Title of Invention

MELT GRANULATED PHARMACEUTICAL COMPOSITIONS OF RHEIN OR DIACEREIN

Abstract The present invention relates to melt granulated pharmaceutical compositions of rhein or diacerein, or salts or esters or prodrugs thereof which are bioequivalent to a 50 mg diacerein formulation marketed under the trade name Art 50. The composition exhibits no variability in fed as compared to fasted state conditions. The composition also results in significant reduction in soft stools effects as compared to Art 20. The invention also relates to processes for the preparation of such compositions.
Full Text 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:
MELT GRANULATED PHARMACEUTICAL COMPOSITIONS OF RHEIN OR DIACEREIN
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 relates to melt granulated pharmaceutical compositions of rhein or diacerein, or salts or esters or prodrugs thereof which are bioequivalent to a 50 mg diacerein formulation marketed under the trade name Art 50®. The composition exhibits no variability in fed as compared to fasted state conditions. The composition also results in significant reduction in soft stools, effects as compared to Art 50®. The invention also relates to processes for the preparation of such compositions.
The following specification particularly describes the invention and the manner in which it is to be performed.


4. Description
The present invention relates to melt granulated pharmaceutical compositions of rhein or diacerein, or salts or esters or prodrugs thereof which are bioequivalent to a 50 mg diacerein formulation marketed under the trade name Art 50®. The composition exhibits no variability in fed as compared to fasted state conditions. The composition also results in significant reduction in soft stools effects as compared to Art 50®. The invention also relates to processes for the preparation of such compositions.
FORMULA I
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.





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.
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.
In spite of the attempts in the prior art, described above, the inventors are not aware of successful attempts to improve the absorption of diacerein and significant reduction in soft stool effect. As described below, the inventors have surprisingly found that composition of the invention results in a higher rate and extent of absorption from the gastrointestinal tract and significant reduction (at least 25%) in soft stool effect. The inventors also have surprisingly found that the formulations can be given with or without food without affecting the rate and extent of absorption.
Thus, the composition of the present invention, overcome 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.


The invention is directed to melt granulated oral pharmaceutical compositions of rhein or diacerein, which are bioequivalent to commercially available diacerein 50 mg solid oral dosage form (Art 50). The administration of the composition to a human subject in a fasted state is bioequivalent to administration of the composition to a subject in fed state in particular as defined by Cmax, Tmax and AUC guidelines given by US FDA and EMEA. The melt-granulated compositions of the present invention are bioequivalent to commercially available diacerein 50 mg solid oral dosage form (Art 50), as to whether the compositions are administered with or without food.
The present inventors while working on the diacerein formulation have surprisingly found when diacerein is melt granulated with pharmaceutically acceptable excipient, the obtained melt significantly enhances the solubility of diacerein and percent drug release of diacerein as compared to Art 50®. Art 50® releases about 14% of diacerein in 60 minutes, whereas pharmaceutical composition of the present invention releases 100% of diacerein in 30 minutes. This leads to increased bioavailability. The increased bioavailability further leads to reduction in side effects i.e. soft stools.
One of the aspects of the present invention provides a pharmaceutical composition comprising 20 to 45 mg of rhein or diacerein, or salts or esters or prodrugs thereof melt granulated with pharmaceutically acceptable carriers, wherein one or both of the rate and extent of absorption of the rhein or diacerein is equal or greater than that obtained by a 50 mg diacerein formulation marketed under the trade name Art 50®.
Another aspect of the present invention provides pharmaceutical composition comprising 20 to 45 mg of rhein or diacerein, or salts or esters or prodrugs thereof, melt granulated with pharmaceutically acceptable carriers, wherein one or both of the rate and extent of absorption of the rhein or diacerein is equal or greater than that obtained by a 50 mg diacerein formulation marketed under the trade name Art 50® and the composition can be taken with or without food.


Another aspect of the present invention provides a process of preparing pharmaceutical composition of rhein or diacerein, or salts thereof, which process comprises of mixing rhein or diacerein, or salts thereof with one or more pharmaceutically acceptable carriers, granulating said mixture by melting, mixing, congealing, optionally with one or more pharmaceutically acceptable excipients.
The "pharmaceutical composition" of the present invention as used herein, is meant for oral administration to mammals and refers to tablets, capsules, granules, beads, caplets, disc, pills, sachet, suspension, spheroids, minitablets, granules in a capsule, beads in a capsule, minitablets in a capsule, and the like.
"Bioequivalency" is established by a 90% Confidence Interval (CI) of between 0.80 and 1.25 for both Cmax and AUC under USFDA regulatory guidelines, or a 90% CI for AUC of between 0.80 to 1.25 and a 90% CI for Cmax of between 0.70 to 1.43 under the European EMEA regulatory guidelines.
The term "confidence interval" as used herein refers to plain meaning known to ordinary skill in the art. Confidence interval refers to a statistical range with a specified probability that a given parameter lies within the range.
The term "covariance" as used herein refers to plain meaning known to ordinary skill in the art. It is a statistical measure of the variance of two random variables that are observed or measured in the same mean time period. This measure is equal to the product of the deviations of corresponding values of the two variables from their respective means.
Bioequivalence studies were carried out between Art 50 and composition of the invention both in fed state and fasted state. The study was monitored in terms of Cmax, AUC, Tmax achieved with the test product and reference product (Art 50). Table 2 gives bioequivalence data of Art 50 and test product.


The composition of the invention exhibits pharmacokinetic profile characterized by Cmax of about 3.15 to 6.0mg/ml, Tmax of about 2.4 to 5.0h, AUC0-t of about 16.4 to 40 mg.h/ml, AUCf of about 16.7 to 40 mg.h/ml.
At 90% confidence interval; area under the concentration time curve (AUCf-t and /or AUCf) and maximum plasma concentration (Cmax) values of composition of the invention lies between 0.70 and 1.70 as compared to that obtained by a 50 mg diacerein formulation marketed under the trade name Art 50®.
Advantages of the compositions of the invention, include, but are not limited to: (1) smaller solid dosage form size; (2) smaller doses of drug required to obtain the same pharmacological effect; (3) increased bioavailability; (4) substantially similar pharmacokinetic profiles of the rhein or diacerein, compositions when administered in the fed versus the fasted state; (5) bioequivalency of the diacerein compositions when administered in the fed versus the fasted state.
The pharmaceutical composition of the present invention may be prepared by melting the pharmaceutically acceptable carrier and mixing diacerein optionally along with one or more surfactant with molten mass, followed by congealing. Congealed solid may be sized into granules. Granules may be mixed with other pharmaceutically acceptable excipients and may be formulated into suitable dosage form.
Suitable pharmaceutically acceptable carriers comprise one or more of fatty esters, fatty acids and salts thereof, fatty alcohols, fatty amines, fatty amides, glycerides, glycolipids, steroids, natural and synthetic waxes, polyethylene glycol (PEG) or derivatives and the like.
Polyethylene glycol or its derivatives may comprise PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG 4000, PEG 6000, PEG 8000, PEG 20000, potyglycolyzed glycerides, polyethylene glycol-polyoxyethylenes, polyethylene glycol polypropylenes, polyethylene glycol-polyoxypropylenes.


Fatty esters may comprise triglyceryl ester, glyceryl distearate, glyceryl tristearate, glyceryl monostearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monolaurate, glyceryl dodecosanoate, glyceryl tridecosanoate, glyceryl monodecosanoate, glyceryl monocaprate, glyceryl dicaprate, glyceryl tricaprate, glyceryl monomyristate, glyceryl dimyristate, glyceryl trimyristate, glyceryl monodecanoate, glyceryl didecosanoate, glyceryl tridecosanoate, and the like.
Fatty acids may comprise acids having 12 to 28 carbons, e.g., stearic acid, palmitic acid, lauric acid, eleostearic acid, etc. Fatty alcohols may comprise compounds having from 16 to 44 carbons, e.g., stearic alcohol, palmitol, etc.
Glycerides may comprise monoglycerides, diglycerides, triglycerides, glycolipids, steroids and organic salts of fatty acids having from 12 to 29 carbons. Examples thereof comprise stearin, palmitin, castor wax, lecithin, hydrogenated cottonseed oil, hydrogenated tallow, magnesium stearate and calcium and aluminum salts of palmitic and other fatty acids.
Waxes may comprise paraffin wax, beeswax, carauba, jojoba, microcrystalline, palm, spermaceti, wool wax and other room temperature-solid hydrocarbon waxes.
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. Suifabte-stirfactaRtS'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.


The pharmaceutical composition comprises of pharmaceutically acceptable excipients wherein excipients are selected from a group comprising one or more of fillers, binders, lubricants, disintegrants, glidants, and the like.
Suitable filler may inlcude one or more of, microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar and the like.
Suitable binder may include one or more of, povidone, starch, stearic acid, gums, hydroxypropylmethyl cellulose 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 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.
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.


Table 1: Comparative dissolution data of ART 50 vs Composition of the invention

Time (min) % drug released (Art 50) % drug released (Composition of the invention)
5 3 38
10 4 74
15 5 88
20 7 97
30 9 100
45 11 100
60 14 100
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.


Table-2: Bioequivalence data of the composition of the invention against Art 50 with respect to pharmacokinetic parameters

S.No Pharmacokinetic parameters Art 50 Composition of the invention
1 Cmax (Mg/ml) 3.058 5.15
2 Tmax (h) 5.39 4.05
3 AUCo-t (ugh/ml) 22.688 25.169
4 AUC«>(ugh/ml) 22.816 25.363


Table-3: Bioequivalence data with respect to Test (Art GT) to reference (Art 50) Ratios (T/R ratios) at 90% Confidence Interval (C.I.)

S.No Pharmacokinetic parameters Ratio 90% C.I. %CV
Lower Upper
1 Cmax (mg/ml) 111.96 90.32 152.86 27.11
2 AUCo-t (mgh/ml) 115.68 79.83 139.11 26.22
3 AUCf(mgh/ml) 109.58 78.73 138.32 27.36


Example 1
Table 4 provides the composition of batches of the present invention.
Table 4

No Ingredients % Composition
Part I
1 PEG 6000 40-60
Part II
2 Diacerein 9.50
4 Lactose 5-40
5 Croscarmellose sodium 10-25
6 Silicified microcrystalline cellulose 1-25
7 Magnesium stearate 1-15
Procedure: PEG 6000 was melted and mixed at 60-70°C along with diacerein, to form a homogenous dispersion followed by congealing while mixing at room temperature. Congealed solid was sized through sieve to get granules of uniform size. Granules thus obtained were mixed with lactose, croscarmellose sodium, silicified microcrystalline cellulose, lubricated with magnesium stearate and filled into hard gelatin capsules.


Example 2
Table 5 provides the composition of batches of the present invention.
Table 5

No Ingredients % Composition
Part I
1 PEG 6000 40-60
2 Poloxamer 5-40
Part II
3 Diacerein 11.26
4 Sodium lauryl sulfate 1-20
Part III
5 Silicified microcrystalline cellulose 1-25
6 Lactose 5-40
7 Croscarmellose sodium 1-40
8 Magnesium stearate 1-15
Procedure: Poloxamer and PEG 6000 were melted and mixed at 60-70°C along with diacerein, sodium lauryl sulfate to form a homogenous dispersion followed by congealing while mixing at room temperature. Congealed solid was sized through sieve to get granules of uniform size. Granules thus obtained were mixed with lactose, silicified microcrystalline cellulose, croscarmellose sodium and lubricated with magnesium stearate and filled into hard gelatin capsules.


WE CLAIM:
1) A pharmaceutical composition comprising 20 to 45 mg of rhein or diacerein, or salts or esters or prodrugs thereof, melt granulated with pharmaceutically acceptable carriers, wherein one or both of the rate and extent of absorption of the rhein or diacerein is equal or greater than that obtained by a 50 mg diacerein formulation marketed under the trade name Art 50®.
2) The composition of claim 1, wherein the pharmaceutically acceptable carriers comprises one or more fatty esters, fatty acids and salts thereof, fatty alcohols, fatty amines, fatty amides, glycerides, glycolipids, steroids, natural and synthetic waxes, and polyethylene glycol (PEG) or derivatives.
3) The composition of claim 1, wherein the composition exhibits a maximum plasma concentration (Cmax) from about 3.15 to about 6.0mg/ml.
4) The composition of claim 1, wherein the composition exhibits a time to reach maximum plasma concentration (Tmax) from about 2.4h to about 5.0h.
5) The composition of claim 1, wherein the composition exhibits an area under the concentration time curve (AUCo-t)from about 16.4 to about 40 mg.h/ml.
6) The composition of claim 1, wherein pharmaceutically acceptable excipients comprises one or more of fillers, lubricants, disintegrants, surfactants and glidants.
7) The composition of claim 1, wherein the composition comprises one or more of tablets, capsules, granules, beads, caplets, disc, pills, sachet, suspension, spheroids, minitablets, granules in a capsule, beads in a capsule and minitablets in a capsule.


8) The composition of claim 1, wherein the composition can be taken with or without food.
9) A process of preparing pharmaceutical composition of rhein or diacerein, or salts thereof, which process comprises of mixing rhein or diacerein, or salts thereof with one or more pharmaceutically acceptable carriers, granulating said mixture by melting, mixing, congealing, optionally with one or more pharmaceutically acceptable excipients.
10) The process of claim 9, wherein the pharmaceutically acceptable carriers
comprises one or more fatty esters, fatty acids and salts thereof, fatty alcohols,
fatty amines, fatty amides, glycerides, glycolipids, steroids, natural and synthetic
waxes, and polyethylene glycol (PEG) or derivatives.



ABSTRACT
The present invention relates to melt granulated pharmaceutical compositions of rhein or diacerein, or salts or esters or prodrugs thereof which are bioequivalent to a 50 mg diacerein formulation marketed under the trade name Art 50®. The composition exhibits no variability in fed as compared to fasted state conditions. The composition also results in significant reduction in soft stools effects as compared to Art 50®. The invention also relates to processes for the preparation of such compositions.


Documents:

577-mum-2008-abstract.doc

577-mum-2008-abstract.pdf

577-MUM-2008-CLAIMS(AMENDED)-(16-8-2011).pdf

577-MUM-2008-CLAIMS(AMENDED)-(29-6-2012).pdf

577-MUM-2008-CLAIMS(AMENDED)-(4-3-2011).pdf

577-MUM-2008-CLAIMS(MARKED COPY)-(29-6-2012).pdf

577-MUM-2008-CLAIMS(MARKED COPY)-(4-3-2011).pdf

577-mum-2008-claims.doc

577-mum-2008-claims.pdf

577-MUM-2008-CORRESPONDENCE 31-7-2008.pdf

577-mum-2008-description (provisional).pdf

577-MUM-2008-FORM 18 1-8-2008.pdf

577-mum-2008-form 2(title page)-(24-3-2008).pdf

577-MUM-2008-FORM 3(4-3-2011).pdf

577-mum-2008-form-1.pdf

577-mum-2008-form-2.doc

577-mum-2008-form-2.pdf

577-MUM-2008-GENERAL POWER OF ATTORNEY(16-8-2011).pdf

577-MUM-2008-GENERAL POWER OF ATTORNEY(4-3-2011).pdf

577-MUM-2008-REPLY TO HEARING(29-6-2012).pdf

577-MUM-2008-REPLY TO EXAMINATION REPORT(16-8-2011).pdf

577-MUM-2008-REPLY TO EXAMINATION REPORT(4-3-2011).pdf


Patent Number 256416
Indian Patent Application Number 577/MUM/2008
PG Journal Number 24/2013
Publication Date 14-Jun-2013
Grant Date 13-Jun-2013
Date of Filing 24-Mar-2008
Name of Patentee WOCKHARDT LTD
Applicant Address D4-MIDC AREA, CHIKHALTHANA, AURANGABAD
Inventors:
# Inventor's Name Inventor's Address
1 SANDAL ROSHAN LAL C/O NARINDRA MEDICAL HALL, GRAIN MARKET, TALWANDI BHAI, DIST.:FEROZPUR-142050.
2 THAKKAR VIKRANT S/O SMT.SAVITRI RANI, H.NO.5, 4-MAZLA, SHANTI NAGAR, SAMPAT-131001.
3 JAIN GIRISH KUMAR 4-SHARDA NIKETAN, TEACHERS'COLONY, PITAM PURA-110034.
4 DABRE RAHUL SUDHAKAR 15 A UJJWAL SOCIETY, NARENDRANAGAR, NAGPUR-440015.
PCT International Classification Number A61K9/20; A61K31/192; A61K31/235
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA