excipients, wherein rhein or diacerein is present in admixture with water soluble cyclodextrins or its derivatives thereof.
In yet another aspect of the present invention there is provided a pharmaceutical composition comprising rhein or diacerein, or salts thereof along with water-soluble cyclodextrins or derivatives thereof optionally with one or more pharmaceutical^ acceptable excipients, wherein rhein or diacerein is present in the form of complex with water-soluble cyclodextrins or its derivatives thereof.
In yet another aspect of the present invention there is provided a process of preparing pharmaceutical composition comprising rhein or diacerein, or salts thereof, which process comprises of: a) triturating rhein or diacerein with suitable water soluble cyclodextrin or its derivative thereof optionally with one or more suitable solvents, b) mixing triturate of step a) optionally with one or more pharmaceutically acceptable excipients.
In yet another aspect of the present invention there is provided a pharmaceutical composition, which comprises of rhein or diacerein, or salts thereof along with water-soluble cyclodextrins or its derivatives thereof optionally with one or more pharmaceutically acceptable excipients; and wherein the formulation exhibits a dissolution profile such that within 30 minutes more than 75% 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 Tampon 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.
Suitable water soluble cyclodextrin derivatives may be one or more of, P-cyclodextrin, a-cyclodextrin, y-cyclodextrins, hydroxypropyl- a-cyclodextrin,


hydroxypropyl-P-cyclodextrin, dimethyl - b- cylcodextrin, 2-hydroxyethyl p -cyclodextrin, trimethyl - p -cyclodextrin, sulfonated cyclodextrins and the like. Suitable solvents are those known to the ordinary skill in the art and include but not limited to one or more of water, ethanol, methanol, isopropyl alcohol, butanol, and the like.
The complex of diacerein and cyclodextrin can be prepared by various processes including anti-solvent technique, solvent evaporation, kneading, spray drying, colloidal milling, high speed mixing, trituration or simple mixing. The diacerein can be present in an amount relative to the cyclodextrin, such that a molar ratio between the diacerein and the cyclodextrin is from about 1:1 to 1:10
The pharmaceutical composition comprises of pharmaceutically acceptable excipients wherein excipients may include fillers, lubricants, disintegrants, and glidants.
Suitable filler may be one or more of, microcrystalline cellulose, silicified microcrystalline cellulose, sorbitol, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar 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 triturating diacerein with suitable cyclodextrin with one or more suitable solvents, drying the diacerein-cyclodextrin triturate, mixing the dried triturate optionally with other pharmaceutically acceptable excipients and converting the mixture into suitable dosage form.
The pharmaceutical composition of the present invention can be prepared by triturating diacerein with suitable cyclodextrin, mixing the triturate optionally with other pharmaceutically acceptable excipients and converting the mixture 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 Qty/Caps (%w/w)
1 Diacerein 10-90
2 Hydroxy propyl beta cylodextrin 20-65
3 Purified water q.s.
4 Sorbitol 0.5-20
5 Crospovidone 5-40
6 Silicified microcrystalline cellulose 15-50
7 Sodium stearyl fumarate 0.5-2
Procedure: Diacerein and hydroxypropyl beta cyclodextrin are mixed and triturated with water for few minutes. Diacerein hydroxypropyl cyclodextrin complex thus formed is dried, sized to suitable size and mixed with sorbitol, crospovidone, silicified microcrystalline cellulose and sodium stearyl fumarate. The final mixture is filled in to hard gelatin capsules of suitable size.


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

Time (min) % drug released (Art 50) % drug released (Example-I)
5 3 39
10 15 4 69
5 81
20 7 87
30 9 91
45 11 93
60 14 96
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 Tampon phosphate buffer at 37 °C ± 0.5°C was used as medium.


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

S.No. Ingredients Qty/Caps (%w/w)
1 Diacerein 10-90
2 Hydroxy propyl beta cylodextrin 20-65
34 Purified water:isopropylalcoholSorbitol q.s. 0.5-20
5 6~7 Crospovidone 5-40
Silicified microcrystalline cellulose 15-50
Sodium stearyl fumarate 0.5-2
Procedure: Diacerein and hydroxypropyl beta cyclodextrin are mixed and triturated with water/isopropyl mixture for few minutes. Diacerein hydroxypropyl cyclodextrin complex thus formed is dried, sized to suitable size and mixed with sorbitol, crospovidone, silicified microcrystalline cellulose and sodium stearyl fumarate. The final mixture is filled in to hard gelatin capsules of suitable size.


Table 4: Comparative dissolution data of ART 50 vs Diacerein capsules prepared as per example II

Time (min) % drug released (Art 50) % drug released (Example-ll)
5 3 33
10 4 62
15 5 73
20 7 79
30 9 83
45 60 11 90
14 94
Table 4 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 Tampon phosphate buffer at 37 °C ± 0.5°C was used as medium.


Example-Ill
Table-5 Composition of Diacerein Capsules (50mg)
S.No. Ingredients Qty/Caps (%w/w)
1 Diacerein 10-90
2 Hydroxy propyl beta cyclodextrin 20-65
3 Sorbitol 0.5-20
4 Crospovidone 5-40
5 Silicified microcrystalline cellulose 15-50
6 'Sodium stearyl fumarate 0.5-2

Procedure: Diacerein and hydroxypropyl beta cyclodextrin are mixed and triturated for few minutes. Diacerein hydroxypropyl cyclodextrin complex thus formed is mixed with sorbitol, crospovidone, silicified microcrystalline cellulose and sodium stearyl fumarate. The final mixture is filled in to hard gelatin capsules of suitable size.

Example -IV
Table-6 Composition of Diacerein Tablets (50mg)

S.No.1 Ingredients Qty/Tabs (%w/w)
Diacerein 10-90
2 Hydroxy propyl beta cylodextrin 20-65
3 Purified water q.s.
4 Sorbitol 0.5-20
5 Crospovidone 5-40
6 Silicified microcrystalline cellulose 15-50
7 Sodium stearyl fumarate 0.5-2
Procedure: Diacerein and hydroxypropyl beta cyclodextrin are mixed and triturated with water for few minutes. Diacerein hydroxypropyl cyclodextrin complex thus formed is dried, sized to suitable size and mixed with sorbitol, crospovidone, silicified microcrystalline cellulose and sodium stearyl fumarate. The final mixture is compressed into tablets using suitable tooling.


Table 7: Comparative dissolution data of ART 50 vs Diacerein capsules prepared as per example IV

Time (min) % drug released (Art 50) % drug released (Example-IV)
5 3 62
10 4 78
15 5 85
20 7 88
30 45 9 91
11 94
60 14 98
Table 7 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 Tampon phosphate buffer at 37 °C ± 0.5°C was used as medium.


WE CLAIM:
1) A pharmaceutical composition comprising rhein or diacerein, or salts thereof along with water-soluble cyclodextrins or its derivatives thereof optionally with one or more pharmaceutically acceptable excipients.
2) A pharmaceutical composition comprising rhein or diacerein, or salts thereof along with water-soluble cyclodextrins or its derivatives thereof optionally with one or more pharmaceutically acceptable excipients, wherein rhein or diacerein is present in admixture with water-soluble cyclodextrins or its derivatives thereof.
3) A pharmaceutical composition comprising rhein or diacerein, or salts thereof along with water-soluble cyclodextrins or derivatives thereof optionally with one or more pharmaceutically acceptable excipients, wherein rhein or diacerein is present in the form of complex with water-soluble cyclodextrins or its derivatives thereof.
4) A process of preparing pharmaceutical composition comprising rhein or diacerein, or salts thereof, which process comprises of: a) triturating rhein or diacerein with suitable water soluble cyclodextrin or its derivative thereof optionally with one or more suitable solvents, b) mixing triturate of step a) optionally with one or more pharmaceutically acceptable excipients.
5) A pharmaceutical composition, which comprises of rhein or diacerein, or salts thereof along with water-soluble cyclodextrins or its derivatives thereof optionally with one or more pharmaceutically acceptable excipients; and wherein the formulation exhibits a dissolution profile such that within 30 minutes more than 75% 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 Tampon phosphate buffer at 37 °C ± 0.5°C.


6) The pharmaceutical composition as per any preceding claims comprises one or more 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.
7) The pharmaceutical composition as per any preceding claims, wherein the cyclodextrins comprises one or more of, b-cyclodextrin, a-cyclodextrin, y-cyclodextrins, hydroxypropyl- a-cyclodextrin, hydroxypropyl-b-cyclodextrin, dimethyl - b- cyclodextrin, 2-hydroxyethyl (b -cyclodextrin, trimethyl - b -cyclodextrin, sulfonated cyclodextrins and the like.
8) The pharmaceutical composition as per any preceding claims, wherein diacerein or salts thereof and water soluble cyclodextrin are present in a molar ratio of about 1:1 to 1:10.
9) The process of claim 4, wherein suitable solvents comprise one or more of water, ethanol, methanol, isopropyl alcohol, butanol, and the like.
10)The pharmaceutical composition of claim 1-5, wherein pharmaceutically 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 along with water-soluble cyclodextrins or derivatives thereof 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.