Indian Patents. 271196:"A PHARMACEUTICAL COMPOSITION COMPRISING SUPERSATURABLE SELF EMULSIFYING DRUG DELIVERY SYSTEM OF RHEIN OR DIACEREIN OR SALTS THEREOF"

Title of Invention	"A PHARMACEUTICAL COMPOSITION COMPRISING SUPERSATURABLE SELF EMULSIFYING DRUG DELIVERY SYSTEM OF RHEIN OR DIACEREIN OR SALTS THEREOF"
Abstract	There is provided a supersaturable self-emulsifying drug delivery system comprising rhein or diacerein, or salts, or esters, or prodrug thereof optionally with one or more pharmaceutically acceptable excipients. 18

Full Text	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: SUPERSATURABLE SELF EMULSIFYING DRUG DELIVERY SYSTEM OF RHEIN OR DIACEREIN OR SALTS THEREOF 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 There is provided a supersaturable self-emulsifying drug delivery system comprising rhein or diacerein, or salts, or esters, or prodrug thereof optionally with one or more pharmaceutically acceptable excipients. The following specification particularly describes the invention and the manner in which it is to be performed. 4. Description There is provided a supersaturable self-emulsifying drug delivery system comprising rhein or diacerein, or salts or esters, or prodrug thereof optionally with one or more pharmaceuticaly 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 C19H1208. OH O OH Formula-I Formula-ll 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. 3 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 inventors have discovered while working on the diacerein composition, that when diacerein is formulated 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). However, the high surfactant level typically present in self-emulsifying drug delivery system leads to gastrointestinal side effects as well as a reduction in the free drug concentration and thus a reduced rate of intestinal absorption. The inventors have now developed supersaturable self-emulsifying drug delivery system (S-SEDDS) in an attempt to reduce the surfactant side effects and achieve rapid absorption of poorly soluble drugs. The S-SEDDS compositions contain a reduced surfactant level as compared to conventional SEDDS system, hence leading to reduced Gl side effects. The supersaturable self-emulsifying drug delivery system comprises polymers in a pharmaceutically acceptable vehicle comprising oil and/or emulsifiers, which forms an emulsion on contact with an aqueous environment. The polymers prevent precipitation of the drug by generating and maintaining a 4 supersaturated state in vivo. The system generates a supersaturated solution of the drug when the composition is released from an appropriate dosage form into an aqueous medium. Art 50 releases about 13% of diacerein in 120 minutes, whereas pharmaceutical composition of the invention releases more than 60 % of diacerein in 120 minutes. This leads to increased bioavailability. The increased bioavailability further leads to reduction in side effects i.e. soft stools. In one of the embodiments of the invention, there is provided a pharmaceutical composition comprising supersaturable self-emulsifying drug delivery system of rhein or diacerein, or salts or esters, or prodrug thereof optionally with one or more pharmaceutically acceptable excipients. In another embodiment of the invention, there is provided a pharmaceutical composition comprising supersaturable self-emulsifying drug delivery system of rhein or diacerein, or salts or esters or prodrugs thereof and pharmaceutically acceptable polymers, optionally with one or more pharmaceutically acceptable excipients. In another embodiment of the invention, there is provided a pharmaceutical composition comprising supersaturable self-emulsifying drug delivery system of rhein or diacerein, or salts or esters, or prodrug thereof and pharmaceutically acceptable polymers in a pharmaceutically acceptable vehicle, optionally with one or more pharmaceutically acceptable excipients. In another embodiment of the invention, there is provided a pharmaceutical composition comprising supersaturable self-emulsifying drug delivery system of rhein or diacerein, or salts or esters, or prodrug thereof and pharmaceutically acceptable polymers in a pharmaceutically acceptable vehicle, optionally with one or more pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable vehicle comprises one or more emulsifiers. 5 In another embodiment of the invention, there is provided a pharmaceutical composition comprising supersaturable self-emulsifying drug delivery system of rhein or diacerein, or salts or esters, or prodrug thereof and pharmaceutically acceptable polymers in a 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 embodiment of the invention, there is provided a pharmaceutical composition comprising supersaturable self-emulsifying drug delivery system of rhein or diacerein, or salts or esters, or prodrug thereof, and wherein the composition exhibits a dissolution profile such that within 120 minutes at least 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 Tampon phosphate buffer at 37 °C ± 0.5°C. In still another embodiment of the invention, there is provided a process of preparing a pharmaceutical composition comprising supersaturable self-emulsifying drug delivery system of rhein or diacerein, or salts or esters, or prodrug thereof, which process comprises of mixing rhein or diacerein or salts or esters or prodrugs thereof with suitable emulsifiers and pharmaceutically acceptable polymers 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; polyoxylated 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 6 glycol esters of fatty acids, such as Labrafils, Labrafacs, and Labrasols; cremophores; glycerol monocaprylate/caprate, such as Capmul 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 pharmaceutical^ acceptable polymers prevent the precipitation of the drug, leading to a supersaturated solution of the drug when the composition is released from an appropriate dosage form into an aqueous medium. Suitable polymers include one or more of cellulosic polymers or its derivatives including hydroxypropyl methyl cellulose, hydroxy methylcellulose, hydroxy ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose, polyacrylate/ polyalcohol copolymers, gums, polyacrylate/ polyacrylamide copolymers, polyvinyl alcohol polymers, acrylic/methacrylic copolymers, carboxyvinyl polymers, galactomannans, polyanhydrides, polyamino acids, polysaccharides, or the derivatives thereof. The composition 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 composition is in contact with an aqueous environment, for example in the gastrointestinal tract, the composition spontaneously forms an emulsion. If desired, the composition 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. 7 The pharmaceutical composition of the invention may be prepared by mixing rhein or diacerein or salts or esters or prodrugs thereof with suitable emulsifiers and other pharmaceutically acceptable polymers optionally with other pharmaceutical additives and the mixture is converted 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 -1 Table-1 Composition of diacerein capsules S.No. Ingredients %w/w 1 Diacerein 5-90 2 Labrafil 1-70 3 Labrasol 10-90 4 Cremophor 5-70 5 Methocel 2-50 Procedure: Diacerein was mixed with labrafil, labrasol, cremophor and methocel to form a mixture. The mixture was sonicated/homogenized and filled into hard gelatin capsules. Gelatin band was 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 -1) 15 2 39 30 6 50 45 8 56 60 10 58 90 11 61 120 13 62 Table 2 provides the dissolution data for diacerein capsules 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 with sinker. 9 Example - II Table-3 Composition of diacerein capsules S.No. Ingredients %w/w 1 Diacerein 5-90 2 Labrafil 1-70 3 Labrasol 10-90 4 Cremophor 5-70 5 Gelucire 5-60 6 HPC 2-50 Procedure: Diacerein was mixed with labrafil, labrasol, cremophor, Gelucire and HPC to form mixture. The mixture was sonicated/homogenized and filled into hard gelatin capsules. Gelatin band was 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 - II) 15 2 24 30 6 44 45 8 55 60 10 63 90 11 71 120 13 76 Table 4 provides the dissolution data for diacerein capsules 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 with sinker. Example - III Table-5 Composition of diacerein capsules S.No. Ingredients %w/w 1 Diacerein 5-90 2 Labrafil 1-70 3 Labrasol 10-90 4 Cremophor 5-70 5 Gelucire 5-60 6 HPC 2-50 Procedure: Diacerein was mixed with labrafil, labrasol, cremophor, Gelucire and HPC to form a mixture. The mixture was sonicated/homogenized for and filled into hard gelatin capsules. Gelatin band was 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 - III) 15 2 28 30 6 51 45 8 65 60 10 73 90 11 81 120 13 84 Table 6 provides the dissolution data for diacerein capsules (40 mg) 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 with sinker. Example - IV Table-7 Composition of diacerein capsules S.No. Ingredients %w/w 1 Diacerein 5-90 2 Labrafil 1-70 3 Labrasol 10-90 4 Cremophor 5-70 5 Gelucire 5-60 6 HPC 2-50 Procedure: Diacerein was mixed with labrafil, labrasol, cremophor, Gelucire and HPC to form a mixture. The mixture was sonicated/homogenized and filled into hard gelatin capsules. Gelatin band was 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) 15 2 14 30 6 34 45 8 50 60 10 62 90 11 78 120 13 85 Table 8 provides the dissolution data for diacerein capsules 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 with sinker. Example - V Table-9 Composition of diacerein capsules S.No. Ingredients %w/w 1 Diacerein 5-90 2 Labrafil 1-70 3 Labrasol 10-90 4 Cremophor 5-70 5 Gelucire 5-60 6 HPC 2-50 Procedure: Diacerein was mixed with labrafil, labrasol, cremophor, Gelucire and HPC to form a mixture. The mixture was sonicated/homogenized for few minutes and filled into hard gelatin capsules. Gelatin band was 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) 15 2 39 30 6 71 45 8 87 60 10 96 90 11 100 120 13 100 Table 10 provides the dissolution data for diacerein capsules 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 with sinker. Example - VI Table-11 Composition of diacerein capsules S.No. Ingredients %w/w 1 Diacerein 5-90 2 Labrafil 1-70 3 Cremophor 5-70 4 Gelucire 5-60 5 HPC 2-50 Procedure: Diacerein was mixed with labrafil, cremophor, Gelucire and HPC to form a mixture. The mixture was sonicated/homogenized for few minutes and filled into hard gelatin capsules. Gelatin band was applied to the filled hard gelatin capsules. Table 12: Comparative dissolution data of ART 50 vs Diacerein capsules prepared as per example VI Time (min) % drug released (Art 50) % drug released (Example - V) 15 2 9 30 6 28 45 8 44 60 10 60 90 11 82 120 13 93 Table 12 provides the dissolution data for diacerein capsules prepared as per the formula given in Table 11. 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 with sinker. WE CLAIM: 1) A pharmaceutical composition comprising supersaturable self-emulsifying drug delivery system of rhein or diacerein or salts or esters or prodrug thereof, optionally with one or more pharmaceutically acceptable excipients. 2) A pharmaceutical composition comprising supersaturable self-emulsifying drug delivery system of rhein or diacerein or salts or esters or prodrug thereof along with pharmaceutically acceptable polymers in a pharmaceutically acceptable vehicle optionally with one or more pharmaceutically acceptable excipients. 3) The composition of claim 2, wherein the pharmaceutically acceptable vehicle comprises one or more emulsifiers and/or oils. 4) A pharmaceutical composition comprising supersaturable self-emulsifying drug delivery system of rhein or diacerein or salts thereof, wherein the composition exhibits a dissolution profile such that within 120 minutes at least 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 Tampon phosphate buffer at 37 °C ± 0.5°C. 5) The composition of claim 3, wherein the 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 and gelucires. 6) The composition of claim 3, wherein the oils comprises one or more of neobee oil; miglyol derivatives, soy oil, almond oil, olive oil, peanut oil, other fatty acid esters of glycerols, and medium chain triglycerides. 7) The composition of claim 2, wherein the pharmaceutical^ acceptable polymers comprise one or more of cellulose derivatives, polyacrylate/ polyalcohol copolymers, gums, polyacrylate/ polyacrylamide copolymers, polyvinyl alcohol polymers, acrylic/methacrylic copolymers, carboxyvinyl polymers, galactomannans, polyanhydrides, polyamino acid, polysaccharides or derivatives thereof. 8) The composition as per any preceding claims 1 and 2, further comprising antioxidants, colorants, flavoring agents, preservatives. 9) The composition as per any preceding claims is further filled into hard gelatin capsules, soft gelatin capsules or HPMC capsules. 10) A process of preparing a pharmaceutical composition comprising supersaturable self-emulsifying drug delivery system of rhein or diacerein, or salts or esters, or prodrug thereof, which process comprises of mixing rhein or diacerein or salts or esters or prodrugs thereof with suitable emulsifiers and pharmaceutically acceptable polymers optionally 'with other pharmaceutical additives and converting the mixture into suitable dosage form. Dated this 24THday of May 2008 For Wockhardt Limited (Mandar Kodgule) Authorized Signatory

Full Text

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:
SUPERSATURABLE SELF EMULSIFYING DRUG DELIVERY SYSTEM OF
RHEIN OR DIACEREIN OR SALTS THEREOF
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
There is provided a supersaturable self-emulsifying drug delivery system comprising rhein or diacerein, or salts, or esters, or prodrug thereof optionally with one or more pharmaceutically acceptable excipients.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. Description
There is provided a supersaturable self-emulsifying drug delivery system comprising rhein or diacerein, or salts or esters, or prodrug thereof optionally with one or more pharmaceuticaly 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 C19H1208.
OH O OH

Formula-I

Formula-ll

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.
3

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 inventors have discovered while working on the diacerein composition, that when diacerein is formulated 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). However, the high surfactant level typically present in self-emulsifying drug delivery system leads to gastrointestinal side effects as well as a reduction in the free drug concentration and thus a reduced rate of intestinal absorption. The inventors have now developed supersaturable self-emulsifying drug delivery system (S-SEDDS) in an attempt to reduce the surfactant side effects and achieve rapid absorption of poorly soluble drugs. The S-SEDDS compositions contain a reduced surfactant level as compared to conventional SEDDS system, hence leading to reduced Gl side effects. The supersaturable self-emulsifying drug delivery system comprises polymers in a pharmaceutically acceptable vehicle comprising oil and/or emulsifiers, which forms an emulsion on contact with an aqueous environment. The polymers prevent precipitation of the drug by generating and maintaining a
4

supersaturated state in vivo. The system generates a supersaturated solution of the drug when the composition is released from an appropriate dosage form into an aqueous medium. Art 50 releases about 13% of diacerein in 120 minutes, whereas pharmaceutical composition of the invention releases more than 60 % of diacerein in 120 minutes. This leads to increased bioavailability. The increased bioavailability further leads to reduction in side effects i.e. soft stools.
In one of the embodiments of the invention, there is provided a pharmaceutical composition comprising supersaturable self-emulsifying drug delivery system of rhein or diacerein, or salts or esters, or prodrug thereof optionally with one or more pharmaceutically acceptable excipients.
In another embodiment of the invention, there is provided a pharmaceutical composition comprising supersaturable self-emulsifying drug delivery system of rhein or diacerein, or salts or esters or prodrugs thereof and pharmaceutically acceptable polymers, optionally with one or more pharmaceutically acceptable excipients.
In another embodiment of the invention, there is provided a pharmaceutical composition comprising supersaturable self-emulsifying drug delivery system of rhein or diacerein, or salts or esters, or prodrug thereof and pharmaceutically acceptable polymers in a pharmaceutically acceptable vehicle, optionally with one or more pharmaceutically acceptable excipients.
In another embodiment of the invention, there is provided a pharmaceutical composition comprising supersaturable self-emulsifying drug delivery system of rhein or diacerein, or salts or esters, or prodrug thereof and pharmaceutically acceptable polymers in a pharmaceutically acceptable vehicle, optionally with one or more pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable vehicle comprises one or more emulsifiers.
5

In another embodiment of the invention, there is provided a pharmaceutical composition comprising supersaturable self-emulsifying drug delivery system of rhein or diacerein, or salts or esters, or prodrug thereof and pharmaceutically acceptable polymers in a 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 embodiment of the invention, there is provided a pharmaceutical composition comprising supersaturable self-emulsifying drug delivery system of rhein or diacerein, or salts or esters, or prodrug thereof, and wherein the composition exhibits a dissolution profile such that within 120 minutes at least 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 Tampon phosphate buffer at 37 °C ± 0.5°C.
In still another embodiment of the invention, there is provided a process of preparing a pharmaceutical composition comprising supersaturable self-emulsifying drug delivery system of rhein or diacerein, or salts or esters, or prodrug thereof, which process comprises of mixing rhein or diacerein or salts or esters or prodrugs thereof with suitable emulsifiers and pharmaceutically acceptable polymers 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; polyoxylated 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
6

glycol esters of fatty acids, such as Labrafils, Labrafacs, and Labrasols; cremophores; glycerol monocaprylate/caprate, such as Capmul 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 pharmaceutical^ acceptable polymers prevent the precipitation of the drug, leading to a supersaturated solution of the drug when the composition is released from an appropriate dosage form into an aqueous medium. Suitable polymers include one or more of cellulosic polymers or its derivatives including hydroxypropyl methyl cellulose, hydroxy methylcellulose, hydroxy ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose, polyacrylate/ polyalcohol copolymers, gums, polyacrylate/ polyacrylamide copolymers, polyvinyl alcohol polymers, acrylic/methacrylic copolymers, carboxyvinyl polymers, galactomannans, polyanhydrides, polyamino acids, polysaccharides, or the derivatives thereof.
The composition 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 composition is in contact with an aqueous environment, for example in the gastrointestinal tract, the composition spontaneously forms an emulsion.
If desired, the composition 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.
7

The pharmaceutical composition of the invention may be prepared by mixing rhein or diacerein or salts or esters or prodrugs thereof with suitable emulsifiers and other pharmaceutically acceptable polymers optionally with other pharmaceutical additives and the mixture is converted 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 -1
Table-1 Composition of diacerein capsules

S.No. Ingredients %w/w
1 Diacerein 5-90
2 Labrafil 1-70
3 Labrasol 10-90
4 Cremophor 5-70
5 Methocel 2-50
Procedure: Diacerein was mixed with labrafil, labrasol, cremophor and methocel to form a mixture. The mixture was sonicated/homogenized and filled into hard gelatin capsules. Gelatin band was 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 -1)
15 2 39
30 6 50
45 8 56
60 10 58
90 11 61
120 13 62
Table 2 provides the dissolution data for diacerein capsules 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 with sinker.
9

Example - II
Table-3 Composition of diacerein capsules

S.No. Ingredients %w/w
1 Diacerein 5-90
2 Labrafil 1-70
3 Labrasol 10-90
4 Cremophor 5-70
5 Gelucire 5-60
6 HPC 2-50
Procedure: Diacerein was mixed with labrafil, labrasol, cremophor, Gelucire and HPC to form mixture. The mixture was sonicated/homogenized and filled into hard gelatin capsules. Gelatin band was 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 - II)
15 2 24
30 6 44
45 8 55
60 10 63
90 11 71
120 13 76
Table 4 provides the dissolution data for diacerein capsules 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 with sinker.
Example - III
Table-5 Composition of diacerein capsules

S.No. Ingredients %w/w
1 Diacerein 5-90
2 Labrafil 1-70
3 Labrasol 10-90
4 Cremophor 5-70
5 Gelucire 5-60
6 HPC 2-50
Procedure: Diacerein was mixed with labrafil, labrasol, cremophor, Gelucire and HPC to form a mixture. The mixture was sonicated/homogenized for and filled into hard gelatin capsules. Gelatin band was 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 - III)
15 2 28
30 6 51
45 8 65
60 10 73
90 11 81
120 13 84

Table 6 provides the dissolution data for diacerein capsules (40 mg) 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 with sinker.
Example - IV
Table-7 Composition of diacerein capsules

S.No. Ingredients %w/w
1 Diacerein 5-90
2 Labrafil 1-70
3 Labrasol 10-90
4 Cremophor 5-70
5 Gelucire 5-60
6 HPC 2-50
Procedure: Diacerein was mixed with labrafil, labrasol, cremophor, Gelucire and HPC to form a mixture. The mixture was sonicated/homogenized and filled into hard gelatin capsules. Gelatin band was 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)
15 2 14
30 6 34
45 8 50
60 10 62
90 11 78
120 13 85
Table 8 provides the dissolution data for diacerein capsules 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 with sinker.
Example - V
Table-9 Composition of diacerein capsules

S.No. Ingredients %w/w
1 Diacerein 5-90
2 Labrafil 1-70
3 Labrasol 10-90
4 Cremophor 5-70
5 Gelucire 5-60
6 HPC 2-50
Procedure: Diacerein was mixed with labrafil, labrasol, cremophor, Gelucire and HPC to form a mixture. The mixture was sonicated/homogenized for few minutes and filled into hard gelatin capsules. Gelatin band was 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)
15 2 39
30 6 71
45 8 87
60 10 96
90 11 100
120 13 100
Table 10 provides the dissolution data for diacerein capsules 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 with sinker.
Example - VI
Table-11 Composition of diacerein capsules

S.No. Ingredients %w/w
1 Diacerein 5-90
2 Labrafil 1-70
3 Cremophor 5-70
4 Gelucire 5-60
5 HPC 2-50
Procedure: Diacerein was mixed with labrafil, cremophor, Gelucire and HPC to form a mixture. The mixture was sonicated/homogenized for few minutes and filled into hard gelatin capsules. Gelatin band was applied to the filled hard gelatin capsules.

Table 12: Comparative dissolution data of ART 50 vs Diacerein capsules prepared as per example VI

Time (min) % drug released (Art 50) % drug released (Example - V)
15 2 9
30 6 28
45 8 44
60 10 60
90 11 82
120 13 93
Table 12 provides the dissolution data for diacerein capsules prepared as per the formula given in Table 11. 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 with sinker.

WE CLAIM:
1) A pharmaceutical composition comprising supersaturable self-emulsifying drug delivery system of rhein or diacerein or salts or esters or prodrug thereof, optionally with one or more pharmaceutically acceptable excipients.
2) A pharmaceutical composition comprising supersaturable self-emulsifying drug delivery system of rhein or diacerein or salts or esters or prodrug thereof along with pharmaceutically acceptable polymers in a pharmaceutically acceptable vehicle optionally with one or more pharmaceutically acceptable excipients.
3) The composition of claim 2, wherein the pharmaceutically acceptable vehicle comprises one or more emulsifiers and/or oils.
4) A pharmaceutical composition comprising supersaturable self-emulsifying drug delivery system of rhein or diacerein or salts thereof, wherein the composition exhibits a dissolution profile such that within 120 minutes at least 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 Tampon phosphate buffer at 37 °C ± 0.5°C.
5) The composition of claim 3, wherein the 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 and gelucires.

6) The composition of claim 3, wherein the oils comprises one or more of neobee oil; miglyol derivatives, soy oil, almond oil, olive oil, peanut oil, other fatty acid esters of glycerols, and medium chain triglycerides.
7) The composition of claim 2, wherein the pharmaceutical^ acceptable polymers comprise one or more of cellulose derivatives, polyacrylate/ polyalcohol copolymers, gums, polyacrylate/ polyacrylamide copolymers, polyvinyl alcohol polymers, acrylic/methacrylic copolymers, carboxyvinyl polymers, galactomannans, polyanhydrides, polyamino acid, polysaccharides or derivatives thereof.
8) The composition as per any preceding claims 1 and 2, further comprising antioxidants, colorants, flavoring agents, preservatives.
9) The composition as per any preceding claims is further filled into hard gelatin capsules, soft gelatin capsules or HPMC capsules.
10) A process of preparing a pharmaceutical composition comprising supersaturable self-emulsifying drug delivery system of rhein or diacerein, or salts or esters, or prodrug thereof, which process comprises of mixing rhein or diacerein or salts or esters or prodrugs thereof with suitable emulsifiers and pharmaceutically acceptable polymers optionally 'with other pharmaceutical additives and converting the mixture into suitable dosage form.
Dated this 24THday of May 2008 For Wockhardt Limited

(Mandar Kodgule) Authorized Signatory

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Patent Number

271196

Indian Patent Application Number

1115/MUM/2008

PG Journal Number

07/2016

Publication Date

12-Feb-2016

Grant Date

08-Feb-2016

Date of Filing

26-May-2008

Name of Patentee

WOCKHARDT LTD.

Applicant Address

D-4MIDC Area, Chikalthana, Aurangabad-431210 MAHARASHTRA,INDIA

Inventors:

#	Inventor's Name	Inventor's Address
1	JAIN,GIRISH KUMAR	4-Sharda Niketan, Teachers'Colony, Pitam Pura, DELHI-110034-INDIA
2	NAKHAT, PREMCHAND DALICHANDJI	C/o Gurukrupa Medicals & Electronics At.Post: Lohi(Bazar), Tq.Darwha Dist.:Yavatmal MAHARASHTRA india
3	MANDAOGADE,PRASHANT MANOHAR	Sanmati Colony,Shegaon Road, PO VMV, Amravati-444 604, MAHARASHTRA,INDIA
4	TALWAR , MUNISH	Flat No,3 Group Housing Society No.37, Sector 20 Panchkula; HARYANA,INDIA

PCT International Classification Number

A61K9/107; A61K9/48; A61K31/222

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA