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:
SELF EMULSIFYING DRUG DELIVERY SYSTEM OF DIACEREIN OR
SALTS THEREOF
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 self-emulsifying drug delivery system comprising rhein or diacerein, or salts thereof optionally with one or more pharmaceutical^ 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 self-emulsifying drug delivery system comprising rhein or diacerein, or salts thereof 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 U19H12U8.
OH O OH
Formula-
H .C . .0 O O . CH ,
Formula-I
~>

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. Here sodium lauryl sulfate acts a wetting agent and is just co micronized with diacerein and the formulation is in solid form and not a liquid or emulsion or self-emulsifying system.


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 formulated in pharmaceutically acceptable vehicle which comprises of 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 (Marketed formulation of diacerein). Art 50 releases about 14% of diacerein in 60 minutes, whereas pharmaceutical composition of the present invention releases more than 85% of diacerein in 60 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 self-emulsifying drug delivery system comprising rhein or diacerein, or salts thereof optionally with one or more pharmaceutically acceptable excipients.


In another aspect of the present invention there is provided a self-emulsifying drug delivery system comprising rhein or diacerein, or salts thereof in pharmaceutical^ acceptable vehicle optionally with one or more pharmaceutically acceptable excipients.
In another aspect of the present invention there is provided a self-emulsifying drug delivery system comprising rhein or diacerein, or salts thereof in pharmaceutically acceptable vehicle optionally with one or more pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable vehicle comprises one or more emulsifiers.
In another aspect of the present invention there is provided a self-emulsifying drug delivery system comprising rhein or diacerein, or salts thereof in pharmaceutically acceptable vehicle optionally with one or more pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable vehicle comprises one or more emulsifiers and/or oil.
In yet another aspect of the present invention there is provided a self-emulsifying drug delivery system comprising rhein or diacerein, or salts thereof optionally with one or more pharmaceutically acceptable excipients; and wherein the formulation exhibits a dissolution profile such that within 30 minutes more than 75% 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 Tampon phosphate buffer at 37 °C ± 0.5°C.
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.
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 formulation can have a liquid or semi-solid form, and, if desired, can be 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.
If desired, the formulation may further include other conventional pharmaceutical additives known to the ordinary skill in the art which include but not limited to antioxidants, colorants, flavoring agents, preservatives and the like.
The pharmaceutical composition of the present invention can be prepared by mixing diacerein or salts thereof with suitable emulsifiers optionally with other pharmaceutical additives and converting the mixture 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 -I

Table-1 Composition of diacerein capsules
Ingredients
S.No.
Diacerein
jlabrafil
Labrasol
Tween 80

%w/w
10-90
1-40
10-90
10-60

Procedure: Diacerein is mixed with labrafil, labrasol and tween 80 for few minutes. The mixture thus obtained is sonicated for few minutes and filled into hard gelatin capsules. Gelatin band is applied to the filled hard gelatin capsules.


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)
5 3 43
10 15 4 61
5 _H 73
20 7 78
30 9 85
45 11 90
60 14 92
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 Tampon phosphate buffer at 37 °C ± 0.5°C was used as medium.
<
Example -II
Table-3 Composition of diacerein capsules
S.No. Ingredients %w/w
1 Diacerein 10-90
2 Labrafac 1-60
3 Labrasol 10-90
4 Tween 80 10-60

Procedure: Diacerein is mixed with labrafac, labrasol and tween 80 for few minutes. The mixture thus obtained is sonicated for few minutes and filled into hard gelatin capsules. Gelatin band is applied to the filled hard gelatin capsules.


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-ll)
5 3 39
10 15 4 64
5 75
20 7 80
30 45 9 87
11 92
60 14 97
Table 4 provides the dissolution data for diacerein capsules (50mg) 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 Tampon phosphate buffer at 37 °C ± 0.5°C was used as medium.


Example -III
Table-5 Composition of diacerein capsules

S.No. Ingredients
1 2 Diacerein
Triacetin
3 Labrasol
4 Tween 80

%w/w
10-90
1-60
10-90
10-60

Procedure: Diacerein is mixed with triacetin, labrasol and tween 80 for few minutes. The mixture thus obtained is sonicated for few minutes and filled into hard gelatin capsules. Gelatin band is applied to the filled hard gelatin capsules.


Table 6: Comparative dissolution data of ART 50 vs Diacerein capsules prepared as per example III

Time (min) % drug released (Art 50) % drug released (Example-Ill)
5 3 48
10 4 63
15 5 74
30 7 83
45 9 87
60 11 90
Table 6 provides the dissolution data for diacerein capsules (50mg) prepared as per the formula given in Table 5. 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.


Example -IV
Table-7 Composition of diacerein capsules

S.No. Ingredients
1 Diacerein
2 Capmul
3 Acconon
4 Tween 80

%w/w
10-90
10-90
10-90
10-60

Procedure: Diacerein is mixed with capmul, acconon and tween 80 for few minutes. The mixture thus obtained is sonicated for few minutes and filled into hard gelatin capsules. Gelatin band is applied to the filled hard gelatin capsules.


Table 8: Comparative dissolution data of ART 50 vs Diacerein capsules prepared as per example IV

Time (min) % drug released (Art 50) % drug released (Example-IV)
5 10 3 36
4 55
15 30 5 68
7 79
45 9 85
60 11 89
Table 8 provides the dissolution data for diacerein capsules (50mg) prepared as per the formula given in Table 7. 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.


Example -V
Table-9 Composition of diacerein capsules

S.No. Ingredients
1 Diacerein
2 Labrafac
3 Labrasol
4 5 Acconon Tween 80

%w/w
10-90
1-60
10-90
10-90 10-60

Procedure: Diacerein is mixed with labrafac, labrasol, acconon and tween 80 for few minutes. The mixture thus obtained is sonicated for few minutes and filled into hard gelatin capsules. Gelatin band is applied to the filled hard gelatin capsules.


Table 10: Comparative dissolution data of ART 50 vs Diacerein capsules prepared as per example V

Time (min) % drug released (Art 50) % drug released (Example-V)
5 3 33
10 4 56
15 ' 5 7 67
30 81
45 9 86
60 11 88
Table 10 provides the dissolution data for diacerein capsules (50mg) prepared as per the formula given in Table 9. 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.


WE CLAIM:
1) A self-emulsifying drug delivery system comprising rhein or diacerein, or salts thereof in pharmaceutically acceptable vehicle optionally with one or more pharmaceutically acceptable excipients.
2) A self-emulsifying drug delivery system comprising rhein or diacerein, or salts thereof in pharmaceutically acceptable vehicle optionally with one or more pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable vehicle comprises one or more emulsifiers.
3) A self-emulsifying drug delivery system comprising rhein or diacerein, or salts thereof in pharmaceutically acceptable vehicle optionally with one or more pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable vehicle comprises one or more emulsifiers and/or oil.
4) A self-emulsifying drug delivery system comprising rhein or diacerein, or salts thereof optionally with one or more pharmaceutically acceptable excipients; and wherein the formulation exhibits a dissolution profile such that within 30 minutes more than 75% 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 Tampon phosphate buffer at 37 °C ± 0.5°C.
5) The self emulsifying drug delivery system of claim 2 and 3, wherein emulsifiers comprises one or more of polyoxyethylene glycerol esters of fatty acids, polyoxylated castor oil, ethylene glycol esters, propylene glycol esters, glyceryl esters of fatty acids, sorbitan esters, polyglyceryl esters, fatty alcohol ethoxylates, ethoxylated propoxylated block copolymers, polyethylene glycol esters of fatty acids, cremophores; glycerol monocaprylate/caprate, Gelucires, and the like.


6) The self emulsifying drug delivery system of claim 3, wherein oils comprises one or more of Neobee oil; Miglyol derivatives, soy oil, almond oil, olive oil, peanut oil, other fatty acid esters of glycerols, medium chain triglycerides, and the like.
7) The self emulsifying drug delivery system of claim 1-4, further comprising antioxidants, colorants, flavoring agents, preservatives and the like.
8) The self emulsifying drug delivery system of claim 1-4 is further filled into hard gelatin capsules, soft gelatin capsules or HPMC capsules and the like.





ABSTRACT
The present invention provides a self-emulsifying drug delivery system comprising rhein or diacerein, or salts thereof optionally with one or more pharmaceutically acceptable excipients. The composition of the present invention may exhibit improved bioavailability along with reduced undesirable side effects.