FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)

1. TITLE OF THE INVENTION:
“Diacerein dispersible tablet formulation”

2. APPLICANT (S)

(a) NAME: LYKA LABS LIMITED.

(b) NATIONALITY: Indian Company incorporated under the Companies
Act 1956

(c) ADDRESS: 101, Shivshakti Industrial Estate, Andheri- Kurla Road,
Andheri (East) Mumbai-400 059, Maharashtra, India

3 PREAMBLE TO THE DESCRIPTION

The following specification particularly describes the invention:
Technical field of the invention
The present invention refers to a pharmaceutical composition comprising Diacerein, in the form of dispersible tablets. The pharmaceutical composition is particularly useful for Osteoarthritis.
Background and prior art
Osteoarthritis is a type of arthritis which is caused due to the breakdown and eventual loss of the cartilage of the joints of bones which normally causes pain and swelling. It occurs more frequently with aging and commonly affects the hands, feet, spine, hips and knees. For the treatment of osteoarthritis, Diacerein (4,5-bis(acetyloxy)-9,10-dioxo-2-anthracene carboxylic acid or diacetylrhein) is used as oral dosage form. The mode of action of Diacerein differs from non-steroidal anti-inflammatory drugs (NSAIDs) and other conventional forms of drug therapy. It is a slow acting drug which normally slows down the cartilage breakdown and relieves pain and swelling.
Diacerein is entirely converted into rhein before biodispersion and have been shown to inhibit the synthesis and activities of interleukin-1 (IL-1), as well as to stimulate anabolic processes occur in cartilage.
Diacerein dispersible tablets offer many added benefits over conventional tablet dosage forms. These solid dosage form disperses in water and are particularly useful for subjects that require oral medication but have difficulty in swallowing oral dosage forms such as tablets/capsules.
Very often convalescent, aged people have difficulty in swallowing tablets and capsules.
US 5952383 discloses a pharmaceutical composition for oral administration comprising diacerein, rhein or one of their salts in the form of a wafer capsule or a gelatin capsule. In US 6610750, rhein or a rhein derivative, preferably diacerein, either alone or in
2

combination with analgesics, antipyretics, cortico-steroids, anti-inflammatory agents for treating osteoarthritis are described. The use of diacerein or a pharmaceutically acceptable derivative thereof for the manufacture of a pharmaceutical composition for the treatment of psoriasis or diseases associated therewith, such as psoriatic arthritis is described in US 6844365.
Clinical trials have shown that Diacerein is highly effective in relieving the symptoms of osteoarthritis. Moreover, results from studies conducted in vitro, in animals and in humans indicate that it may be able to modify the course of the disease. It has slow-acting effects, particularly 2-4 weeks after the start of treatment and significantly after 4-6 weeks, but persists for several months after administration ceases.
Therefore, there is a need to provide dispersible tablets of Diacerein, which are suitably formulated to spontaneously disintegrate in water within 3 minutes prior to administration thereby increasing the ease of administration for geriatric patients who have difficulty in swallowing. These tablets are sweetened and flavoured to make them palatable. Taste masking of active ingredient is also done in Diacerein dispersible tablet thereby increasing patient compliance
Object of the invention
The object of the present invention is to provide a Diacerein dispersible tablet
composition useful for the treatment of Osteoarthritis.
Another object of the invention is to provide a Diacerein dispersible tablet composition
which has the advantages of better dispersion, shorter disintegration time and ease of
administration for patients who have difficulty in swallowing.
The tablet can be placed in water prior to administration to form a uniform dispersion
within 3 minutes. The tablets are suitably sweetened and flavoured.
Summary of the Invention:
The present invention discloses Diacerein dispersible tablet composition useful for the treatment of Osteoarthritis. The dispersible tablet composition of the present invention has the advantages of better dispersion, shorter disintegration time and ease of
3

administration for patients who have difficulty in swallowing. The tablet can be placed in water prior to administration to form a uniform dispersion within 3 minutes. The tablets are suitably sweetened and flavoured.
Detailed Description of the invention
The present invention provides dispersible pharmaceutical composition of Diacerien and the process of preparation thereof.
The present pharmaceutical composition comprises Diacerein and pharmaceutically accepted excipients selected from diluents, film formers, disintegrants, binders, flavours, sweeteners, lubricants, and/or glidants.
Diluents are selected from Microcrystalline cellulose, Lactose, Mannitol, Maize starch etc. However the diluent chosen for present invention is Microcrystalline cellulose. This diluent alone or in combination may be used in the range from 15-80% weight of the total formulation.
The said microcrystalline cellulose (Avicel PH 101/Avicel PH 102) is used as a diluent for better compressibility and also to aid in disintegration. The said microcrystalline cellulose (Avicel PH 101/Avicel PH 102) is used in the range of 15 - 60 %.
Disintegrants are selected from Croscarmellose Sodium, ethyl cellulose, Microcrystalline cellulose (Avicel pH 102), Hydroxypropyl cellulose LH 11.
The said Microcrystalline cellulose (Avicel PH 101/Avicel PH 102 ) is used in the range of 15% to 50%
The said Croscarmellose sodium provides superior dispersion time of the formulation. It may be used in the range from 2.0%> weight upto 15% weight of total formulation. The said Hydroxypropyl cellulose LH -11 is used in the range of 2 - 15 %.
Film formers may be used as binders to mask the bitter taste may be selected from Ethyl cellulose, Hydroxy propyl methyl cellulose, Hydroxy propyl cellulose, Povidone K-30. It may be used alone or in combination in the range of 0.25 % -3 %. The preferred ingredient is ethyl cellulose is used in the range of 0.25 - 2 %.
4

The Lubricants may be selected from Hydrogenated casor oil, Stearic acid, Magnesium stearate preferably selected lubricant is Magnesium Stearate in the range of 0.25 - 2 %.
The Sweeteners may be chosen from artificial sweeteners such as aspartame, sodium Saccharin or sweetener from natural origin like sodium glycyrrhizinate, preferably selected is Aspartame in the range of 1 - 5 %.
Suitable flavour may be chosen such as pineapple, mango, lemon , peppermint flavour. The flavour used is preferably pineapple flavour in the range of 0.25 - 2 %.
The process for manufacture of Diacerein dispersible tablet composition is as follows:
i) sifting Diacerein and Microcrystalline Cellulose through 40 mesh sieve;
ii) mixing the sifted ingredients of step i) for sufficient time to get uniform blend;
iii) preparing binder solution using Ethyl cellulose/Povidone K-30/Hydroxy propyl
methyl cellulose or Hydroxy propyl cellulose in and Iso propyl alcohol alone or mixture
of Isopropyl alcohol with Methylene chloride or purified water in the ratio from 1:1 to
1:3.
iv) granulating the blend of step ii) with binder solvent of step iii) to obtain wet mass of
suitable consistency;
v) passing the wet mass through mesh sieve;
vi) drying the granules in tray dryer at 50 - 55 °C for sufficient time;
vii) Size the dried granules by passing through 40 mesh sieve.
viii) sifting colloidal silicon dioxide, croscarmellose sodium, Microcrystalline cellulose
(Avicel PH 102), Hydroxy Propyl Cellulose LH 11, magnesium stearate/Hydrogenated
castor oil, Pineapple flavour and Aspartame through 40 mesh sieve;
ix) mixing dried granules of step vii) and sifted lubricants of step viii) for sufficient time
to get uniform blend;
x) compressing the lubricated granules on Rotary Machine.
Thus, the present invention provides Diacerein dispersible tablet composition which disintegrates within 3 minutes to form a uniform dispersion.
5

The granulating solvent used may be a mixture of Isopropyl alcohol and purified water in the ratio 2:1 to 1:2, more preferably 1:1
The tablet composition can be administered orally at the optimal daily dosage of 50 mg twice daily.
The invention can be illustrated by the following non-limiting Examples.
Examples:
Example 1:
Composition:
Each of the 190mg tablet comprises:

Sr.No. Ingredients Ingredient Specification Qty/tablet
1 Diacerein I. H. S. 51 mg
2 Microcrystalline cellulose I. P. 25 mg
3 Ethyl cellulose LP. 2mg
4 Microcrystalline cellulose (Avicel PH 102) LP. 75.5 mg
5 Croscarmellose Sodium USP/NF 14 mg
6 Colloidal Silicon Dioxide LP. 1 mg
7 Hydroxy propyl Cellulose LH 11 LP. 12 mg
8 Magnesium Stearate LP. 1.5 mg
9 Pineapple Flavour I. H. S. 2mg
10 Aspartame LP. 6mg
11 Isopropyl Alcohol LP. q.s.
190 mg
Method of manufacture of Diacerein tablet composition:
i) sift 51 gm Diacerein and 25 gm Microcrystalline Cellulose through 40 mesh sieve;
ii) mix the sifted ingredients of step 1 for sufficient time to get uniform blend;
iii) prepare binder solution using 2 gm Ethyl cellulose and 30 ml Iso propyl alcohol;
6

iv) granulate the blend of step 2 with binder solution of step 3 to obtain wet mass of
suitable consistency;
v) pass the wet mass through suitable mesh sieve;
vi) dry the granules in tray dryer at 50 - 55 °C for sufficient time;
vii) size the dried granules by passing through 40 mesh sieve;
viii) sift 1 gm colloidal silicon dioxide, 14 gm croscarmellose sodium, 75.7 gm Avicel PH
102, 12 gm Hydroxy Propyl Cellulose LH 11, 1.50 gm magnesium stearate, 2 gm
Pineapple flavour and 6 gm Aspartame through 40 mesh sieve;
ix) mix dried granules of step 7 and sifted lubricants of step 8 for sufficient time to get
uniform blend;
x) compress the lubricated granules on Rotary Machine using 8 mm, circular, flat punches
to obtain yellow coloured circular, flat tablets with break line on one side and other side
plain.
Average Wt./tablet : 190mg+/-2%
Dispersion Time : Not more than 3 minutes
Hardness : 2-4 kg/cm2
Friability : Not more than 1%w/w
Uniformity of Dispersion:
Place 2 tablets in 100 ml of water and stir gently until completely dispersed. A smooth
dispersion is obtained which passes through a screen with a nominal mesh aperture of 710
microns.
Disintegration Test:
A) Disintegration Test of tablet composition is carried out on D. T. apparatus using
water at 24 - 26°C.
Disintegration time: less than 3 mins.
B) Disintegration Test of tablet composition is carried out in a 25 ml glass beaker
containing 15 ml of water.
Disintegration time: less than 3 mins.
7

The above test results show that the tablet composition is uniformly dispersible.
Example 2:
Composition:
Each of the 190mg tablet comprises:

Sr.No. Ingredients Ingredient Specification Qty/tablet
1 Diacerein I. H. S. 51 mg
2 Microcrystalline cellulose (Avicel PH 101) I. P. 99.5mg
3 Povidone K-30 LP. 3mg
4 Croscarmellose Sodium USP/NF 14 mg
5 Colloidal Silicon Dioxide I. P. 1 mg
6 ^ Hydroxy propyl Cellulose LH 11 LP. 12 mg
7 Magnesium Stearate LP. 1.5 mg
8 Pineapple Flavour LH. S. 2mg
9 Aspartame LP. 6mg
10 Isopropyl Alcohol: Water (1:1) LP. q.s.
190mg
Method of manufacture of Diacerein tablet composition:
i) sift 51 gm Diacerein, 99.5 gm Microcrystalline Cellulose(Avicel PH-101) and
12.0gm Hydroxy propyl cellulose (HPC LH-1 l)through 40 mesh sieve;
ii) mix the sifted ingredients of step 1 for sufficient time to get uniform blend;
iii) Prepare binder solution using 3.0 gm Povidone K-30 in isopropyl alcohol
: purified water mixture (1:1)
iv) granulate the blend of step 2 with binder solution of step 3 to obtain wet mass of
suitable consistency;
v) pass the wet mass through suitable mesh sieve;
vi) dry the granules in tray dryer at 50 - 55 °C for sufficient time;
vii) size the dried granules by passing through 40 mesh sieve;
viii) sift 1 gm colloidal silicon dioxide, 14 gm croscarmellose sodium, 1.50gm
8

magnesium stearate, 2 gm Pineapple flavour and 6 gm Aspartame through
40 mesh sieve;
ix) mix dried granules of step 7 and sifted lubricants of step 8 for sufficient time to
get uniform blend;
x) compress the lubricated granules on Rotary Machine te using 8 mm, circular,
flat punches to obtain yellow coloured circular, flat tablets with break line
on one side and other side plain.
Average Wt./tablet : 190mg+/-2%
Dispersion Time : Not more than 3 minutes
Hardness : 2-4 kg/cm2
Friability : Not more than 1%w/w
Uniformity of Dispersion:
Place 2 tablets in 100 ml of water and stir gently until completely dispersed. A smooth
dispersion is obtained which passes through a screen with a nominal mesh aperture of 710
microns.
Disintegration Test:
A) Disintegration Test of tablet composition is carried out on D. T. apparatus using water at 24 - 26°C. Disintegration time: less than 3 mins.
B) Disintegration Test of tablet composition is carried out in a 25 ml glass beaker containing 15 ml of water.Disintegration time: less than 3 mins.
The above test results show that the tablet composition is uniformly dispersible.
Alternatively only Isopropyl alcohol may be used as the granulating solvent as stated in example 2 above.
Example 3:
Composition:
Each of the 190mg tablet comprises:
9

Sr.No. Ingredients Ingredient Specification Qty/tablet
1 Diacerein I. H. S. 51 mg
2 Microcrystalline cellulose LP. 25 mg
3 Hydroxy propyl methyl cellulose LP. 1.5 mg
4 Microcrystalline cellulose (Avicel PH 102) LP. 75.5 mg
5 Croscarmellose Sodium USP/NF 14.5 mg
6 Colloidal Silicon Dioxide LP. 1 mg
7 Hydroxy propyl Cellulose LH-11 LP. 12 mg
8 Magnesium Stearate LP. 1.5 mg
9 Pineapple Flavour I. H. S. 2mg
10 Aspartame LP. 6mg
11 Isopropyl Alcohol +purified water(l:l) LP. q.s.
190 mg
Method of manufacture of Diacerein tablet composition:
i) sift 51 gm Diacerein and 25.0 gm Microcrystalline Cellulose through 40 mesh sieve.
ii) mix the sifted ingredients of step 1 for sufficient time to get uniform blend;
iii) Prepare binder solution using 1.5 gm Hydroxy propyl methyl cellulose in
Isopropyl alcohol + purified water mixture (1:1)
iv) granulate the blend of step 2 with binder solution of step 3 to obtain wet mass of
suitable consistency;
v) pass the wet mass through suitable mesh sieve;
vi) dry the granules in tray dryer at 50 - 55 °C for sufficient time;
vii) size the dried granules by passing through 40 mesh sieve;
viii) sift 75.5 gm Microcrystalline cellulose (Avicel PH 102), 1 gm colloidal silicon
dioxide, 12.0 gm Hydroxy propyl cellulose (HPC LH-11), 14.5 gm croscarmellose
sodium, 1.50gm magnesium stearate, 2 gm Pineapple flavour and 6 gm
Aspartame through 40 mesh sieve;
ix) mix dried granules of step 7 and sifted lubricants of step 8 for sufficient time to
get uniform blend;
x) compress the lubricated granules on Rotary Machine te using 8 mm, circular,
10

flat punches to obtain yellow coloured circular, flat tablets with break line on one side and other side plain.
Average Wt./tablet : 190mg+/-2%
Dispersion Time : Not more than 3 minutes
Hardness : 2-4 kg/cm2
Friability : Not more than 1 % w/w
Uniformity of Dispersion:
Place 2 tablets in 100 ml of water and stir gently until completely dispersed. A smooth
dispersion is obtained which passes through a screen with a nominal mesh aperture of 710
microns.
Disintegration Test:
A) Disintegration Test of tablet composition is carried out on D. T. apparatus using water at 24 - 26°C. Disintegration time: less than 3 mins.
B) Disintegration Test of tablet composition is carried out in a 25 ml glass beaker containing 15 ml of water.Disintegration time: less than 3 mins.
The above test results show that the tablet composition is uniformly dispersible. Alternatively Isopropyl alcohol : Methylene chloride may be used as the granulating solvent instead of Isopropyl alcohol: purified water as stated in example 3 above.
Example 4:
Composition:
Each of the 190mg tablet comprises:

Sr.No. Ingredients Ingredient Specification Qty/tablet
1 Diacerein I. H. S. 51 mg
2 Microcrystalline cellulose I. P. 25 mg
3 Hydroxy propyl cellulose LP. 1.5 mg
11

4 Microcrystalline cellulose (Avicel PH 102) I.P. 75.5 mg
5 Croscarmellose Sodium USP/NF 14.5 mg
6 Colloidal Silicon Dioxide I.P. 1 mg
7 Hydroxy propyl Cellulose (HPC LH-11) I.P. 12 mg
8 Magnesium Stearate I.P. 1.5 mg
9 Pineapple Flavour I. H. S. 2mg
10 Aspartame I.P. 6mg
11 Isopropyl Alcohol +purified water(1:1) I.P. q.s.
190 mg
Method of manufacture of Diacerein tablet composition:
i) sift 51 gm Diacerein and 25.0 gm Microcrystalline Cellulose through 40 mesh sieve.
ii) mix the sifted ingredients of step 1 for sufficient time to get uniform blend;
iii) Prepare binder solution using 1.5 gm Hydroxy propyl cellulose in
Isopropyl alcohol + purified water mixture (1:1)
iv) granulate the blend of step 2 with binder solution of step 3 to obtain wet mass of
suitable consistency;
v) pass the wet mass through suitable mesh sieve;
vi) dry the granules in tray dryer at 50 - 55 °C for sufficient time;
vii) size the dried granules by passing through 40 mesh sieve;
viii) sift 75.5 gm Microcrystalline cellulose (Avicel PH 102), 12.0 gm Hydroxy propyl
cellulose (HPC LH-11), 1 gm colloidal silicon dioxide, 14.5 gm croscarmellose
sodium, 1.50gm magnesium stearate,
2 gm Pineapple flavour and 6 gm Aspartame through 40 mesh sieve;
ix) mix dried granules of step 7 and sifted lubricants of step 8 for sufficient time to
get uniform blend;
x) compress the lubricated granules on Rotary Machine te using 8 mm, circular,
flat punches to obtain yellow coloured circular, flat tablets with break line
on one side and other side plain.
Average Wt./tablet : 190mg+/-2%
Dispersion Time : Not more than 3 minutes
12

Hardness : 2-4 kg/cm2
Friability : Not more than 1%w/w
Uniformity of Dispersion:
Place 2 tablets in 100 ml of water and stir gently until completely dispersed. A smooth
dispersion is obtained which passes through a screen with a nominal mesh aperture of 710
microns.
Disintegration Test:
A) Disintegration Test of tablet composition is carried out on D. T. apparatus using water at 24 - 26°C. Disintegration time: less than 3 mins.
B) Disintegration Test of tablet composition is carried out in a 25 ml glass beaker containing 15 ml of water.Disintegration time: less than 3 mins.
The above test results show that the tablet composition is uniformly dispersible.
Alternatively Isopropyl alcohol: Methylene chloride may be used as the granulating solvent instead of Isopropyl alcohol: purified water as stated in example 4 above.
Example 5:
Composition:
Each of the 190mg tablet comprises:

Sr.No. Ingredients Ingredient Specification Qty/tablet
1 Diacerein I. H. S. 51 mg
2 Microcrystalline cellulose (Avicel PH 101) LP. 92.5mg
3 Hydroxypropyl cellulose LH-21 LP. 10 mg
4 Croscarmellose Sodium USP/NF 14 mg
5 Colloidal Silicon Dioxide LP. 1 mg
6 Hydroxy propyl Cellulose LH 11 LP. 12 mg
7 Magnesium Stearate LP. 1.5 mg
13

8 Pineapple Flavour I. H. S. 2mg
9 Aspartame I. P. 6mg
10 Isopropyl Alcohol: Water (1:1) LP. q.s.
190 mg
Method of manufacture of Diacerein tablet composition:
i) sift 51 gm Diacerein and 92.5 gm Microcrystalline Cellulose (Avicel PH-101)and 10.0
gm Hydroxy propyl cellulose LH-21 through 40 mesh sieve.
ii) mix the sifted ingredients of step 1 for sufficient time to get uniform blend;
iii) granulate the blend of step 2 with Isopropyl alcohol alone or mixture of
Isopropyl alcohol with Methylene chloride or Purified water in the ratio of 1:1 to
1:3. to obtain wet mass of suitable consistency;
iv) pass the wet mass through suitable mesh sieve;
v) dry the granules in tray dryer at 50 - 55 °C for sufficient time;
vi) size the dried granules by passing through 40 mesh sieve;
vii) sift 1 gm colloidal silicon dioxide, 14.0 gm croscarmellose sodium, 12.0gm
Hydroxy propyl cellulose (HPC LH-11), 1.50gm magnesium stearate, 2 gm
Pineapple flavour and 6 gm Aspartame through 40 mesh sieve;
ix) mix dried granules of step 7 and sifted lubricants of step 8 for sufficient time to
get uniform blend;
x) compress the lubricated granules on Rotary Machine te using 8 mm, circular,
flat punches to obtain yellow coloured circular, flat tablets with break line
on one side and other side plain.
Average Wt./tablet : 190mg+/-2%
Dispersion Time : Not more than 3 minutes
Hardness : 2-4 kg/cm2
Friability : Not more than 1%w/w
14

Uniformity of Dispersion:
Place 2 tablets in 100 ml of water and stir gently until completely dispersed. A smooth
dispersion is obtained which passes through a screen with a nominal mesh aperture of 710
microns.
Disintegration Test:
A) Disintegration Test of tablet composition is carried out on D. T. apparatus using water at 24 - 26°C. Disintegration time: less than 3 mins.
B) Disintegration Test of tablet composition is carried out in a 25 ml glass beaker containing 15 ml of water.Disintegration time: less than 3 mins.
The above test results show that the tablet composition is uniformly dispersible. Alternatively Isopropyl alcohol: Methylene chloride may be used as the granulating solvent instead of Isopropyl alcohol: purified water as stated in example 4 above. Although the present invention has been disclosed and illustrated with reference to certain specific embodiments thereof, other different specific embodiments will readily occur to those skilled in the art based upon the teachings herein. The present invention should only be limited, therefore, by all embodiments which are covered by the spirit and scope of the appended claims.
Dated this 3rd day of April 2007

15