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:
LOW DOSE WET GRANULATED DIACEREIN COMPOSITIONS
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
The present invention provides an immediate release wet granulated pharmaceutical composition comprising from about 20 mg to about 45 mg of rhein or diacerein, or salts or esters or prodrugs thereof, wherein the composition exhibits no significant difference in rate and/or an extent of absorption of the rhein or diacerein or salts or esters or prodrugs thereof, as compared to a 50 mg diacerein formulation currently marketed under the trade name'Art 50®. The compositions exhibit no variability in the rate and the extent of absorption when given under fed or fasted state conditions.
The following specification particularly describes the invention and the manner in which it is to be performed.


4. Description
The present invention provides an immediate release wet granulated pharmaceutical composition comprising from about 20 mg to about 45 mg of rhein or diacerein, or salts or esters or prodrugs thereof, wherein the composition exhibits no significant difference in rate and/or an extent of absorption of the rhein or diacerein or salts or esters or prodrugs thereof, as compared to a 50 mg diacerein formulation currently marketed under the trade name Art 50®. The compositions exhibit no variability in the rate and the extent of absorption when given under fed or fasted state conditions. The compositions also result in a significant reduction in soft stool effect. The invention also relates to processes for the preparation of such compositions.
FORMULA I
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Chemically, rhein is 9,10-dihydro-4, 5-dihydroxy-9, 10-dioxo-2-anthracene carboxylic acid having a structure of Formula J and diacerein is 4,5-bis (acetyloxy) 9,10-dihydro-4, 5-dihydroxy-9, 10-dio*o-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.



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 swellabie cross-linked polymer with drug.
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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
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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-rnicronization 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.
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The invention is directed to wet granulated ora\ pharmaceutical composition comprising from about 20 mg to about 45 mg of rhein or diacerein, or salts or esters or prodrugs thereof, which is bioequivalent to commercially available diacerein 50 mg solid oral dosage form (Art 50®). The administration of the composition to a human subject in a fasted state is bioequivalent to administration of the composition to a subject in a fed state, in particular as defined by Cmax, Tmax and AUC guidelines given by US FDA and EMEA. The composition of the present invention is bioequivalent to commercially available diacerein 50 mg solid oral dosage form (Art 50®), and the compositions can be administered with or without food.
The present inventors while working on the diacerein formulations have surprisingly found that when rhein or diacerein, or salts or esters or prodrugs thereof is granulated with a suitable solvent or mixture of solvents; it leads to significant increase in solubility of diacerein leading to increased percent drug release of diacerein as compared to Art 50® Art 50® (prepared by dry compaction) releases about 14% of diacerein in 60 minutes, whereas pharmaceutical composition of the present invention (prepared by wet granulation) releases more than 65% of diacerein in 60 minutes (Table 2, 4). This leads to increased bioavailability. The increased bioavailability further leads to drastic reduction in side effects i.e. soft stools.
One of the aspects of the present invention provides an immediate release wet granulated pharmaceutical composition comprising from about 20 mg to about 45 mg of rhein or diacerein, or salts or esters or prodrugs thereof, wherein the composition exhibits no significant difference in rate and/or an extent of absorption of the rhein or diacerein or salts or esters or prodrugs thereof, as compared to a 50 mg diacerein formulation currently marketed under the trade name Art 50®.
Another aspect of the present invention provides an immediate release wet granulated pharmaceutical composition comprising from about 20 mg to about 45
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mg of rhein or diacerein, or salts or esters or prodrugs thereof, wherein the ' composition exhibits no significant difference" in rate and/or an extent of absorption of the rhein or diacerein or salts or esters or prodrugs thereof, as compared to a 50 mg diacerein formulation currently marketed under the trade name Art 50® and the composition can be taken with or without food.
In yet another aspect of the present invention there is provided a process of preparing immediate release pharmaceutical composition comprising from about 20 mg to about 45 mg of rhein or diacerein, or salts or esters or prodrugs thereof, wherein the process comprises of
a) mixing rhein or diacerein, or salts thereof with other pharmaceutically acceptable excipients to form a premix;
b) granulating said premix of step a) with suitable solvent;
c) converting the granules of step b) into suitable dosage form
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, isopropyl alcohol, acetone, methylene chloride and the like.
In yet another aspect of the present invention there is provided an immediate release wet granulated pharmaceutical composition comprising from about 20mg to about 45 mg of rhein or diacerein or salts or esters or prodrugs thereof and wherein the formulation exhibits a dissolution profile such that within 60 minutes more than 60% 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.
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"Bioequivalency" is established by a 90% Confidence Interval (CI) of between 0.80 and 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 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 term "covariance" as used herein refers to plain meaning known to ordinary skill in the art. It is a statistical measure of the variance of two random variables that are observed or measured in the same mean time period. This measure is equal to the product of the deviations of corresponding values of the two variables from their respective means.
Bioequivalence studies were carried out between Art 50 and composition of the invention both in fed state and fasted state. The study was monitored in terms of Cmax, AUC, Tmax achieved with the test product and reference product (Art 50). Table 2 gives bioequivalence data of Art 50 and test product.
The composition of the invention exhibits pharmacokinetic profile characterized by Cmax of about 3.15 to 6.0ug/ml, Tmax of about 2.2 to 5.0h, AUC0-t of about 16.4 to 40 ug.h/ml, AUCΦof about 16.7 to 40 ug.h/ml .
At 90% confidence interval; area under the concentration time curve (AUC0-t and /or AUCΦ) and maximum plasma concentration (Cmax) values of composition of the invention lies between 0.70 and 1.40 as compared to that obtained by a 50 mg diacerein formulation marketed under the trade name Art 50®.
Advantages of the compositions of the invention, include, but are not limited to: (1) smaller solid dosage form size; (2) smaller doses of drug required to obtain the same pharmacological effect; (3) increased bioavailability; (4) substantially similar pharmacokinetic profiles of the rhein or diacerein, compositions when
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administered in the fed versus the fasted state; (5) bioequivaiency of the diacerein compositions when administered in the fed versus the fasted state.
The pharmaceutical composition of the present invention can be prepared by mixing diacerein with other excipients, granulating the pre-mix with suitable solvent, drying the granules, lubricating the granules and converting the final mixture into suitable dosage form.
The pharmaceutical composition comprises of pharmaceutically acceptable excipients wherein excipients may include binders, fillers, lubricants, disintegrants, and glidants.
Suitable binder may be selected from a group comprising one or more of, povidone, starch, stearic acid, gums, celluloses and the like.
Suitable filler may be selected from a group comprising one or more of, microcrystalline cellulose, 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 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, crosspovidone, 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
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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 (44mg).

S. No Ingredients Quantity (mg per tablet)
Intragranular
1 Diacerein 44.00
2 Povidone 11.50
3 Lactose 220.30
4 Croscarmellose sodium 11.50
5 Colloidal silicon dioxide 5.75
6 Hydroxy propyl methyl cellulose 20.00
Extragranular
7 Colloidal silicon dioxide 5.75
8 Magnesium stearate 1.20
Procedure: Diacerein is mixed with lactose, croscarmellose sodium, colloidal silicon dioxide, hydroxy propyl methyicellulose and granulated with aqueous solution of povidone. Granules are dried, mixed with colloidal silicon dioxide and lubricated with magnesium stearate and filled into hard gelatin capsules of suitable size.
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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)
10 4 17
20 7 28
30 9 39
45 11 54
60 14 68
90 16 94
120 19 100
Table 2 provides the dissolution data for diacerein capsules (44mg) 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.
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EXAMPLE 2
Table 3: Composition of diacerein Capsules (45mg),

S. No Ingredients Quantity (mg per tablet)
Intragranular
1 Diacerein 45.00
2 Povidone 11.50
3 Lactose 219.30
4 Croscarmellose sodium 11.50
5 Colloidal silicon dioxide 5.75
6 Hydroxy propyl methyl cellulose 20.00
Extragranular
7 Colloidal silicon dioxide 5.75
8 Magnesium stearate 1.20
Procedure: Diacerein is mixed with lactose, croscarmellose sodium, colloidal silicon dioxide, hydroxy propyl methylcellulose and granulated with aqueous solution of povidone. Granules are dried, mixed with colloidal silicon dioxide and fubricated with magnesium stearate and filled into hard gelatin capsules of suitable size.
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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-I)
10 4 18
20 7 26
30 9 37
45 11 57
60 14 72
90 16 96
120 19 100
Table 4 provides the dissolution data for diacerein capsules (45mg) 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.
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Table-5: Bioequivalence data of the composition of the invention against Art 50 with respect to pharmacokinetic parameters

S.No Pharmacokinetic parameters Art 50 Composition of the invention
1 Cmax(μg/ml) 3.058 3.48
2 Tmax (h) 5.39 4.80
3 AUCo-t (μgh/ml) 22.688 22.82
4 AUCΦ(μgh/ml) 22.816 23.62
Table-6: Bioequivalence data with respect to Test (Composition of the invention) to reference (Art 50) Ratios (T/R ratios) at 90% Confidence Interval (C.I.)

S.No Pharmacokinetic parameters Ratio 90% C.I. %CV

Lower Upper

1 Cmax(μg/ml) 113.79 97.56 179.09 25.23
2 AUCo-1 (μgh/ml) 100.57 89.48 150.17 22.39
3 AUCΦ(μgh/ml) 103.51 85.26 148.29 23.79
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WE CLAIM:
1. An immediate release wet granulated pharmaceutical composition comprising from about 20 mg to about 45 mg of rhein or diacerein, or salts or esters or prodrugs thereof, wherein the composition exhibits no significant difference in rate and/or an extent of absorption of the rhein or diacerein or salts or esters or prodrugs thereof, as compared to a 50 mg diacerein formulation currently marketed under the trade name Art 50®.
2) The composition of claim 1, wherein the composition exhibits a maximum plasma concentration (Cmax) from about 3.15 to about 6.0ug/ml.
3) The composition of claim 1, wherein the composition exhibits a time to reach maximum plasma concentration (Tmax) from about 2.2 to about 5.Oh.
4) The composition of claim 1, wherein the composition exhibits an area under the concentration time curve (AUC0-t)from about 16.4 to about 40 μg.h/ml.
5) The composition of claim 1, wherein the composition can be taken with or without food.
6) A process of preparing immediate release pharmaceutical composition
comprising from about 20 mg to about 45 mg of rhein or diacerein, or salts or
esters or prodrugs thereof, wherein the process comprises of
a) mixing rhein or diacerein, or salts thereof with other pharmaceutically acceptable excipients to form a premix;
b) granulating said premix of step a) with suitable solvent;
c) converting the granules of step b) into suitable dosage form.
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7) The process of claim 6, wherein suitable solvent comprises one or more of water, methanol, ethanol, isopropyl alcohol, acetone and methylene chloride.
8) An immediate release wet granulated pharmaceutical composition comprising from about 20mg to about 45 mg of rhein or diacerein or salts or esters or prodrugs thereof; and wherein the formulation exhibits a dissolution profile such that within 60 minutes more than 60% 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.
9) The pharmaceutical composition of claim 1 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.
10) The pharmaceutical composition of claim 1, further comprises of one or more
pharmaceutically acceptable excipients.

Dated this 2THday of July, 2008

For Wockhardt Limited
(Mandar Kodgule) Authorized Signatory

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