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:
SELF EMULSIFYING PHARMACEUTICAL COMPOSITIONS OF RHEIN OR DIACEREIN
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 self emulsifying drug delivery system based compositions of rhein or diacerein, or salts or esters or prodrugs thereof which are bioequivalent to a 50 mg diacerein formulation marketed under the trade name Art 50®. The composition exhibits no variability in fed as compared to fasted state conditions. The composition also results in significant reduction in soft, stools, effects as compared to Art 50®. The invention also relates to processes for the preparation of such compositions.
The following specification particularly describes the invention and the manner in which it is to be performed.


4. Description
The present invention relates to self emulsifying drug delivery system based compositions of rhein or diacerein, or salts or esters or prodrugs thereof which are bioequivalent to a 50 mg diacerein formulation marketed under the trade name Art 50®
The composition exhibits no variability in fed as compared to fasted state conditions. The composition also results in significant reduction in soft stools effects as compared to Art 50®. 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 self-emulsifying drug delivery system (SEDDS) based oral pharmaceutical compositions of rhein or diacerein, or salts or esters or prodrugs thereof, which are bioequivalent to 50mg diacerein formulation marketed under the trade name 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 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 50mg diacerein formulation marketed under the trade name Art 50®; as to whether the compositions are administered with or without food.
Though self-emulsifying drug delivery system is known technique, but it is highly difficult to predict for which drugs it will work. As there are various drug related factors which vary from drug to drug and hence influence its improvement in bioavailability like pKa, solubility profile both in oil and water, stability aspects in different media. Non-availability of many products in market based on this technique in spite of being known in art, it indicates that the selection of a drug with this technique and specific set of emulsifiers and oils is highly unpredictable.
The present inventors have noticed that using SEDDS technology with other known water insoluble drugs like irbesartan, aripiprazole, entacapone, does not result in any significant increase in solubility of above-mentioned poorly soluble drugs. It was observed that it does not make any significant difference either in solubility or percent release of these poorly soluble drugs, whether these drugs are present alone in formulation or along with self-emulsifying delivery vehicle.
The assays conducted by the present inventors have unexpectedly demonstrated that diacerein can be efficiently formulated by using SEDDS technology, although it has an altogether different pharmacokinetic (absorption only from upper part of intestine, entero-hepatic circulation, soft stool problem) and physico-chemical profile (typical pKa of 4.5, instability under acidic and alkaline conditions).


The present inventors while working on the diacerein formulation have surprisingly found when diacerein is formulated in pharmaceutically acceptable vehicle which comprises oil and/or emulsifiers, which forms an emulsion on contact with an aqueous environment i.e in self emulsifying drug delivery system, it results in significant increase in solubility of diacerein and percent drug release of diacerein as compared to Art 50®. Art 50® releases about 14% of diacerein in 60 minutes, whereas pharmaceutical composition of the present invention releases more than 85% of diacerein in 30 minutes. This leads to increased bioavailability. The increased bioavailability further leads to significant reduction in side effects i.e. soft stools.
One of the aspects of the present invention provides a composition comprising 20 to 45 mg of rhein or diacerein, or salts or esters or prodrugs thereof in pharmaceutically acceptable vehicle, 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®, wherein the composition is a self emulsifying drug delivery system comprising of one or more emulsifiers.
Another aspect of the present invention provides a composition comprising 20 to 45 mg of rhein or diacerein, or salts or esters or prodrugs thereof in pharmaceutically acceptable vehicle, 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®, wherein the composition is a self emulsifying drug delivery system comprising of one or more emulsifiers and the composition can be taken with or without food.
The "pharmaceutical composition" of the present invention as used herein, is meant for oral administration to mammals and refers to a liquid or semi-solid form, filled into hard gelatin capsules, soft gelatin capsules, HPMC


(hydroxypropyl methyl cellulose) capsules. When formulation contacts an aqueous environment, for example in the gastrointestinal tract, the formulation spontaneously forms an emulsion.
"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 0.4 to 5.0h, AUC0-t of about 16.4 to 40 mg.h/ml, AUCÆ of about 16.7 to 40 mg.h/ml.
At 90% confidence interval; area under the concentration time curve (AUCo-t and /or AUCÆ) and maximum plasma concentration (Cmax) values of composition of the invention lies between 0.70 and 1.70 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 mixing diacerein or salts thereof with suitable emulsifiers and/or oils optionally with other pharmaceutical additives and converting the mixture into suitable dosage form.
Suitable emulsifiers are those known to ordinary skill in the art and include but not limited to one or more of polyoxyethylene glycerol esters of fatty acids, such as Tagats; polooxylated castor oil, ethylene glycol esters, such as glycol stearate and distearate; propylene glycol esters, such as propylene glycol myristate; glyceryl esters of fatty acids, such as glyceryl stearates and monostearates; sorbitan esters, such as spans and tweens; polyglyceryl esters, such as polyglyceryl 4-oleate; fatty alcohol ethoxylates, such as Brij type emulsifiers; ethoxylated propoxylated block copolymers, such as poloxamers; polyethylene glycol esters of fatty acids, such as Labrafils, Labrafacs, and Labrasols; cremophores; glycerol monocaprylate/caprate, such as Campmul CM 10; Gelucire, Capryol, Captex, Acconon, transcutol, triacetin and the like.
Preferably, mixture of high HLB surfactant like tweens and low HLB surfactant like polyethylene glycol esters of fatty acids, such as Labrafils, Labrafacs, and Labrasols is used. The tweens may be present at concentration range of about 5-50% w/w; preferably from 10-40% w/w. Labrafacs, Labrasils or Labrasols may be present at concentration range of about 5-70% w/w; preferably from 7-45%.
Suitable oils are those known to ordinary skill in the art and include but not limited to one or more of Neobee oil; Miglyol derivatives (fractionated coconut


oil), soy oil, almond oil, olive oil, peanut oil, other fatty acid esters of glycerols, medium chain triglycerides and the like.
The pharmaceutical composition of the invention may include one or more of other auxiliary agents known in the art like antioxidants, colorants, flavoring agents, preservatives 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) % drug released (Composition of the invention)
5 3 43
10 4 61
15 5 73
20 7 78
30 9 85
45 11 90
60 14 92
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.


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 5.35
2 Tmax (h) 5.39 1.25
3 AUCo-t (mgh/ml) 22.688 27.149
4 AUCf(mgh/ml) 22.816 27.332


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) 121.94 91.33 162.82 28.15
2 AUCo-t (mgh/ml) 105.69 79.73 140.10 27.42
3 AUC