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:
ORALLY DISINTEGRATING COMPOSITIONS OF RHEIN OR DIACEREIN OR SALTS THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D4-MIDC Area, Chikalthana,
Aurangabad - 431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides an orally disintegrating pharmaceutical composition, in the form of tablet comprising rhein or diacerein, or salts or esters or prodrug thereof, along 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
The present invention provides an orally disintegrating pharmaceutical composition, in the form of tablet comprising rhein or diacerein, or salts or esters or prodrug thereof, along with one or more pharmaceutically acceptable excipients.
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.

FORMULA I


FORMULA II
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.


Current dosing of diacerein is twice a day using immediate release capsule (Art 50). The capsule forms, are however difficult to swallow, especially for geriatric patients. Further, the fear of swallowing, or choking on such solid shaped articles is still a concern in certain populations especially geriatrics. It is estimated that almost 50% of the population have problems of swallowing tablets or capsules (Seager in Journal of Pharmacol. And Pharm. Pages 375-382, 1998). Capsule dosage forms become sticky when wetted by saliva, and if patient experiences difficulty in swallowing on first attempt, then the capsule must often be discarded. Furthermore, if a capsule partially dissolves in patient's mouth, as can result from unsuccessful swallowing or the capsule getting stuck in the orthodontic appliance, the resulting very unpleasant taste can make it difficult to persuade the patient to take another dose. Additionally, these dosage forms are difficult to carry, store and handle. Moreover, the difficulties associated with capsules result in decreased patient compliance. Orally dissolving formulations of rhein or diacerein are beneficial for many reasons. Their characteristic advantage such as administration without liquid, anywhere, anytime lead to their suitability in situations where patients have difficulty in swallowing especially geriatrics and particularly those with neurological disorders. In addition to convenient dosing, it leads to no choking, more fast disintegration and hence rapid release.
Design of orally disintegrating tablet requires a significant amount of research work in order to develop a process that maintains enough porosity inside the compressed tablet for fast dissolving or fast melting while maintaining the mechanical strength of the tablet. It was a significant challenge to obtain suitable orally disintegrating tablets comprising rhein or diacerein according to the invention because quite a number of issues had to be accommodated: High bioavailability of diacerein had to be ensured, the oral disintegrating tablet had to be palatable to the patient and its stability, especially the chemical stability of the active substance within the tablet, had to be assured. Moreover, good organoleptic properties, such as an immediate disintegration of tablet to prevent


any adverse feeling in the mouth, and sufficient mechanical strength to allow for appropriate packaging operations, were required. The inventors have overcome these challenges by providing rhein or diacerein comprising oral disintegrating tablets meeting said requirements.
One of the aspects of the present invention provides an orally disintegrating pharmaceutical composition, in the form of tablet, comprising rhein or diacerein, or salts or esters or prodrug thereof, along with one or more pharmaceutically acceptable excipients.
Another aspect of the present invention provides orally disintegrating pharmaceutical composition, in the form of granules, particles or pellets comprising rhein or diacerein, or salts or esters or prodrug thereof, along with one or more pharmaceutically acceptable excipients.
Another aspect of the present invention provides an orally disintegrating pharmaceutical composition, in the form of tablet, comprising rhein or diacerein, or salts or esters or prodrug thereof; wherein the composition exhibits a dissolution profile such that within 15 minutes more than 70% of rhein or diacerein or salts or esters or prodrug thereof 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.
The pharmaceutical composition of the invention may be prepared by physical mixing, wet mixing, spray congealing, hot melt, antisolvent, microfluidization, spray drying and freeze drying.
The tablets of the invention disintegrate in mouth of patient in less than 45 seconds, preferably in less than 30 seconds.


The tablet may vary in shapes such as oval, round, triangle, almond, peanut, pentagonal, trapezoidal, parallelogram and the like.
The pH of 0.5-1 %w/w dispersion of orally disintegrating tablet of the invention may lie in the range of 4-7.0.
The pharmaceutical composition of the invention comprises of pharmaceutically acceptable excipients wherein excipients may include one or more of binders, fillers, disintegrants, glidants, lubricants, surfactants, sweeteners and flavors.
Suitable binder may include one or more of, povidone, starch, stearic acid, gums, celluloses, alginic acids, chitosan, chitin, polyethylene glycol and the like.
Suitable fillers may include one or more of saccharose, glucose, fructose, maltose, maltitol, mannitol, dextrins such as maltodextrins; xylitol, sorbitol, microcrystalline cellulose, titanium dioxide, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar, silicates such as magnesium aluminium silicate and the like.
Suitable disintegrant may include one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
Suitable glidant may include one or more of colloidal silicon dioxide, talc or cornstarch and the like.
Suitable lubricant may include one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl behenate and the like.
Suitable surfactants are those known to ordinary skilled in the art and may include but not limited to amphoteric, non-ionic, cationic or anionic surfactants.


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.
Suitable sweetener may include one or more of monosaccharides, disaccharides and polysaccharides, e.g. xylose, ribose, glucose, mannose, galactose, fructose, sucrose, maltose, invert sugar, partially hydrolyzed starch, corn syrup solids, mannitol, xylitol, D-sorbitol, erythritol, pentitol, hexitol, malitol, dihydrochalcones, monellin, steviosides or glycyrrhizin; saccharin in free acid form, soluble saccharin salts, e.g. sodium or calcium saccharin salts, cyclamate salts or acesulfame K; dipeptide based sweeteners, such as L-aspartic acid derived sweeteners, e.g. aspartame; water-soluble sweeteners derived from naturally occurring water-soluble sweeteners, e.g. sucralose; and protein based sweeteners, e.g. thaumatococcus danielli (Thaumatin I and II) and the like.
Suitable flavoring agents may include those known to the skilled artisan, such as natural, "natural-like" and artificial flavors. These flavors may be chosen e.g. from synthetic flavor oils, flavoring aromatics, oleo-resins and extracts derived e.g. from plants, leaves, flowers or fruits.
Representative flavors may include one or more of spearmint oil, cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds, vanilla, chocolate, coffee, cocoa and citrus oil, lemon, orange, cherry, grape, lime or grapefruit, and fruit essences, e.g. apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple or apricot; mints such as peppermint (including menthol, especially levomenthol), aldehydes and esters, e.g. cinnamyl acetate, cinnamaldehyde, citral, diethylacetal, dihydrocarvyl acetate, eugenyl formate or p-methylanisol; alpha-citral (geranial) and beta-citral (neral); decanal; ethyl vanillin; piperonal (heliotropine); vanillin; alpha-amyl


cinnamaldehyde; butyraldehyde; valeraldehyde; citronellal; decanal; aldehyde C-8; aldehyde C-9; aldehyde C-12; 2-ethyl butyraldehyde; hexenal, i.e. trans-2; tolyl aldehyde; veratraldehyde; 2,6-dimethyl-5-heptenal (melonal); 2-6-dimethyloctanal; 2-dodecenal and the like.
Moreover, the tablets of the invention optionally include usual auxiliaries known in the art such as saliva stimulating agents like citric acid, lactic acid, malic acid, succinic acid, ascorbic acid, adipic acid, fumaric acid, tartaric acids; cooling sensation agents like maltitol, monomenthyl succinate, ultracool; stabilizers like gums, agar; taste masking agents like acrylic polymers, copolymers of acrylates, celluloses, resins; coloring agents like titanium dioxide, natural food colors, dyes suitable for food, drug and cosmetic applications; preservatives like alpha-tocopherol, citric acid, butylated hydroxytoluene, butylated hydroxyanisole, ascorbic acid, fumaric acid, malic acid, sodium ascorbate or ascorbic acid palmitate or effervescing agents like citric acid, tartaric acid, sodium bicarbonate, sodium carbonate and the like.
The pharmaceutical composition of the invention may be prepared by mixing rhein or diacerein or salts or esters or prodrugs thereof with other pharmaceutically acceptable excipients, and optionally compressing the mixture into tablets.
The pharmaceutical composition of the invention may also be prepared by suspending mixture of rhein or diacerein or salts or esters or prodrugs thereof with other pharmaceutically acceptable excipients in surfactant solution and granulating the mixture of other pharmaceutically acceptable excipients with said suspension, drying the granules, optionally compressing the granules into tablets.
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 provides the composition of batches of the present invention.
Table 1

S.No Ingredients %W/W
1 Diacerein 7.5-37.50
2 Microcrystalline Cellulose 5-80
3 Crospovidone 2-10
4 Croscarmellose Sodium 2-10
5 Hydroxy propyl Cellulose 2-10
6 Aspartame 0.1-5
7 Acesulfame 0.1-5
8 Butterscotch and Tuttyfruity flavor 0.1-5
9 Mannitol 5-80
10 Citric Acid 0.25-10
11 Sodium Bi Carbonate 0.25-10
12 Colloidal Silicon Dioxide 0.5-2.5
13 Magnesium Stearate 0.5-2
Procedure: Butterscotch and tuttyfruity flavor, aspartame, acesulfame were triturated together and added to microcrystalline cellulose by sifting to form a blend. The blend was admixed with diacerein, mannitol, polyplasdone, croscarmellose sodium, citric acid, sodium bicarbonate and hydroxypropyl cellulose to form a uniform mixture. The mixture was blended with colloidal silicon dioxide and lubricated by magnesium stearate. The lubricated blend was compressed into suitable sized tablets using suitable tooling. The tablet disintegrates in about 20-27 seconds.


Example 2:
Table 2 provides the composition of batches of the present invention.
Table 2

S.No Ingredients %w/w
1 Diacerein 7.5-37.50
2 Methacrylic acid divinyl benzene copolymer potassium salt 1-10
3 Microcrystalline Cellulose 5-75
4 Crospovidone 2-10
5 Croscarmellose Sodium 2-10
6 Hydroxy propyl Cellulose 2-10
7 Aspartame 0.1-5
8 Pineapple flavor 0.1-5
9 Mannitol 5-75
10 Colloidal Silicon Dioxide 0.25-2.5
11 Magnesium Stearate 0.25-2
Procedure: Pineapple flavor and aspartame were added to microcrystalline cellulose by sifting to form a blend. Diacerein and methacrylic acid divinyl benzene copolymer potassium salt were sifted together and added to the above blend. The blend was admixed with mannitol, polyplasdone, croscarmellose sodium, and hydroxypropyl cellulose to form uniform mixture. The mixture was blended with colloidal silicon dioxide. The blend was lubricated with magnesium stearate. The lubricated blend was compressed into suitable sized tablets using suitable tooling. The tablet disintegrates in about 30 seconds.


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

S.No Ingredients %w/w
1 Diacerein 7.5-37.50
2 Magnesium aluminum Silicate 2-20
3 Microcrystalline Cellulose 5-80
4 Crospovidone 2-10
5 Croscarmellose Sodium 2-10
6 Hydroxy propyl Cellulose 2-10
7 Aspartame 0.1-5
8 Lemon flavor 0.1-5
9 Mannitol 5-80
10 Colloidal Silicon Dioxide 0.25-2.5
11 Magnesium Stearate 0.25-2
Procedure: Lemon flavor, magnesium aluminum silicate and aspartame were added to microcrystalline cellulose by sifting to form a blend. The blend was admixed with diacerein, mannitol, polyplasdone, croscarmellose sodium, and hydroxypropyl cellulose to form uniform mixture. The mixture was blended with colloidal silicon dioxide. The blend was lubricated with magnesium stearate. The lubricated btend was compressed into suitable sized tablets using suitable tooling. The tablet disintegrates in about 20-27 seconds.


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

S.No Ingredients %w/w
1 Diacerein 7.5-37.50
2 Microcyrstalline Cellulose 5-80
3 Crospovidone 2-10
4 Croscarmellose Sodium 2-10
5 Hydroxy propyl Cellulose 2-10
6 Sodium Lauryl Sulfate 0.5-2.5
7 Docusate Sodium 0.1-2.5
8 Purified Water q.s.
9 Isopropyl Alcohol q.s.
10 Aspartame 0.1-5
11 Acesulfame 0.1-5
12 Butterscotch and tutty fruity flavor 0.1-5
13 Mannitol 5-80
14 Glycine 0.1-5
15 Colloidal Silicon Dioxide 0.25-2.5
16 Magnesium Stearate 0.25-2
Procedure: Docusate Sodium was dissolved in isopropyl alcohol and sodium lauryl sulphate was dissolved in purified water and the two solutions were mixed together. Diacerein, acesulfame, aspartame, glycine, and flavor were sifted together and subjected to homogenization with the above solution. The suspension was used for granulation using base of mannitol. Granulated mass was dried and subsequently sized to form uniform granules. Microcrystalline Cellulose, polyplasdone, croscarmellose sodium, and hydroxypropyl cellulose were admixed along with granules and blended with colloidal silicon dioxide. The blend was lubricated with magnesium stearate. The lubricated blend was compressed into suitable sized tablets using suitable tooling.


Example 5:
Table 5 provides the composition of batches of the present invention.
Table 5

S.No Ingredients %w/w
1 Diacerein 7.5-37.50
2 Pregelatinized Starch 5-20
3 Crospovidone 2-10
4 Croscarmellose Sodium 2-10
5 Hydroxy propyl Cellulose 2-10
6 Poloxamer 2-10
7 Acesulfame 0.1-5
8 Sucralose 0.1-5
9 Tropical banana flavor 0.1-5
10 Lactose 5-80
11 Mannitol 5-80
12 Menthol 0.01-0.5
13 Colloidal Silicon Dioxide 0.25-2.5
14 Sodium Stearyl fumarate 0.25-2
Procedure: Poloxamer was dissolved in purified water. Diacerein, acesulfame, sucralose and flavors were sifted together and subjected to homogenization with the above solution. The suspension was used for granulation using base of lactose. Granulated mass was dried. Menthol was dissolved in isopropyl alcohol and then sprayed/added on to the lactose drug loaded base granules and dried. Dried granules were sized to form uniform granules. Pregelatinized Starch, mannitol, polyplasdone, croscarmellose sodium, and hydroxypropyl cellulose were admixed along with granules and blended with colloidal silicon dioxide. The blend was lubricated by magnesium stearate. The lubricated blend was compressed into suitable sized tablets using suitable tooling.


WE CLAIM:
1) An orally disintegrating pharmaceutical composition, in the form of tablet, comprising rhein or diacerein, or salts or esters or prodrug thereof, along with one or more pharmaceutically acceptable excipients.
2) An orally disintegrating pharmaceutical composition, in the form of granules, particles or pellets comprising rhein or diacerein, or salts or esters or prodrug thereof, along with one or more pharmaceutically acceptable excipients.
3) An orally disintegrating pharmaceutical composition, in the form of tablet, comprising rhein or diacerein, or salts or esters or prodrug thereof; wherein the composition exhibits a dissolution profile such that within 15 minutes more than 70% of rhein or diacerein or salts or esters or prodrug thereof 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.
4) The tablet of claim 1 or 3, wherein the said tablet disintegrates in mouth of patient in less than 45 seconds.
5) The composition of claim 1 or 2, wherein the other pharmaceutically acceptable excipients comprises one or more of binders, fillers, disintegrants, glidants, lubricants, surfactants, sweeteners and flavors.
6) The composition of claim 5, wherein the binder comprises one or more of, povidone, starch, stearic acid, gums, celluloses, alginic acids, chitosan, chitin, and polyethylene glycol.
7) The composition of claim 5, wherein the filler comprises one or more of saccharose, glucose, fructose, maltose, maltitol, mannitol, dextrins such as maltodextrins; xylitol, sorbitol, microcrystalline cellulose, titanium dioxide, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar and silicates.


8) The composition of claim 5, wherein the disintegrant comprises one or more of starch, croscarmellose sodium, crospovidone and sodium starch glycolate.
9) The composition of claim 5, wherein the 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 and cremophore RH 40.
10) An orally disintegrating pharmaceutical composition substantially as herein
described.






ABSTRACT
The present invention provides an orally disintegrating pharmaceutical composition, in the form of tablet comprising rhein or diacerein, or salts or esters or prodrug thereof, along with one or more pharmaceutically acceptable excipients. The invention also relates to the process of preparation of such compositions.