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:
DIACEREIN COMPOSITIONS FOR TREATMENT OF OSTEOARTHRITIS
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D-4, MIDC, Chikalthana,
Aurangabad (M.S.) INDIA.
(a) NAME: NEGMA-LERADS
(b) NATIONALITY: FRENCH
(c) ADDRESS: SAS, FRANCE.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a pharmaceutical composition comprising diacerein or salts thereof along with sugar alcohols, 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.
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4. Description
The present invention provides a pharmaceutical composition comprising diacerein or salts thereof along with sugar alcohols, optionally with one or more pharmaceutically acceptable excipients.
Diacerein, (Formula I), 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 C19H12O8.

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.
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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.
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.
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There are numerous prior art references, which quote use of sugar alcohols like mannitol, sorbitol etc as fillers in formulation or as sensory cue agents i.e which impart feeling of cooling in mouth in case of orally disintegrating tablets (WO2007080601, EP589981B1, EP906089B1, EP1109534B1, US6328994, WO2007001086, US20070196494, US20060240101, WO2006057912, US20060057199,). Sugar alcohols like mannitol are employed in most orally disintegrating formulations and not in conventional immediate release formulations as sensory cue agents as orally disintegrating tablets disintegrate in mouth instead of disintegrating in gastrointestinal tract as in case of conventional immediate release tablets.
The present inventors have noticed that sugar alcohols like mannitol or sorbitol when used along with other known water insoluble drugs like fenofibrate, irbesartan, aripiprazole, entacapone, either as physical mixture or in the form of complex, 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 sugar alcohols.
The present inventors while working on the diacerein formulation have surprisingly found when diacerein is present along with sugar alcohols, either as physical mixture or in form of any sort of complex or any other physical or chemical association, 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 about 80-100% diacerein in 60 minutes.
This significant increase in percent release of diacerein is due to dispersion of diacerein in sugar alcohol matrix leading to improved wettability, solubility, and hence increased percent release. This may lead to increased bioavailability. The
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increased bioavailability may further lead to reduction in side effects i.e. soft stools.
One of the aspects of the present invention provides a pharmaceutical composition comprising diacerein or salts thereof along with sugar alcohols, optionally with one or more pharmaceutically acceptable excipients.
In another aspect of the present invention there is provided a pharmaceutical composition comprising diacerein or salts thereof along with sugar alcohols, optionally with one or more pharmaceutically acceptable excipients, wherein diacerein is present in admixture with sugar alcohol.
In another aspect of the present invention there is provided a pharmaceutical composition comprising diacerein or salts thereof along with sugar alcohols, optionally with one or more pharmaceutically acceptable excipients, wherein diacerein is present in the form of complex with sugar alcohol.
In another aspect of the present invention there is provided a pharmaceutical composition comprising diacerein or salts thereof along with sugar alcohols, optionally with one or more pharmaceutically acceptable excipients, wherein diacerein is adsorbed on sugar alcohol.
In another aspect of the present invention there is provided a pharmaceutical composition comprising diacerein or salts thereof characterized by the crystallographic data shown in fig 1.
In another aspect of the present invention there is provided a pharmaceutical composition comprising diacerein or salts thereof having X-ray diffraction peaks at angle 2 theta of 9.6 and 13.52 degrees.
X-ray diffraction pattern of the pharmaceutical composition of the present invention comprising diacerein or salts thereof is shown in Figure 1. X-ray diffraction pattern of plain Diacerein is shown in Figure 2.
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The X-ray spectroscopic analysis of the samples obtained demonstrated the presence of a new crystallographically different entity, as shown on Fig. 1 representing the spectrum of the samples of the present invention (Example 4) compared with a plain diacerein (Fig 2).
In yet another aspect of the present invention there is provided a pharmaceutical composition, which comprises of diacerein or salts thereof along with sugar alcohols 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 phosphate buffer at 37 °C ± 0.5°C.
In another aspect of the present invention there is provided a method of improving the solubility of diacerein or salts thereof, wherein diacerein or salts there of is associated with one or more sugar alcohols.
In another aspect of the present invention, there is provided a process of preparation of pharmaceutical composition, which process comprises of spraying an organic solution of diacerein or salts thereof optionally with sugar alcohols or one or more pharmaceutically acceptable excipients in a flow of a fluid under supercritical pressure to form particles and collecting the said particles.
Suitable fluid used under supercritical pressure may include but not limited to carbon dioxide, water, ethane, xenon and the like.
Suitable organic solvents used for preparing organic solution of diacerein or salts thereof are those known to ordinary skill in the art and may include one or more of N-methyl-pyrrolidone, dimethyl sulfoxide, dimethylacetamide, tetrahydrofuran, ketones and the like.
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Suitable sugar alcohols may include one or more of mannitol, maltitol, maltol, sorbitol, lactitol, xylitol and the like.
The pharmaceutical composition of the present invention can be present in the form of tablet, capsule, powder, disc, caplet, granules, pellets, granules in capsule, minitablets, minitablets in capsule, pellets in capsule, sachet and other dosage forms suitable for oral administration.
In the pharmaceutical composition of the present invention, diacerein can be present in an amount relative to the sugar alcohol, such that such that a molar ratio between the diacerein and the sugar alcohol is from about 1:1 to 1:10.
The diacerein-sugar alcohol composition can be prepared by various processes including anti-solvent technique, solvent evaporation, kneading, spray drying, colloidal milling, high speed mixing, trituration.
The diacerein-sugar alcohol composition prepared by anti-solvent method using supercritical fluid results in better increase in solubility and percent release of diacerein as compared to composition containing mere diacerein-sugar alcohol mixture.
The pharmaceutical composition comprises of pharmaceutically acceptable excipients wherein excipients may include fillers, lubricants, disintegrants, and glidants.
Suitable filler may be one or more of, microcrystalline cellulose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar and the like.
Suitable lubricant may be one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl behenate and the like.
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Suitable glidant may be one or more of colloidal silicon dioxide, talc or cornstarch and the like.
Suitable disintegrant may be one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
The pharmaceutical composition can be prepared by spraying an organic solution of diacerein or salts thereof in a flow of fluid under supercritical pressure to form microparticles, which are collected on suitable sugar alcohol bed, mixed with other pharmaceutically acceptable excipients and converted into suitable dosage form.
The pharmaceutical composition can be prepared by spraying an organic solution of diacerein or salts thereof and suitable sugar alcohol in a flow of fluid under supercritical pressure to form microparticles, which are collected mixed with other pharmaceutically acceptable excipients and converted into suitable dosage form.
The pharmaceutical composition of the present invention can also be prepared by triturating diacerein with sugar alcohol, drying the triturate, mixing the dried triturate with other pharmaceutically acceptable excipients and converting the mixture into suitable dosage form.
The pharmaceutical composition of the present invention can also be prepared by triturating diacerein with sugar alcohol along with one or more surfactants, drying the triturate, mixing the dried triturate with other pharmaceutically acceptable excipients and converting the mixture into suitable dosage form.
Suitable surfactants are those known to ordinary skilled in the art and may include but not limited to amphoteric, non-ionic, cationic or anionic surfactants.
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Suitable surfactants comprises one or more of 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 glycerides, 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.
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Example-1
Table-1 Composition of diacerein capsules
S.No. Ingredients %w/w
Part I
1 Diacerein 10-90
2 Sorbitol 0.5-20
Part II
3 Microcrystalline cellulose 5-60
4 Croscarmellose sodium 1-25
5 Magnesium stearate 1-15

Procedure: Diacerein is mixed with sorbitol and triturated with minimum amount of water to form a pasty mass. Pasty mass is dried, sieved to form granules and mixed with microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The final mixture is filled into hard gelatin capsules.
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Table 2: Comparative dissolution data of ART 50 vs Diacerein capsules prepared as per example 1

Time (min) % drug released (Art 50) % drug released (Example-1)
5 3 29
10 4 53
15 5 68
20 7 76
30 9 82
45 11 89
60 14 90
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 phosphate buffer at 37 °C ± 0.5°C was used as medium.
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Example -2
Table-3 Composition of diacerein capsules
S.No. Ingredients %w/w
Part I
1 Diacerein 10-60
2 Sorbitol 0.5-20
3 Docusate sodium 1-20
4 Sodium lauryl sulfate 1-20
Part II
5 Glycine 1-20
6 Lactose 5-40
7 Crospovidone 5-40

Procedure: Diacerein is mixed with sorbitol, sodium docusate, sodium lauryl sulfate and triturated with minimum amount of water to form a pasty mass. Pasty mass is dried, sieved to form granules and mixed with glycine, lactose and crospovidone. The final mixture is filled into hard gelatin capsules.
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Table 4: Comparative dissolution data of ART 50 vs Diacerein capsules prepared as per example 2

Time (min) % drug released (Art 50) % drug released (Example-2)
5 3 16
10 4 35
15 5 50
20 7 60
30 9 72
45 11 78
60 14 82
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 phosphate buffer at 37 °C ± 0.5°C was used as medium.
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Example 3
Table-5 Composition of diacerein capsules
S.No. Ingredients %w/w
Part I
1 Diacerein 10-90
2 N-methyl pyrrolidone qs
3 Mannitol 10-90
Part II
4 Microcrystalline cellulose 5-60
5 Croscarmellose sodium 1-25
6 Magnesium stearate 1-15

Procedure: Diacerein is dissolved in N-methyl pyrrolidone and sprayed (Spray rate: 3ml/min) in a flow of carbon dioxide (15 Kg/h) under supercritical pressure (100 bars, 40°C) on bed of mannitol placed into spray reactor. The particles thus formed are recovered on bed of mannitol and mixed with microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The final mixture is filled into hard gelatin capsules.
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Table 6: Comparative dissolution data of ART 50 vs Diacerein capsules prepared as per example 3

Time (min) % drug released (Art 50) % drug released (Example-3)
5 3 27
10 4 45
15 5 60
20 7 69
30 9 82
45 11 88
60 14 95
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 phosphate buffer at 37 °C ± 0.5°C was used as medium.
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Example-4
Table-7 Composition of diacerein capsules
S.No. Ingredients %w/w
Part I
1 Diacerein 10-90
2 Mannitol 10-90
3 N-methyl pyrrolidone qs
Part II
3 Microcrystalline cellulose 5-60
4 Croscarmellose sodium 1-25
5 Magnesium stearate 1-15

Procedure: Diacerein and mannitol are dissolved in N-methyl pyrrolidone and sprayed (Spray rate: 3ml/min) in a flow of carbon dioxide (15 Kg/h) under supercritical pressure (100 bars, 40°C) in spray reactor. The particles thus formed are recovered and mixed with microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The final mixture is filled into hard gelatin capsules.
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Table 8: Comparative dissolution data of ART 50 vs Diacerein capsules prepared as per example 4

Time (min) % drug released (Art 50) % drug released (Example-4)
5 3 92
10 4 100
15 5 100
20 7 100
30 9 100
45 11 100
60 14 100
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 phosphate buffer at 37
°C ± 0.5°C was used as medium.
Comparative dissolution profile of Art 50, Example 1, 2, and 4 is shown in figure
3.
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WE CLAIM:
1. A pharmaceutical composition comprising diacerein or salts thereof along with sugar alcohols, optionally with one or more pharmaceutically acceptable excipients.
2. A pharmaceutical composition comprising diacerein or salts thereof along with sugar alcohols, optionally with one or more pharmaceutically acceptable excipients, wherein diacerein is present in admixture with sugar alcohol.
3. A pharmaceutical composition comprising diacerein or salts thereof along with sugar alcohols, optionally with one or more pharmaceutically acceptable excipients, wherein diacerein is present in the form of complex with sugar alcohol.
4. A pharmaceutical composition comprising diacerein or salts thereof along with sugar alcohols, optionally with one or more pharmaceutically acceptable excipients, wherein diacerein is adsorbed on sugar alcohol.
5. A pharmaceutical composition comprising diacerein or salts thereof characterized by the crystallographic data shown in fig 1.
6. A pharmaceutical composition comprising diacerein or salts thereof having X-ray diffraction peaks at angle 2 theta of 9.6 and 13.52 degrees.
7. A pharmaceutical composition, which comprises of diacerein or salts thereof along with sugar alcohols 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 phosphate buffer at 37 °C ± 0.5°C.
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8. The pharmaceutical composition as per any preceding claims, wherein sugar alcohols comprise one or more of mannitol, maltitol, maltol, sorbitol, lactitol, xylitol and the like.
9. The pharmaceutical composition as per any preceding claims, wherein diacerein can be present in an amount relative to the sugar alcohol, such that a molar ratio between the diacerein and the sugar alcohol is from about 1:1 to 1:10.
10. The pharmaceutical composition as per any preceding claims, wherein composition comprises one or more of tablet, capsule, powder, disc, caplet, granules, pellets, granules in capsule, minitablets, minitablets in capsule, pellets in capsule, sachet or other dosage forms suitable for oral administration.
11. The pharmaceutical composition as per any preceding claims, wherein pharmaceutically acceptable excipients comprises one or more of fillers, lubricants, disintegrants, and glidants.
12. The pharmaceutical composition of claim 8, wherein sugar alcohol is sorbitol.
13. The pharmaceutical composition of claim 8, wherein sugar alcohol is mannitol.
14. A method of improving the solubility of diacerein or salts thereof, wherein diacerein or salts there of is associated with one or more sugar alcohols.
15. A process of preparation of pharmaceutical composition, which process comprises of spraying an organic solution of diacerein or salts thereof optionally with sugar alcohols or one or more pharmaceutically acceptable excipients in a flow of a fluid under supercritical pressure to form particles and collecting the said particles.
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16. The process of claim 15, wherein supercritical fluid comprises one or more of carbon dioxide, water, ethane, xenon and the like.
17. The process of claim 15, wherein organic solution of diacerein or salts thereof is sprayed in a flow of fluid under supercritical pressure to form particles which are collected on suitable sugar alcohol bed.
18. The process of claim 15, wherein organic solution of diacerein or salts thereof along with sugar alcohol is sprayed in a flow of fluid under supercritical pressure to form particles which are collected.
19. The process of claim 15, wherein organic solvent comprises one or more of N-methyl-pyrrolidone, dimethyl sulfoxide, dimethylacetamide, tetrahydrofuran, ketones.
20. The pharmaceutical composition of claim 11, wherein filler comprises one or more of, microcrystalline cellulose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar.
21. The pharmaceutical composition of claim 11, wherein lubricant comprises one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl behenate.
22. The pharmaceutical composition of claim 11, wherein glidant comprises one or more of colloidal silicon dioxide, talc or cornstarch.
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23. The pharmaceutical composition of claim 11, wherein disintegrant comprises one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate.


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ABSTRACT
The present invention provides a pharmaceutical composition comprising diacerein or pharmaceutically acceptable salts thereof along with sugar alcohols, optionally with one or more pharmaceutically acceptable excipients. The invention also relates to processes for the preparation of such compositions. The composition of the present invention may exhibit improved bioavailability along with reduced undesirable side effects.
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