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:
PHARMACEUTICAL COMPOSITIONS OF RHEIN OR DIACEREIN OR SALTS THEREOF
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 relates to pharmaceutical compositions comprising rhein or diacerein, or salts or esters or prodrugs thereof having average particle size from about 0.1 microns to about 30 microns, which are bioequivalent to a 50 mg diacerein formulation currently marketed under the trade name Art 50®. It also relates to compositions of rhein or diacerein, or salts or esters, or prodrugs thereof, wherein diacerein is not co-micronized with any surfactant. 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 relates to pharmaceutical compositions comprising rhein or diacerein, or salts or esters or prodrugs thereof having average particle size from about 0.1 microns to about 30 microns, preferably from 0.1 microns to 0.20 microns, which are bioequivalent to a 50 mg diacerein formulation currently marketed under the trade name Art 50®. It also relates to compositions of rhein or diacerein, or salts or esters or prodrugs thereof, wherein diacerein is not co-micronized with any surfactant. 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
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 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 invention is directed to oral pharmaceutical compositions of rhein or diacerein, or salts or esters or prodrugs thereof having an average particle size from 0.1 microns to 30 microns, preferably from 0.2 micron to 20 microns, which are 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 compositions of the present invention are 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 having an average particle size from about 0.1 microns to about 30 microns is used; it leads to significant increase in solubility of diacerein leading to increased percent drug release of diacerein as compared to Art 50®. Art 50® (wherein the particle size of diacerein is more than 43 u) releases about 14% of diacerein in 60 minutes, whereas pharmaceutical composition of the present invention (wherein the average particle size of diacerein is from 0.1 microns to 30 microns, preferably from 0.2 micron to 20 microns) releases about 100% of diacerein in 15 minutes (Table 1). 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 oral pharmaceutical composition comprising 20 to 45 mg of rhein or diacerein, or salts or esters or prodrugs thereof wherein the average particle size is from about 0.1 microns to about 30 microns, thus providing a rate and/or an extent of absorption of the rhein or diacerein which 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 an oral pharmaceutical composition comprising 20 to 45 mg of rhein or diacerein, or salts or esters or prodrugs thereof having an average particle size from about 0.1 microns to about 30 microns, 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® and the composition can be taken with or without food.
Another aspect of the present invention provides a method of making a pharmaceutical composition, the method comprising providing particles of rhein or diacerein, or salts or esters or prodrugs thereof, wherein the particles have an average particle size from about 0.1 microns to about 30 microns; forming a mixture by mixing the particles of rhein or diacerein or salts or esters thereof with one or more pharmaceutically acceptable excipients; and forming the mixture into a pharmaceutical dosage form.
The "pharmaceutical composition" of the present invention as used herein, is meant for oral administration to mammals and refers to tablets, capsules, granules, beads, caplets, disc, pills, sachet, suspension, spheroids, minitablets, granules in a capsule, beads in a capsule, minitablets in a capsule, and the like.
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®). Further, the compositions can be administered with or without food. The compositions of the invention result in significant reduction of soft stools as a side effect, which is encountered with Art 50®.
"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 6.0mg/ml, Tmax of about 2.2 to 5.0h, AUC0.t of about 16.4 to 40 mg.h/ml, AUC0 of about 16.7 to 40 mg.h/ml.
At 90% confidence interval; area under the concentration time curve (AUCo-t and /or AUCD) 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 administered in the fed versus the fasted state; (5) bioequivalency of the diacerein compositions when administered in the fed versus the fasted state.
The pharmaceutical composition of the present invention may be prepared by dispersing diacerein or salts thereof optionally with pharmaceutically acceptable


excipients in suitable liquid dispersion medium and wet milling the dispersion through suitable mill to get a suitable size. Microparticulate dispersion of diacerein or salts thereof may be spray dried in fluidized bed processor. Dried mixture may be mixed with other pharmaceutically acceptable excipients and may be converted into suitable dosage form.
Wet milling technique results in better reduction of particle size of diacerein or rhein i.e. smaller particle size up to 0.1 microns can be achieved with this technique which is otherwise difficult to achieve with dry milling technique. Additionally, wet milling prevents fuming of dust particles and loss resulting from the same.
Suitable liquid dispersion medium are those known to the ordinary skill in the art and include but not limited to one or more of water, ethanol, isopropyl alcohol, butanol, hexane, glycols, vegetable oils, mineral oils, and the like.
Suitable means applied to reduce the particle size of rhein or diacerein or salts or esters or prodrugs thereof are those known to ordinary skill in the art and include but not limited to one or more of nano mill, ball mill, attritor mill, vibratory mill, sand mill, bead mill, jet mill, dyno mill, ultrasonication, pressure homogenizer microfluidizer, and the like.
The pharmaceutical composition comprises of pharmaceutically acceptable excipients wherein excipients may include fillers, lubricants, disintegrants, surfactants, and glidants.
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.
Suitable surfactants may include one or more of amphoteric, non-ionic, cationic or anionic surfactants. For example, 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 gtycerides, poloxamer, cremophore RH 40, 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.


Table 1: Comparative dissolution data of ART 50 vs Composition of the invention

Time (min) % drug released(Art 50 with particle size morethan 43M) % drug released(Composition of the inventionwith particle size from 0.1- 30M)
5 3 55
10 4 93
15 5 100
20 7 100
30 9 100
45 11 100
60 14 100
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-2: 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 (mg/ml) 3.058 4.050
2 Tmax (h) 5.39 4.47
3 AUCo-t(mgh/ml) 22.688 25.559
4 AUCf(mgh/ml) 22.816 25.675


Table-3: 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 (mg/ml) 132.42 99.59 176.08 27.73
2 AUCo-t (mgh/ml) 112.65 87.42 145.17 24.59
3 AUCf(mgh/ml) 112.53 87.16 145.29 24.77


Example 1
Table 4 provides the composition of batches of the present invention.
Table 4

S.No. Ingredients %w/w
Part-I
1 Diacerein 11.26
2 Povidone 5-40
3 Water q.s.
Part-ll
4 Starch 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 pressure homogenizer one or more times to get a desired particle size (0.1 u). 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 5 provides the composition of batches of the present invention.
Table 5

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 (0.8u). 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.


Example 3
Table 6 provides the composition of batches of the present invention.
Table 6

S.No. Ingredients %w/w
Part-!
1 Diacerein 9.50
2 Hydroxypropyl methyl cellulose 10-50
3 Water q.s.
Part-ll
4 Povidone 5-40
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 pressure homogenizer one or more times to get a desired particle size (5u). The microparticulate dispersion was spray dried in glatt. Dried mass was blended with silicified microcrystalline cellulose, microcrystalline cellulose, croscarmellose sodium, lubricated with magnesium stearate and lubricated blend was filled into hard gelatin capsules of suitable size.


Example 4
Table 7 provides the composition of batches of the present invention.
Table 7

S.No. Ingredients %w/w
Part-I
1 Diacerein 9.50
2 Microcrystalline cellulose 5-40
3 Water q.s.
Part-ll
4 Starch 10-50
5 Silicified microcrystalline cellulose 5-70
6 Croscarmellose sodium 1-15
7 Magnesium stearate 0.1-3
Procedure: Diacerein and hydroxypropyl methylcellulose was dispersed in sufficient quantity of water to get uniform dispersion. Diacerein dispersion was passed through pressure homogenizer one or more times to get a desired particle size (12u). 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 5
Table 8 provides the composition of batches of the present invention.
Table 8

S.No. Ingredients %w/w
Part-I
1 Diacerein 11.80
2 Povidone 5-40
3 Water q.s.
Part-ll
4 Sucrose 10-50
5 Starch 10-50
6 Silicified microcrystalline cellulose 5-70
7 Croscarmellose sodium 1-15
8 Magnesium stearate 0.1-3
Procedure: Diacerein and hydroxypropyl methylcellulose was dispersed in sufficient quantity of water to get uniform dispersion. Diacerein dispersion was passed through pressure homogenizer one or more times to get a desired particle size (15u). The microparticulate dispersion was spray dried in glatt. Dried mass was blended with sucrose, silicified microcrystalline cellulose, starch, croscarmellose sodium, lubricated with magnesium stearate and lubricated blend was filled into hard gelatin capsules of suitable size.


Example 6
Table 9 provides the composition of batches of the present invention.
Table 9

S.No. Ingredients %w/w
Part-I
1 Diacerein 12.50
2 Hydroxypropyl methyl cellulose 5-40
3 Water q.s.
Part-ll
4 Sucrose 10-50
5 Starch 10-50
6 Silicified microcrystalline cellulose 5-70
7 Croscarmellose sodium 1-15
8 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 (22m). The microparticulate dispersion was spray dried in glatt. Dried mass was blended with sucrose, silicified microcrystalline cellulose, starch, 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 having a rate and/or an extent of absorption of the rhein or diacerein equal to or greater than that obtained by a 50 mg diacerein formulation marketed under the trade name Art 50® wherein the average particle size of diacerein is from 0.1 microns to 30 microns.
2) The composition of claim 1, wherein the composition exhibits a maximum plasma concentration (Cmax) from about 3.15 to about 6.0mg/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 5.0h.
4) The composition of claim 1, wherein the composition exhibits an area under the concentration time curve (AUCo-t)from about 16.4 to about 40 mg.h/ml.
5) The composition of claim 1, wherein the composition can be taken with or without food.
6) A method of making a pharmaceutical composition, the method comprising providing particles of rhein or diacerein, or salts or esters or prodrugs thereof, wherein the particles have an average particle size from about 0.1 microns to about 20 microns; forming a mixture by mixing the particles of rhein or diacerein or salts or esters* thereof with one or more pharmaceutically acceptable excipients; and forming the mixture into a pharmaceutical dosage form.
7) The method of claim 6, wherein providing the particles comprises dispersing rhein or diacerein, or salts or esters or prodrugs thereof in a suitable liquid dispersion medium and reducing the particle size of said rhein or diacerein, or salts or esters or prodrugs thereof.


8) The method of claim 7, wherein the suitable liquid dispersion medium
comprises one or more of water, ethanol, isopropyl alcohol, butanol, hexane, glycols, vegetable oils, and mineral oils.
9) The method of claim 7, wherein the particle size reduction is carried out by wet
milling technique.
10) The composition according to claim 1 or 2, with the proviso that diacerein is
not comicronized with a surfactant.

ABSTRACT
The present invention relates to pharmaceutical compositions comprising rhein or diacerein, or salts or esters or prodrugs thereof having average particle size from about 0.1 microns to 30 microns, preferable from 0.1 microns to 0.20 microns which are bioequivalent to a 50 mg diacerein formulation currently marketed under the trade name Art 50®. It also relates to compositions of rhein or diacerein, or salts or esters or prodrugs thereof, wherein diacerein is not co-micronized with any surfactant.
The compositions exhibit no variability in the rate and the extent of absorption when given under fed or fasted state conditions. The composition further results in a significant reduction in soft stool effect. The invention also relates to processes for the preparation of such compositions.
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