FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
ORAL COMPOSITIONS OF DIACEREIN OR SALTS THEREOF WITH REDUCED SOFT STOOL EFFECTS
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D4-MIDC Area, Chikalthana,
Aurangabad - 431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a pharmaceutical composition comprising 20 to 45 mg of rhein or diacerein, or salts or esters or prodrugs thereof, characterized in that said composition exhibits at least 25% reduction in soft stool effect as compared to a 50 mg diacerein formulation marketed under the trade name Art 50®.
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 20 to 45 mg of rhein or diacerein, or salts or esters or prodrugs thereof, characterized in that said composition exhibits at least 25% reduction in soft stool effect as compared to a 50 mg diacerein formulation marketed under the trade name Art 50®
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.
OH O OH

FORMULA I

FORMULA II
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 with drug and coating membrane or granules of drug coated with 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 of diacerein, rhein and their salts along with liquid


support systems like oils, suspending agents, homogenizing agents and other excipients.
It is known that when 50 mg diacerein formulation currently marketed under the trade name Art 50® is given orally in fasted conditions, due to fast gastric emptying, most of the diacerein remains unabsorbed and unabsorbed diacerein gets converted to rhein before reaching colon, and at colonic site, rhein degrades to rhein-9-anthrone which causes significant soft stool effect. This soft stool effect is observed in about 50% of the patients after first few doses of Art 50®. In fact, about 30-40% soft stool effect is expected due to inherent pharmacokinetic property of diacerein, i.e diacerein undergoes enterohepatic circulation, wherein rhein gets conjugated in liver to form rhein-glucuronide, which on reaching colon gets converted to rhein-9-anthrone and hence causes soft stool effect.
On the other hand, when Art 50® is given in fed conditions, the gastric emptying is delayed in presence of food. The longer residence time in upper part of the gastrointestinal tract accompanied with gastric fluids results in increased absorption of diacerein. This increase in absorption is upto 25% leading to comparatively less amount of unabsorbed diacerein to reach colon and hence reduction in soft stool effect. However, this reduction in soft stool effect is not significant. It was also observed that when the diacerein formulation described in EP 904060 comprising co-micronized diacerein with sodium lauryl sulfate is given, it results in some reduction in soft stool effect but the reduction is not significant (i.e upto 18% only). This reduction in soft stool effect is not due to dose reduction but it is related to increased absorption of diacerein leading to lesser amount of unabsorbed diacerein reaching colon. The diacerein formulation described in EP 904060 also exhibits drastic variation in both fed and fasted conditions. So, prior art formulations are discriminatory with respect to both fast and fed conditions. Additionally, prior art formulations are also eclipsed with undesirable soft stool effect.


Although the prior art addresses the improvement of bioavailability of diacerein by co-micronization or using liquid support systems, there still exists a need to develop new formulations or compositions which are likely to achieve a higher rate and extent of absorption of diacerein leading to improved bioavailability and at the same time shows significant reduction in soft stool effect.
In spite of the attempts in the prior art, described above, the inventors are not aware of successful attempts to improve the absorption of diacerein and significant reduction in soft stool effect. As described below, the inventors have surprisingly found that composition of the invention results in a higher rate and extent of absorption from the gastrointestinal tract and significant reduction (at least 25%) in soft stool effect. The inventors also have surprisingly found that the formulations can be given with or without food without affecting the rate and extent of absorption.
Thus, the composition of the present invention, overcome all the commonly encountered problems exemplified in prior art. When the composition of the present invention is given orally, diacerein gets completely absorbed in upper part of intestine and there remains no unabsorbed diacerein reaching colon, resulting in a significant reduction in soft stools effect from about 60-70%. Furthermore, the composition of the invention is bioequivalent to 50 mg diacerein formulation currently marketed under the trade name Art 50® showing no variability whether administered in fed as compared to fasted state conditions.
The present inventors have further noticed that there is no need to co-micronize diacerein with any surfactant to get a formulation, which is bioequivalent to the commercially available diacerein 50 mg solid oral dosage form (Art 50®).
One of the aspects of the present invention provides an oral pharmaceutical composition comprising 20 to 45 mg of rhein or diacerein, or salts or esters or prodrugs thereof, characterized in that said composition exhibits at least 25%


reduction in soft stool effect as compared to a 50 mg diacerein formulation marketed under the trade name Art 50®.
Another aspect of the present invention provides an oral pharmaceutical composition comprising 20 to 45 mg of rhein or diacerein, or salts or esters or prodrugs thereof, wherein one or both of the rate and extent of absorption of the rhein or diacerein is equal or greater than that obtained by a 50 mg diacerein formulation marketed under the trade name Art 50®; characterized in that said composition exhibits at least 25% reduction in soft stool effect as compared to a 50 mg diacerein formulation marketed under the trade name Art 50®.
Another aspect of the present invention provides a pharmaceutical composition comprising 20 to 45 mg of rhein or diacerein, or salts or esters or prodrugs thereof, wherein one or both of the rate and the extent of absorption of the rhein or diacerein is equal to or greater than that obtained by a 50 mg diacerein formulation marketed under the trade name Art 50®
Another aspect of the present invention provides a pharmaceutical composition comprising 20 to 45 mg of rhein or diacerein, or salts or esters or prodrugs thereof, wherein the composition exhibits a maximum plasma concentration (Cmax) from about 3.15 to about 6.0mg/ml and/or a time to reach maximum plasma concentration (Tmax) from about 2.2 to about 5.Oh and/or an area under the concentration time curve (AUCo-t )from about 16.4 to about 40 mg.h/ml.
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, lubricants, disintegrants, and glidants.
Suitable filler may be selected from a group comprising one or more of, microcrystalline cellulose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar and the like.
Suitable lubricant may be selected from a group comprising 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.
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 provides the composition of batches of the present invention.
Table 1

S.No. Ingredients %w/w
Part-I
1 Diacerein 11.26
2 Povidone 5-40
3 Starch 10-50
4 Water q.s.
Part-ll
5 Silicified microcrystalline cellulose 5-70
6 Croscarmellose sodium 1-15
7 Magnesium stearate 0.1-3
Procedure: Diacerein and povidone was dispersed in sufficient quantity of water to get uniform dispersion. Diacerein dispersion was passed through mill one or more times to get a desired particle size. The microparticulate dispersion was spray dried in glatt. Dried mass was blended with silicified microcrystalline cellulose, starch, croscarmellose sodium, lubricated with magnesium stearate and lubricated blend was filled into hard gelatin capsules of suitable size.


Example 2
Table 2 provides the composition of batches of the present invention.
Table 2

S.No. Ingredients %w/w
Part-I
1 Diacerein 11.26
2 Povidone 5-40
3 Water q.s.
Part-ll
4 Lactose 10-50
5 Silicified microcrystalline cellulose 5-70
6 Croscarmellose sodium 1-15
7 Magnesium stearate 0.1-3
Procedure: Diacerein and povidone was dispersed in sufficient quantity of water to get uniform dispersion. Diacerein dispersion was passed through microfluidizer one or more times to get a desired particle size. The microparticulate dispersion was spray dried in glatt. Dried mass was blended with silicified microcrystalline cellulose, lactose, croscarmellose sodium, lubricated with magnesium stearate and lubricated blend was filled into hard gelatin capsules of suitable size.


WE CLAIM:
1) An oral pharmaceutical composition comprising 20 to 45 mg of rhein or diacerein, or salts or esters or prodrugs thereof, characterized in that said composition exhibits at least 25% reduction in soft stool effect as compared to a 50 mg diacerein formulation marketed under the trade name Art 50®.
2) An oral pharmaceutical composition comprising 20 to 45 mg of rhein or diacerein, or salts or esters or prodrugs thereof, wherein one or both of the rate and extent of absorption of the rhein or diacerein is equal or greater than that obtained by a 50 mg diacerein formulation marketed under the trade name Art 50®; characterized in that said composition exhibits at least 25% reduction in soft stool effect as compared to a 50 mg diacerein formulation marketed under the trade name Art 50®.

3) A pharmaceutical composition comprising 20 to 45 mg of rhein or diacerein, or salts or esters or prodrugs thereof, wherein one or both of the rate and the extent of absorption of the rhein or diacerein is equal to or greater than that obtained by a 50 mg diacerein formulation marketed under the trade name Art 50®
4) A pharmaceutical composition comprising 20 to 45 mg of rhein or diacerein, or salts or esters or prodrugs thereof, wherein the composition exhibits a maximum plasma concentration (Cmax) from about 3.15 to about 6.0mg/ml and/or a time to reach maximum plasma concentration (Tmax) from about 2.2 to about 5.0h and/or an area under the concentration time curve (AUCo-t)from about 16.4 to about 40 ug.h/ml.
5) The pharmaceutical composition as per any preceding claims, wherein the said composition is taken with or without food.


6) The pharmaceutical composition as per any preceding claims, wherein
diacerein is not comicronized with surfactant.
7) 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 or other
dosage forms suitable for oral administration.
8) The pharmaceutical composition as per any preceding claims further
comprises of pharmaceutically acceptable excipients.





ABSTRACT
The present invention provides a pharmaceutical composition comprising 20 to 45 mg of rhein or diacerein, or salts or esters or prodrugs thereof, characterized in that said composition exhibits at least 25% reduction in soft stool effect as compared to a 50 mg diacerein formulation marketed under the trade name Art