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: DIACEREIN COMPOSITIONS 2. APPLICANT (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 melt granulated pharmaceutical composition comprising rhein or diacerein, or salts thereof along with one or more surfactants 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 melt granulated pharmaceutical composition comprising rhein or diacerein, or salts thereof along with one or more surfactants 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 melt granulated with pharmaceutically acceptable excipient, the obtained melt significantly enhances the 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 100% of diacerein in 30 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 melt granulated pharmaceutical composition comprising rhein or diacerein, or salts thereof along with one or more surfactants optionally with one or more pharmaceutically acceptable excipients.
In another general aspect of the present invention there is provided a melt-granulated pharmaceutical composition that includes rhein or diacerein, or salts thereof; polyethylene glycol (PEG) or derivatives thereof along with one or more surfactants optionally with one or more pharmaceutically acceptable excipients.


Suitable polyethylene glycol (PEG) or derivatives thereof may include all PEGs that are liquid at room temperature or that melt upto about 70°C. Suitable polyethylene glycol (PEG) or derivatives thereof comprise one or more of PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG 4000, PEG 6000, PEG 8000, PEG 20000, polyglycolyzed glycerides, polyethylene glycol-polyoxyethylenes, polyethylene glycol polypropylenes, polyethylene glycol-polyoxypropylenes, and the like.
Suitable surfactants are those known to ordinary skilled in the art and may include but not limited to amphoteric, non-ionic, cationic or anionic surfactants. Suitable surfactants comprises 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.
In another aspect of the present invention there is provided a process of preparing melt granulated pharmaceutical composition of rhein or diacerein, or salts thereof, which process comprises of:
a) mixing rhein or diacerein, or salts thereof with one or more PEG or its derivatives in presence of one or more surfactants,
b) granulating said mixture of step a) by melting, mixing, congealing, optionally with one or more pharmaceutically acceptable excipients.
In yet another aspect of the present invention there is provided a melt granulated pharmaceutical composition comprising rhein or diacerein, or salts thereof along with one or more surfactants 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 granules, pellets, beads, spheroids, tablet, minitablet, microtablet, capsule, granules in capsule, pellets in capsule, minitablet in capsule or combinations thereof.
The pharmaceutical composition comprises of pharmaceutically acceptable excipients wherein excipients are selected from a group comprising one or more of fillers, binders, lubricants, disintegrants, glidants, and the like.
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 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 disintegrant may be one or more of, starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
Suitable glidant may be one or more of, colloidal silicon dioxide, talc or cornstarch and the like.
The pharmaceutical composition of the present invention may be prepared by melting the mixture of PEG or its derivative with one or more surfactant, mixing diacerein along with one or more surfactant with molten mass, followed by congealing. Congealed solid may be sized into granules. Granules may be mixed


with other pharmaceutically acceptable excipients and may be formulated 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 1
Table 1: Composition of Diacerein Capsules

No Ingredients % Composition
Part I
1 PEG 6000 40-60
2 Poloxamer 5-40
Part II
3 Diacerein 10-60
4 Sodium lauryl sulfate 1-20
Part III
5 Silicified microcrystalline cellulose 1-25
6 Lactose 5-40
7 Croscarmellose sodium 1-40
8 Magnesium stearate 1-15
Procedure: Poloxamer and PEG 6000 are melted and mixed at 60-70X along with diacerein, sodium lauryl sulfate to form a homogenous dispersion followed by congealing while mixing at room temperature. Congealed solid is sized through sieve to get granules of uniform size. Granules thus obtained are mixed with lactose, silicified microcrystalline cellulose, croscarmellose sodium and lubricated with magnesium stearate and filled into hard gelatin capsules.


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

Time (min) % drug released (Art 501) % drug released (Example-I)
5 3 38
10 4 74
15 5 88
20 7 97
30 9 100
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.


WE CLAIM:
1. A melt granulated pharmaceutical composition comprising rhein or diacerein, or salts thereof along with one or more surfactants optionally with one or more pharmaceutically acceptable excipients.
2. A melt-granulated pharmaceutical composition that includes rhein or diacerein, or salts thereof; polyethylene glycol (PEG) or derivatives thereof along with one or more surfactants optionally with one or more pharmaceutically acceptable excipients.
3. A process of preparing melt granulated pharmaceutical composition of
rhein or diacerein, or salts thereof, which process comprises of:
a) mixing rhein or diacerein, or salts thereof with one or more PEG or its derivatives in presence of one or more surfactants,
b) granulating said mixture of step a) by melting, mixing, congealing, optionally with one or more pharmaceutically acceptable excipients.

4. A melt granulated pharmaceutical composition comprising rhein or diacerein, or salts thereof along with one or more surfactants 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.
5. The pharmaceutical composition of claim 2 and 3, wherein polyethylene glycol (PEG) or its derivatives comprises one or more of PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG 4000, PEG 6000, PEG 8000, PEG 20000, polyglycolyzed glycerides, polyethylene glycol-


polyoxyethylenes, polyethylene glycol polypropylenes, polyethylene glycol-polyoxypropylenes, and the like.
6. The pharmaceutical composition of claim 5, wherein the PEG is PEG 6000.
7. The pharmaceutical composition of claim 1-4, wherein surfactant comprises one or more of amphoteric, non-ionic, cationic or anionic surfactants.
8. The pharmaceutical composition of claim 7, wherein surfactant comprises 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.
9. The pharmaceutical composition of claim 1-4 comprises one or more of granules, pellets, beads, spheroids, tablet, minitablet, microtablet, capsule, granules in capsule, pellets in capsule, minitablet in capsule or combinations thereof.
10. The pharmaceutical composition of claim 1-4, wherein pharmaceutically acceptable excipients comprises one or more of fillers, binders, lubricants, disintegrants, glidants, and the like.





11

ABSTRACT
The present invention provides a melt granulated pharmaceutical composition comprising rhein or diacerein, or salts thereof along with one or more surfactants 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.