FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL 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, D4-MIDC Area, Chikalthana,
Aurangabad - 431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a method of treatment of osteoarthritis comprising administering 20mg to 45mg of rhein or diacerein, or salts or esters or prodrugs thereof to a patient, in a dosage form twice daily from day one of the therapy.
The following specification particularly describes the invention and the manner in which it is to be performed.


4. Description
The present invention provides a method of treatment of osteoarthritis comprising administering 20mg to 45mg of rhein or diacerein, or salts or esters or prodrugs thereof to a patient, in a dosage form twice daily from day one of the therapy.
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.


COOH

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.


It is known that when 50 mg diacerein formulation currently marketed under the trade name Art 50® is given orally in fasted conditions, due to fast gastric emptying, most of the diacerein remains unabsorbed and unabsorbed diacerein gets converted to rhein before reaching colon, and at colonic site, rhein degrades to rhein-9-anthrone which causes significant soft stool effect. This soft stool effect is observed in about 50% of the patients after first few doses of Art 50®. In fact, about 30-40% soft stool effect is expected due to inherent pharmacokinetic property of diacerein, i.e diacerein undergoes enterohepatic circulation, wherein rhein gets conjugated in liver to form rhein-glucuronide, which on reaching colon gets converted to rhein-9-anthrone and hence causes soft stool effect.
On the other hand, when Art 50® is given in fed conditions, the gastric emptying is delayed in presence of food. The longer residence time in upper part of the gastrointestinal tract accompanied with gastric fluids results in increased absorption of diacerein. This increase in absorption is upto 25% leading to comparatively less amount of unabsorbed diacerein to reach colon and hence reduction in soft stool effect. However, this reduction in soft stool effect is not significant. It was also observed that when the diacerein formulation described in EP 904060 comprising co-micronized diacerein with sodium lauryl sulfate is given, it results in some reduction in soft stool effect but the reduction is not significant (i.e upto 18% only). This reduction in soft stool effect is not due to dose reduction but it is related to increased absorption of diacerein leading to lesser amount of unabsorbed diacerein reaching colon. The diacerein formulation described in EP 904060 also exhibits drastic variation in both fed and fasted conditions. So, prior art formulations are discriminatory with respect to both fast and fed conditions. Additionally, prior art formulations are also eclipsed with undesirable soft stool effect.
Due to soft stool effect, prior art formulations (Art 50 and Art 40) are initially given once a day for about two months, so that the patient's gastrointestinal tract gets acclimatized to the side effect of diacerein. After that, the dosage regimen is


scheduled for twice day for both Art 50 and Art 40. So, prior art formulations are also eclipsed with undesirable soft stool effect due to which the dosage regimen is adjusted in such a manner that diacerein is initially administered as once a day for two months followed by twice a day regimen due to severity of soft stool effect associated with these formulations and hence to improve patient compliance.
Although the prior art addresses the improvement of bioavailability of diacerein by co-micronization or using liquid support systems, there still exists a need to develop new formulations or compositions which are likely to achieve a higher rate and extent of absorption of diacerein leading to improved bioavailability and at the same time shows significant reduction in soft stool effect so that diacerein can be given twice daily from day one of the therapy along with reduced soft stool effect.
The present inventors while working on the diacerein formulation have surprisingly found that the composition of the present invention overcomes all the commonly encountered problems exemplified in prior art. When the composition of the present invention is given orally, diacerein gets completely absorbed in upper part of intestine and there remains no unabsorbed diacerein reaching colon, resulting in a significant reduction in soft stools effect from about 60-70%. Furthermore, the composition of the invention is bioequivalent to 50 mg diacerein formulation currently marketed under the trade name Art 50® showing no variability whether administered in fed as compared to fasted state conditions. Since with composition of the invention, there is significant reduction in soft stool effect, so it was noticed that composition of the invention could be administered twice daily from day one of the therapy itself till the therapy is continued.
One of the aspects of the present invention provides a method of treatment of osteoarthritis comprising administering 20mg to 45mg of rhein or diacerein, or salts or esters or prodrugs thereof to a patient, in a dosage form twice daily from day one of the therapy.


The pharmaceutical composition of the present invention may be prepared by dispersing diacerein or salts thereof optionally with pharmaceutically acceptable excipients in suitable liquid dispersion medium and milling the dispersion through suitable mill to get a suitable size. Microparticulate dispersion of diacerein or salts thereof may be spray dried in fluidized bed processor. Dried mixture may be mixed with other pharmaceutically acceptable excipients and may be converted into suitable dosage form.
The suitable dosage form comprises one or more 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.
Suitable liquid dispersion medium are those known to the ordinary skill in the art and include but not limited to one or more of water, ethanol, isopropyl alcohol, butanol, hexane, glycols, vegetable oils, mineral oils and the like.
Suitable means applied to reduce the particle size of rhein or diacerein or salts or esters or prodrugs thereof are those known to ordinary skill in the art and include but not limited to one or more of nano mill, ball mill, attritor mill, vibratory mill, sand mill, bead mill, jet mill, ultrasonication, microfluidization and the like.
The pharmaceutical composition comprises of pharmaceutically acceptable excipients wherein- excipients may include fillers, lubricants, disintegrants, and glidants.
Suitable filler may be selected from a group comprising one or more of, microcrystalline cellulose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar and the like.


Suitable lubricant may be selected from a group comprising one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl behenate and the like.
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.
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
Part-I
1 Diacerein 11.26
2 Povidone 5-40
3 Starch 10-50
4 Water q.s.
Part-ll
5 Silicified microcrystalline cellulose 5-70
6 Croscarmellose sodium 1-15
7 Magnesium stearate 0.1-3
Procedure: Diacerein and povidone was dispersed in sufficient quantity of water to get uniform dispersion. Diacerein dispersion was passed through mill one or more times to get a desired particle size. The microparticulate dispersion was spray dried in glatt. Dried mass was blended with silicified microcrystalline cellulose, starch, croscarmellose sodium, lubricated with magnesium stearate and lubricated blend was filled into hard gelatin capsules of suitable size.


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

S.No. Ingredients %w/w
Part-I
1 Diacerein 11.26
2 Povidone 5-40
3 Lactose 10-50
4 Water q.s.
Part-ll
5 Silicified microcrystalline cellulose 5-70
6 Croscarmellose sodium 1-15
7 Magnesium stearate 0.1-3
Procedure: Diacerein and povidone was dispersed in sufficient quantity of water to get uniform dispersion. Diacerein dispersion was passed through mill one or more times to get a desired particle size. The microparticulate dispersion was spray dried in glatt. Dried mass was blended with silicified microcrystalline cellulose, lactose, croscarmellose sodium, lubricated with magnesium stearate and lubricated blend was filled into hard gelatin capsules of suitable size.


WE CLAIM:
1) A method of treatment of osteoarthritis comprising administering 20mg to 45mg of rhein or diacerein, or salts or esters or prodrugs thereof to a patient, in a dosage form twice daily from day one of the therapy.
2) The method of claim 1, wherein the dosage form comprises one or more of tablet, capsule, powder, disc, caplet, granules, pellets, granules in capsule, minitablets, minitablets in capsule, pellets in capsule, sachet.
3) The method of claim 1, wherein the dosage forms further comprises of pharmaceutically acceptable excipients.
4) The method of claim 4, wherein the pharmaceutically acceptable excipients comprises one or more of fillers, lubricants, disintegrants, and glidants.
5) The method of claim 5, wherein the filler comprises one or more of, microcrystalline cellulose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar.
6) The method of claim 5, wherein the lubricant comprises one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl behenate.


7) The method of claim 5, wherein the glidant comprises one or more of colloidal silicon dioxide, talc or cornstarch.
8) The method of claim 5, wherein the disintegrant comprises one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate.





ABSTRACT
The present invention provides a method of treatment of osteoarthritis comprising administering 20mg to 45mg of rhein or diacerein, or salts or esters or prodrugs thereof to a patient, in a dosage form twice daily from day one of the therapy.
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