WO2009048940A2 - Diacerein pharmaceutical formulations - Google Patents

Abstract

Pharmaceutical formulations comprising diacerein or its derivatives having enhanced solubility properties of diacerein or its derivatives, and useful for administration. Also included are modified release formulations comprising diacerein.

Description

DIACEREIN PHARMACEUTICAL FORMULATIONS

INTRODUCTION

The present invention relates to pharmaceutical formulations comprising diacerein or its derivatives. Further the invention relates to pharmaceutical compositions comprising diacerein or its derivatives having enhanced solubility properties of diacerein or its derivatives, and useful for administration. The invention also relates to modified release compositions comprising diacerein or its salts or esters thereof. The invention further relates to processes to prepare the pharmaceutical formulations and method of using such formulations.

Diacerein has a chemical name 4,5-Diacetyloxy-9,10-dioxo-2-anthracene- 2- carboxylic acid, and structural formula (I) below.

(I) Diacerein and its derivatives are known to possess antiarthhtic and moderate anti-inflammatory, antipyretic and analgesic activity and have a good safety profile. Its molecular weight is 368.294. Its molecular formula is C19H12O8. It is commercially available internationally in an immediate release capsule dosage form under the brand name ARTRODAR®, for the treatment of osteoarthritis. Inactive ingredients of ARTRODAR® include lactose and magnesium stearate. There are numerous other commercially available dosage forms, generally containing 50 mg of diacerein per unit, including a capsule product from Negma- Lerads in France sold as ART 50.

Diacerein is the diacetylated derivative of rhein. Diacerein is a prodrug of rhein, undergoing acetyl esterase-mediated hydrolysis to give rhein, chemically named 4,5-Dihydroxyanthraquinone-2-carboxylic acid, with the structural formula

(II) below.

(H)

Rhein also may be administrated directly.

Rhein and diacerein are disclosed in U.S. Patent No. 4,244,968 as well as in numerous scientific publications. U.S. Patent No. 6,610,750 discloses a method of treating osteoarthritis using rhein or diacerein either alone or in combination with NSAID drugs. U.S. Patent Nos. 4,861 ,599; 6,124,358; 5,952,383, and 5,225,192 disclose various compositions of diacerein.

Rhein and diacerein have the disadvantage of being practically insoluble in water and in alcohols. Upon oral administration, diacerein is completely converted into rhein and this rhein is not completely absorbed by the digestive tract because of its intrinsic properties. This incomplete absorption may cause undesirable side effects such as laxative effects, diarrhea and abdominal pain.

Moreover, as high amounts of diacerein are to be administered to patients affected by arthritis and for long time periods, these high amounts may lead to accumulation of diacerein or its derivatives, such as active the metabolite rhein, in the body leading to undesired effects.

There remains a need for improved delivery of diacerein and its derivatives.

SUMMARY

The present invention relates to pharmaceutical formulations and/or compositions of diacerein, or its derivatives, processes to prepare the formulations and methods of using such formulations in treating various arthritic disorders. In an embodiment the invention includes pharmaceutical formulations comprising compositions of diacerein or its derivatives, wherein compositions has diacerein with enhanced solubility properties.

Further the invention relates to pharmaceutical compositions comprising diacerein and at least one alkalizing agent.

In an embodiment, the invention includes pharmaceutical compositions comprising diacerein and at least one alkalizing agent, wherein a 1 % by weight aqueous suspension or dispersion of the compositions have pH values in the range of about 5 to about 14, or in the range of about 7 to about 12.

Further the invention relates to modified release pharmaceutical compositions comprising diacerein or its derivatives. In an embodiment the invention includes modified release pharmaceutical compositions comprising diacerein in the form of gastro-retentive delivery systems. Further embodiments also include gastro-retentive formulations comprising diacerein.

In one embodiment of the invention, modified release formulations comprise diacerein, and the formulations are designed to release less than about 40% of diacerein to the lower gastrointestinal tract.

In an embodiment the invention includes modified release formulations that release not less than about 50% of the contained diacerein within 2 hours.

In another embodiment the invention relates to modified release formulations that release more than about 50% of the contained diacerein to the upper gastrointestinal tract.

In an embodiment the invention includes to pharmaceutical formulations that provide buccal delivery of diacerein or its derivatives.

In yet another embodiment the invention relates to pharmaceutical formulations that release more than 50% of contained diacerein at pH values less than about 6.8.

Further in an embodiment the invention includes modified release compositions comprising diacerein and at least one rate-controlling material.

In another embodiment the invention includes powder compositions comprising diacerein and at least one hydrophilic polymer, and processes to prepare the same.

In another embodiment, the invention includes stable pharmaceutical formulations comprising compositions of diacerein or its derivatives.

In an embodiment, the invention includes stable pharmaceutical formulations comprising diacerein, having moisture contents less than about 8% w/w.

Further embodiments include stabilizing diacerein in its pharmaceutical formulations, in the presence of an alkalizing agent. In em bod i merits the invention includes methods of treating patients suffering from arthritic disorders and other disorders, using pharmaceutical formulations and/or compositions of the present invention.

An aspect of the invention provides pharmaceutical formulations comprising diacerein, together with one or more of: a) an alkalizing agent; b) a surfactant; and c) a hydrophilic polymer; wherein a dissolution rate of diacerein from the formulation in aqueous media at pH values about 4 to about 14 is at least about twice the dissolution rate of powdered diacerein.

Another aspect of the invention provides pharmaceutical formulations comprising diacerein that release at least about 50 percent of contained diacerein into 900 ml of pH 5.5 phosphate buffer containing 2 percent sodium lauryl sulphate, in USP type Il apparatus with 50 rpm stirring, within about two hours.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is an X-ray powder diffraction (XRD) pattern of diacerein, after dissolving in 1 ,4-dioxane and evaporating the solvent under vacuum, as described in Example 5.

Figure 2 is an X-ray powder diffraction pattern of the milled composition prepared in Example 4.

Figure 3 is an X-ray powder diffraction pattern of the coprecipitate prepared in Example 5.

DETAILED DESCRIPTION

The present invention relates to pharmaceutical formulations and/or compositions of diacerein, or its derivatives. Further the invention relates to pharmaceutical compositions of diacerein or its derivatives with enhanced solubility properties of diacerein or its derivatives useful for administration. The invention also relates to modified release compositions of diacerein or derivatives. The invention further relates to processes to prepare the pharmaceutical compositions and method of using such compositions. An aspect of the present invention provides pharmaceutical formulations comprising diacerein or its derivatives that can be administered orally and afford faster and more complete absorption of the diacerein into the body, and have improved bioavailability, thus making it possible to reduce or eliminate above- described side effects.

Further aspects of the present invention provide modified release pharmaceutical compositions comprising diacerein or its derivatives, thus reducing the dosing frequency and improving patient compliance.

Osteoarthritis is a degenerative joint disease characterized by a fragmentation and erosion of the articular cartilage, which becomes soft, frayed and thinned with alteration of the subchondral bone, hypertrophy of the bone, including outgrowths of marginal osteophytes and changes accompanied by pain and stiffness, and finally by loss of function. Osteoarthritis mainly affects the weight bearing joints. When clinically evident, osteoarthritis is a major cause of morbidity and disability, especially for the elderly, due to joint pain, morning stiffness, and limitation of movement. It commonly involves the neck, lower back, knees, hips and joints of the fingers.

Heretofore, rhein compounds have been used in human and veterinary therapeutics as the active principles of medicaments, in particular as slow acting anti-inflammatory drugs in the treatment of osteoarthritis. In human treatment, rhein derivatives or diacerein have been administered to subjects having active osteoarthritis. The subjects had restricted motion, swelling, and notable pain. Following treatment, in a significant number of instances, the subjects became pain-free, and motion and mobility were restored. Diacerein not only treats the symptoms of osteoarthritis but also aids in interrupting, preventing and controlling cartilage destruction to thereby favorably alter the course of the disease.

The routes of administration for pharmaceutical compositions of the present invention may be oral, buccal, sublingual, intravenous, intraarticular, intramuscular, etc. In the following description, "diacerein" includes both rhein and diacerein, and their derivatives.

The term "derivatives" as used in the description refers to salts, esters, isomers, enantiomers, racemates, metabolites, solvates, and hydrates. Various salts of diacerein may be prepared from different metals such as alkali and alkaline earth metals.

The term "upper part of gastrointestinal tract" means the region between the mouth and the ileo-caecal junction. The term "lower part of gastrointestinal tract" means the region between the ileo-caecal junction to the rectum, inclusive.

The term "modified release" as used in the description includes sustained- release, extended-release, prolonged-release, bi-phasic release, multi-phasic release, delayed-release, and various combinations of two or more thereof. The term "dosage form" or "formulation" as used herein refers to tablets, capsules, mini-tablets, caplets, uncoated micro-particles, micro-particles coated with at least one release-retarding coating, micro-particles coated with at least one delayed-release coating, and any combination thereof. These dosage forms may also be modified release, osmosis modified-release, erosion modified-release, diffusion modified-release, matrix cores, matrix cores coated with release-slowing coatings, enteric coated, dosage forms surrounded by slow or delayed release coatings, gastroretentive dosage forms, or muco-adhesive dosage forms.

When used for buccal delivery, the dosage forms may be compressed tablets, layered tablets, chewable tablets, buccal tablets, buccal sprays, buccal films, sublingual tablets, mouth dissolving tablets, rapidly dissolving tablets, troches, lozenges, effervescent tablets, dispensing tablets, hypodermic tables, tablet triturates, etc.

Diacerein has a poor aqueous solubility. Many approaches are used to improve the solubility and dissolution properties of poorly soluble active ingredients including salt formation, formation of nanoparticles, pH adjustment, use of surfactants, inclusion complexes, use of oily formulations, use of self- emulsifying drug delivery systems, formation of co-precipitates with hydrophilic polymers, and co-milling with hydrophilic excipients, to name a few.

In embodiments the invention includes powder compositions comprising diacerein and at least one pharmaceutically acceptable polymer.

"Powder compositions" as used herein refers to either powders comprising diacerein of defined physicochemical characteristics, or compositions comprising diacerein with a pharmaceutically acceptable polymer in the forms of coprecipitates, premixes, solid dispersions, admixtures with surfactants and/or cyclodextrins, particles of a defined particle size along with emulsifiers and wetting agents, and the like.

The terms "premix," "coprecipitate," and "solid dispersions" as used herein refers to powder compositions comprising diacerein in intimate or non-intimate mixture with one or more pharmaceutically acceptable polymers.

Useful polymers include, but are not limited to, polyvinylpyrrolidones (homopolymers or copolymers of N-vinylpyrrolidone), cellulose derivatives (hydroxypropyl methylcelluloses, hydroxyalkylcelluloses such as hydroxymethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, cyclodextrins, gelatins, hypromellose phthalates, sugars such as lactose, sucrose etc, sugar alcohol such as mannitol, sorbitol, etc., polyhydric alcohols, polyethylene glycols, polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives, and the like. The use of mixtures of more than one of the polymers is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, mixtures are all within the scope of this invention without limitation.

Intimate mixtures of diacerein with excipients may be prepared using any method such as mixing, blending, co-milling, and coprecipitation.

In an embodiment the invention includes processes to make powder compositions comprising diacerein and at least one pharmaceutically acceptable polymer.

Coprecipitation of diacerein and at least one polymer can be carried out in any manner, such as dissolving diacerein and polymer in a solvent, followed by evaporation of the solvent to give an intimate admixture of diacerein and polymer, deposition of a diacerein solution onto a powder blend or pellets, etc.

In a embodiment the invention includes powder compositions of diacerein showing reduced crystallinity of diacerein.

Various solvents suitable for use in preparation of powder compositions include, but are not limited to: 1 ,4 dioxane, acetone, methanol, ethanol, isopropanol, n-propanol, n-butanol, t-butyl alcohol, ethylene glycol, and the like; and chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride and the like.

In an embodiment the present invention includes weight ratios of diacerein to polymer from about 1 :0.1 to about 1 :10. In an embodiment the invention includes concentrations of polymers in the formulations ranging up to about 90% by weight of the total composition.

It has been observed that diacerein increases its solubility in alkaline conditions. In one embodiment the invention includes pharmaceutical formulations comprising compositions of diacerein and at least one alkalizing agent.

Alkalizing agents of the present invention raise the pH of acidic aqueous solutions and include, for example, antacids as well as other pharmaceutically acceptable: (1 ) organic and inorganic bases; (2) salts of strong organic and inorganic acids; (3) salts of weak organic and inorganic acids; (4) buffers; and (5) amino acids. Specific examples of such alkalizing agents include, but are not limited to: aluminum salts such as magnesium aluminum silicate; magnesium salts such as magnesium carbonate, magnesium trisilicate, magnesium aluminum silicate, and magnesium stearate; calcium salts such as calcium carbonate; bicarbonates such as calcium bicarbonate and sodium bicarbonate; phosphates such as monobasic calcium phosphate, dibasic calcium phosphate, dibasic sodium phosphate, thbasic sodium phosphate (TSP), dibasic potassium phosphate, and tribasic potassium phosphate; metal hydroxides such as aluminum hydroxide, sodium hydroxide and magnesium hydroxide; metal oxides such as magnesium oxide; N-methyl glucamine; arginine and salts thereof; amines such as monoethanolamine, diethanolamine, triethanolamine, and tris(hydroxymethyl)aminomethane (TRIS); meglumine; amino acids such as alanine, isoleucine, leucine, methionine, phenylalanine, proline, tryptophan, valine, asparagine, cysteine, glutamine, glycine, serine, threonine, tyrosine, aspartic acid, glutamic acid, arginine, histidine, and lysine; and combinations thereof.

In an embodiment, the invention includes alkalizing agents having concentrations ranging up to about 95% by weight of the total composition. In an embodiment the invention includes weight ratios of diacerein to alkalizing agent from about 1 :1 to about 1 :25, or from about 1 :1 to about 1 :20. In an embodiment, the invention includes pharmaceutical compositions comprising diacerein and at least one alkalizing agent, wherein a 1 % by weight aqueous suspension or dispersion of a composition provides pH values in the range of about 5 to about 14, or in the range of about 7 to about 12. It has been observed that diacerein, in addition to its improvement in solubility in the presence of alkalizing agent, also has a tendency to degrade, hence it appears to be unstable in the presence of an alkalizing agent.

In one of the embodiments the invention includes stable pharmaceutical formulations comprising diacerein.

Further embodiments include stabilizing diacerein in pharmaceutical formulations of diacerein in the presence of an alkalizing agent. Stabilizing diacerein in the presence of alkalizing agents may be accomplished by any mode of physical separation, such as by providing a film-coating barrier between the drug and the alkalizing agent, filling or compressing film coated drug granules or pellets and film coated granules or pellets of alkalizing agent, compressing into multilayer tablets, etc.

In another embodiment, the invention includes stabilizing diacerein in the pharmaceutical formulations of diacerein in the presence of moisture. In an embodiment the invention includes stable pharmaceutical formulations comprising diacerein, wherein moisture content of the formulation is less than about 8% w/w.

One of the means to improve the absorption of diacerein is to use a gastro- retentive drug delivery system. Gastro-retentive systems improve the modified delivery of drugs that have an absorption window (preferably in the upper gastrointestinal tract) by releasing the drug for a prolonged period of time within a desired absorption window and thus providing an optimized bioavailability.

It has been observed that if diacerein is retained in the upper gastrointestinal tract, its absorption may be increased and thus minimize side effects.

Further the invention relates to modified release pharmaceutical formulations comprising diacerein or its derivatives.

In a embodiment the invention includes modified release pharmaceutical formulations comprising diacerein in the form of gastro-retentive delivery systems. In one embodiment of the invention, modified release formulations comprise diacerein, and the formulations are designed to release less than about 40% of diacerein to the lower gastrointestinal tract. In an embodiment the invention includes modified release formulations comprising diacerein, releasing diacerein into the upper gastrointestinal tract to the extent of not less than 50% within 2 hours.

In another embodiment the invention relates to modified release formulations that release more than about 50% of contained diacerein into the upper gastrointestinal tract.

In yet another embodiment the invention relates to modified release formulations compositions that release more than about 50% of contained diacerein into fluids having pH values less than about 6.8. In an embodiment the invention includes modified release pharmaceutical formulations, wherein the formulations may be in a monolithic form or multiparticulate form, or combinations thereof.

In an embodiment the invention includes modified release pharmaceutical formulations comprising diacerein, wherein the formulations in monolithic form may be a matrix and/or a reservoir form.

In an embodiment, the invention includes modified release pharmaceutical compositions comprising diacerein, wherein diacerein is embedded in a matrix comprising at least one release rate-controlling material.

In a further embodiment the invention includes compositions comprising diacerein wherein a release rate-controlling material may be a hydrophilic or hydrophobic material.

Generally, there are two types of coatings: functional coatings and non functional coatings.

A "functional coating" as used herein is defined to mean a coating that affects the release of diacerein. Functional coatings include delayed release coatings, modified release coatings, extended release coatings, enteric coatings, etc.

A "non-functional soluble coating" as used herein is a coating that does not substantially affect the rate of drug release in vitro or in vivo, but will desirably enhance the chemical, biological, physical stability characteristics, or the physical appearance of a dosage form. Non-functional coatings include seal coatings and elegant coatings.

In an embodiment the invention includes compositions of diacerein comprising functional coatings or non functional coatings or combination thereof. In one embodiment of the invention, modified-release dosage forms comprise diacerein, wherein diacerein is in a modified release matrix core which is further coated with at least one rate controlling material. Modified-release matrix cores will can be coated with at least one "release-slowing coating" to further slow the release of the diacerein from the modified-release matrix core.

A modified-release matrix core will desirably comprise at least one polymer that is insoluble, swellable, swellable and erodable, hydrophobic, hydrophilic, erodable, reservoir, or any combination thereof.

The term "core" as used herein is defined to mean a solid vehicle in which diacerein is uniformly or non-uniformly dispersed. The core can be formed by methods and materials well known in the art, such as for example by compressing, fusing, or extruding the diacerein together with at least one pharmaceutically acceptable excipient, and compositions are formulated in various dosage forms including but not limited to multi-particulate dosage forms. In an embodiment the invention includes modified release pharmaceutical formulations comprising diacerein, wherein the formulations are in multi- particulate form wherein diacerein is in a reservoir which is further coated with at least one rate controlling material.

The term "multi-particulate" or "micro-particle" as used herein is defined to mean a plurality of drug-containing units, such as for example microspheres, spherical particles, microcapsules, particles, micro-particles, granules, spheroids, beads, pellets, spherules, and minitablets.

In a embodiment the invention relates to multiparticulate formulations wherein diacerein solution or dispersion is loaded onto inert materials and drug loaded materials are further coated with at least one rate controlling material.

The inert materials used as starting materials generally have sizes ranging from about 50-5000 μm. The inert materials are pharmacologically inert in nature and pharmaceutically compatible. Non-limiting examples of various substances that can be used as inert materials include insoluble inert materials such as glass particles/beads or silicon dioxide, calcium phosphate dihydrate, dicalcium phosphate, calcium sulfate dihydrate, microcrystalline cellulose, cellulose derivatives, calcium carbonate, dibasic calcium phosphate anhydrous, dibasic calcium phosphate monohydrate, thbasic calcium phosphate, magnesium carbonate, magnesium oxide, soluble cores such as sugar spheres having sugars like dextrose, lactose, and anhydrous lactose, spray-dried lactose, lactose monohydrate, mannitol, starches, sorbitol, and sucrose, insoluble inert plastic materials such as spherical or nearly spherical cores or beads of polyvinylchlohde or polystyrene, any other pharmaceutically acceptable insoluble synthetic materials, and the like and mixtures thereof.

Dispersions or solutions containing diacerein may be loaded, optionally along with other pharmaceutically acceptable additives, using any technique such as powder layering, solution spraying or suspension spraying.

In an embodiment, the invention includes modified release pharmaceutical compositions comprising diacerein in the range of about 10 to about 50% by weight, and about 1 to about 99% by weight of rate controlling materials.

Approaches to prolong the gastro residence time include, but are not limited to: low density systems such as floating drug delivery systems, gas generating systems, hydrodynamically balanced systems, raft systems, etc.; mucoadhesive systems; expandable system such as swellable systems, unfolding systems, etc.; high density systems; and by co-administration with drugs or excipients, which alter gastric retention.

Floating or buoyant systems are designed to have a low density and thus should float on gastric contents after administration until the systems either disintegrate (and the resultant particles empty from the stomach) or the systems absorb fluid to affect density such that the systems lose buoyancy and can pass more easily from the stomach with a wave of motility responsible for gastric emptying.

Floating systems comprise one or more hydrocolloids including cellulose derivatives such as methyl celluloses, hydroxypropyl methylcelluloses, hydroxypropyl celluloses (excluding low-substituted hydroxypropyl celluloses), hydroxyethyl celluloses, ethylcelluloses, sodium carboxymethyl celluloses, xanthan gum, guar gum, carrageenan gum, locust bean gum, sodium alginate, agar-agar, gelatin, modified starches, co-polymers of carboxyvinyl polymers, co- polymers of acrylates, and mixtures thereof, as carriers. Upon contact with gastric fluid, the hydrocolloids hydrate and acquire a bulk density less than 1 g/mL, thereby being buoyant in the gastric fluid. The presence of pharmaceutically inert fatty materials having a specific gravity less than one decreases the hydrophilicity and increases the buoyancy of the dosage forms. Floating systems that can be used for the purpose of this invention also include gas generating agents or expandable components which produce a gas such as, for example, carbon dioxide or nitrogen, on contact with gastric juice, in particular under the action of acid. Non-limiting examples of materials used according to the invention are carbonates and hydrogen carbonates of the alkali metals and alkaline earth metals, the ammonium cations or sodium azide, and mixtures thereof.

Swelling and expanding systems are designed to be sufficiently small at administration so as to not make ingestion of a dosage form difficult. Following ingestion they rapidly swell or unfold to a size that precludes passage through the pylorus until after drug release has progressed to a desired degree. Gradual erosion of the system or its breakdown into smaller particles enables it to eventually leave the stomach.

Swelling and expanding systems that can be used for the purpose of this invention include erodible material systems. On imbibing fluid the systems swell over a short period of time to a size that will enable prolonged gastric retention, allowing modified delivery of contained drug to absorption sites in the upper gastrointestinal tract. Because these systems are made of an erodible and hydrophilic material or mixture thereof, they readily erode over a reasonable time period to pass from the stomach.

In an embodiment the invention includes polymers having adequate hydrophilicity to be suitable for use in a swelling and expanding system. Suitable polymers, for example xanthan gum, are indeed hydrophilic due to a large number of appropriate functional groups. These expandable components such as xanthan gum, guar gum, etc. can be optionally modified for the modification of the gas production kinetics, e.g. by coating with or embedding in lipophilic components such as waxes, fats, suitable coatings such as polymethacrylates or polymethylmethacrylates and their derivatives, or similar substances known to the person skilled in the art. Also useful are membrane systems, which comprise materials such as micro porous membranes, porous membranes, and combination of any of the foregoing with a non-porous material film.

Hydrogels are materials that are hydrophilic but insoluble in water. In their hydrated condition they swell to an equilibrium volume, and are elastically deformable but virtually immune to plastic deformation. In their dry state, hydrogels may be structurally rigid. The hydrogels of the expanding compositions of the present invention include, without limitation, hydroxypropyl methylcelluloses, either alone or in combination with hydroxypropyl celluloses and/or cross-linked acrylate materials. Examples of suitable cross-linked acrylate materials include polyacrylic acid crosslinked with allylsucrose and polyacrylic acid cross linked with divinylglycol.

Bioadhesive systems are designed to imbibe fluid following administration such that the outer layer becomes a viscous, tacky material that adheres to the gastric mucosa/mucous layer. This enables gastric retention until the adhesive forces are weakened, for example by continuing hydration of the outer layer of the device or by the persistent application of shear.

A bioadhesive or mucoadhesive substance is a natural or synthetic polymer capable of adhering to a biological membrane (bioadhesive polymer) or the mucous lining of the gastrointestinal tract (mucoadhesive polymer). Polycarbophil (polyacrylic acid cross-linked with divinylglycol, available under as Noveon™ AA- 1 , manufactured and supplied by Noveon Corp.) is a suitable polymer for encouraging adhesion of orally administered dosage forms to the gastric mucosa, thereby prolonging residence time for a system designed to slowly deliver drug to absorptive sites in the upper part of the gastrointestinal tract. Other suitable bioadhesive polymers which may be used in the present invention include chitosan, dextran sodium, poly-L-aspartic acid, polystyrene sulfonic acid, polyvinyl sulfate, polyglutamic acid, bovine serum albumin, ficoll, acidic (high isoelectric point) gelatin, polybrene, polyvinyl methyl imidazole, polygalactosamine, proteins (polyaminoacids) such as polylysine, polyomithine, polyquaternary compounds, prolamine, polyimine, diethylaminoethyldextran (DEAE), DEAE-imine, polyvinylpyridine, polyethylene pyrrolidone, polythiodiethyl aminomethylethylene (PTDAE), polyhistidine, DEAE-methacrylate, DEAE-acrylamide, poly-p- aminostyrene, polyoxethane, copolymethacrylates (e.g., copolymers of HPMA, N- (2-hydroxypropyl)-methacrylamide), Eudragit™ RL, Eudragit™ RS, polyamidoamines, cationic starches, DEAE-dextran and DEAE-cellulose. Chitosan can be employed as a chitosan salt (e.g., the glutamate, lactate, chloride or acetate salts) or as a chitosan derivative such as N-trimethyl chitosan chloride. Gastro-retention of the dosage form may also be achieved by providing a high density to the composition. High-density systems have a density greater than 1 g/mL, such as about 2-3 g/mL, are retained in the rugae of the stomach, and are capable of withstanding its peristaltic movements. Above a threshold density of about 2.4-2.8 g/mL, such systems can be retained in the lower part of the stomach. The components that can be used to manufacture high-density formulations according to the present invention include diluents such as barium sulphate, zinc oxide and titanium dioxide.

In another embodiment, the invention includes gastro retentive system comprising: a) diacehen or its derivative; b) an expandable component which generates gas on contact with gastric juice; and c) a membrane system which totally encompasses components a) and b) above and is expandable by the gas generated by b)upon contact with gastric juices.

Some of the rate controlling materials which constitute membranes and can be used for gastro-retentive systems according to the invention include polyurethanes, polypropylenes, polyvinyl alcohols, polyvinyl acetates, polyacrylic acids and derivatives, polymethylmethacrylic acids and derivatives, polycarbonates, polyvinylidene difluorides, polytetrafluoroethylenes, waxes, oils, and any other desired materials which can be provided with pores of suitable size. Examples of gas generating agents include carbonates and hydrogen carbonates of the alkali metals and alkaline earth metals, ammonium cations, sodium azide, and mixtures thereof.

The invention also includes various gastro-retentive formulations like microparticles, pellets, mini-tablets, tablets and capsules to achieve gastro- retention to release more than about 50% of diacerein into the upper part of the gastrointestinal tract.

Some studies have revealed that oral dosage forms containing finely divided ion exchange resins can provide prolonged gastric residence and uniform distribution within the stomach. In another embodiment, the invention includes modified release pharmaceutical compositions comprising diacerein, prepared by treating anionic or cationic ion exchange resin beads with an acid addition salt of diacerein.

For providing prolonged gastric residence, the particles will need to be small from a mechanical consideration, and of low density so that they might be able to float. A positive charge should also confer an advantage. Adherence to the wall of the stomach will be possible during the emptying process in both the fed and fasted state, assuming that the mucoadhesive properties of the particles have not been modified by the stomach contents, in particular, non-adherent mucous. Chitosan, a popular choice as a coating material because of its regulatory status and its positive charge, binds to mucous.

Microspheres float on the stomach contents, and then adhere to the mucous lining as the stomach empties. The release of drug from the system can be modified to coincide with the half-life emptying of the system from the stomach. In yet another embodiment of the present invention, modified release diacerein compositions comprise diacerein present in microspheres having sizes measured in μm, which would then be made into tablets, capsules, or sachets, and when administered orally into the gastrointestinal tract of a patient the said composition would release more than about 50% of contained diacerein into the upper part of the gastrointestinal tract.

Various mucoadhesive substances that can be used include but are not limited to polyacrylic polymers such as carbomers and their derivatives like polycarbophil, Carbopol® products (supplied by Noveon); ethylene oxide and its derivatives, cellulose derivatives such as hydroxypropyl methylcelluloses (HPMC), hydroxyethyl celluloses (HEC), hydroxypropyl celluloses (HPC) and sodium carboxymethyl celluloses (NaCMC), polyethylene oxides such as POLYOX WSR grades (supplied by DOW Chemical Co.), gelatin, chitosan and sodium alginate.

In yet another embodiment, the present invention provides gastro-retentive delivery systems comprising folded multi-layered polymeric sheets having diacerein-containing compartments, bordered by enveloping layers or strips, which are folded and enveloped in pharmaceutically acceptable soft or hard capsules, the devices being adapted to unfold a multi-layered polymeric sheet when in a subject's stomach by dissolving the outer envelope, and upon unfolding, the diacerein or its pharmaceutically acceptable salt is released from said devices via at least one aperture or pore in an enveloping layer. The invention also provides a method for gastro-retentive delivery of diacerein via this invention; a method of preparing the multi-layered sheets of the invention as well as the use of these multi-layered sheets for the manufacture of a medicament for treating arthritic disorders. The term "multilayered sheet" in the invention means a sheet of adequate dimension to be retained in the stomach by virtue of its size. This sheet can be a combination of one or more polymeric layers, which are compacted together to get an optimum release rate from the sheet. The outer layers of the sheets are insoluble in the gastric region and the middle layer can be a functional layer that accommodates diacerein.

Sometimes to minimize the release of diacerein/rhein into the lower gastrointestinal tract, the pharmaceutical compositions may be modified to release diacerein into the oral or buccal cavity so that a maximum amount of diacerein/rhein is absorbed from the buccal mucosa.

The delivery of drugs through the buccal mucosa is a very well known and convenient way of administering a number of active ingredients for either local or systemic action. Chewable tablets, lozenges, mouth dissolving tablets and other similar oral dosage forms are known to provide buccal delivery. The galenical forms often consist of a soluble diluent, such as sugar, lactose, mannitol or sorbitol, and a binder. Lubricants, flavours, sweetening agents, taste correctors, and one or more active ingredients that do not improve the tableting properties of the mixture, are normally added. These forms dissolve relatively rapidly once in the mouth, within either a few seconds or up to 10 minutes, and deliver both soluble and insoluble active ingredients to the buccal cavity.

An ideal buccal delivery system would stay in the oral cavity for a few hours and release the drug in a unidirectional way toward the mucosa in a controlled- or sustained-release fashion. Muco/bioadhesive polymers will prolong the residence time of the device in the oral cavity. Bilayered devices will ensure the release of the drug occurs in a unidirectional way. Some of the excipients such as chitosan may be used for buccal delivery because they have muco/bio- adhesive properties and can act as an absorption enhancer.

In an embodiment the invention includes pharmaceutical compositions that provide buccal delivery of diacerein or its derivatives. Certain pharmaceutical compositions comprising diacerein or derivatives have the diacerein in an osmotic drug delivery system. In one of the embodiments the osmotic drug delivery system is a dosage form that forcibly dispenses diacerein in total or in part by a pressure created by osmosis or diffusion of fluid into a core, which forces diacerein to be dispensed from the osmotic dosage form. An "osmagent" is used to increase the osmotic pressure of the core, thus, increasing the hydrostatic pressure inside the osmotic dosage form. The osmagent will desirably be either soluble or swellable and be totally or partially solubilized. The osmotic agents that can be used for the purpose of this invention include inorganic and organic compounds that exhibit an osmotic pressure gradient across a semi-permeable wall against an external fluid. Osmotic agents useful in the present invention include, without limitation thereto, sodium chloride, magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, lithium sulfate, potassium acid phosphate, d-mannitol, urea, inositol, magnesium succinate, tartaric acid, carbohydrates such as raffinose, sucrose, glucose, and mixtures thereof.

The semi-permeable wall is permeable to the passage of an external fluid such as water and biological fluids, and is substantially impermeable to the passage of osmotic agents, and the like. Typical materials for forming the wall are cellulose esters, cellulose ethers and cellulose ester-ethers. Representative materials include, without limitation thereto, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di-, and tri-cellulose alkanylates, mono-, di-, and tri-cellulose aroylates, and the like.

A passageway as used herein comprises means and methods suitable for releasing the agent or drug from the osmotic system. The passageway includes an osmotic aperture or osmotic orifice extending through the semi permeable wall. Techniques including mechanical drilling or laser drilling can form an osmotic passageway.

In another embodiment, the invention includes modified release pharmaceutical compositions comprising diacerein and one or more lipids, wherein diacerein is entrapped in lipid vesicles.

In an embodiment the invention includes pharmaceutical formulations comprising compositions of diacerein and at least one pharmaceutically acceptable excipient. Excipients used in the formulations include but are not limited to diluents, binders, disintegrants, surfactants, stabilizers and other excipients that are commonly used in preparation of formulations. Diluents:

Various useful fillers or diluents include, but are not limited to, starches, lactose, mannitol (Pearlitol™ SD200), cellulose derivatives, confectioners sugar and the like. Different grades of lactose include but are not limited to lactose monohydrate, lactose DT (direct tableting), lactose anhydrous, Flowlac™ (available from Meggle Products), Pharmatose™ (available from DMV) and others. Different grades of starches include but are not limited to maize starch, potato starch, rice starch, wheat starch, pregelatinized starch (commercially available as PCS PC10 from Signet Chemical Corporation) and Starch 1500, Starch 1500 LM grade (low moisture content grade) from Colorcon, fully pregelatinized starch (commercially available as National 78-1551 from Essex Grain Products) and others. Different cellulose compounds that can be used include crystalline celluloses and powdered celluloses. Examples of crystalline cellulose products include but are not limited to CEOLUS™ KG801 , Avicel™ PH 101 , PH102, PH301 , PH302 and PH-F20, PH-112 microcrystalline cellulose 114, and microcrystalline cellulose 112. Other useful diluents include but are not limited to carmellose, sugar alcohols such as mannitol (Pearlitol™ SD200), sorbitol, xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate. Binders:

Various useful binders include, but are not limited to, hydroxypropylcelluloses (Klucel™ LF), hydroxypropylcelluloses (Klucel EXF) hydroxypropyl methylcelluloses or hypromelloses (Methocel™), polyvinylpyrrolidones or povidones (PVP-K25, PVP-K29, PVP-K30, PVP-K90), Plasdone™ S 630 (copovidone), powdered acacia, gelatin, guar gum, carbomers (e.g. Carbopol™), methylcelluloses, polymethacrylates, and starches. Disinteg rants:

Various useful disintegrants include, but are not limited to, carmellose calcium (Gotoku Yakuhin Co., Ltd.), carboxymethylstarch sodium (Matsutani Kagaku Co., Ltd., Kimura Sangyo Co., Ltd., etc.), croscarmellose sodium(Ac-di- sol) (FMC-Asahi Chemical Industry Co., Ltd.), crospovidones, examples of commercially available crospovidone products including but not limited to crosslinked povidone, Kollidon™ CL [manufactured by BASF (Germany)], Polyplasdone™ XL, XI-10, and INF-10 [manufactured by ISP Inc. (USA)], and low-substituted hydroxypropylcelluloses. Examples of low-substituted hydroxypropylcelluloses include but are not limited to low-substituted hydroxypropylcellulose LH1 1 , LH21 , LH31 , LH22, LH32, LH20, LH30, LH32 and LH33 (all manufactured by Shin-Etsu Chemical Co., Ltd.). Other useful disintegrants include sodium starch glycolate, colloidal silicon dioxide, and starches. Surfactants:

Surfactants may be ionic or nonionic. Ionic surfactants may be anionic, cationic, or zwitterionic. Anionic surfactants include the alkoyl isethionates, alkyl and alkyl ether sulfates and salts thereof, alkyl and alkyl ether phosphates and salts thereof, alkyl methyl taurates, and soaps such as for example alkali metal salts including sodium or potassium salts of long chain fatty acids. Useful anionic surfactants include sodium stearate, potassium stearate, ammonium stearate, and calcium stearate; thethenolamine stearate, sodium lauryl sulphate, sodium dioctylsulphosuccinate, and sodium dodecylbenzenesulphonate, chenodeoxy cholic acid, 1 -octanesulfonic acid sodium salt, sodium deoxycholate, glycodeoxy cholic acid sodium salt, N-lauroylsarcosine sodium salt, lithium dodecyl sulfate, sodium cholate hydrate, sodium lauryl sulfate (SLS) and sodium dodecyl sulfate (SDS). Nonionic surfactants include polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., the commercially available Tween™ products, such as Tween 20 and Tween 800 from ICI Specialty Chemicals); poloxamers (e.g., Pluronic™ products F68 and F108Q, which are block copolymers of ethylene oxide and propylene oxide); poloxamines (e.g., Tetronic™ 908, also known as poloxamine 908, which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, N. J. )), and Tetronic™ 15080 (T-1508) (BASF Wyandotte Corporation), ethylene glycol stearates, propylene glycol stearates, diethylene glycol stearates, glycerol stearates, sorbitan esters (SPAN™) and polyhydroxyethylenically treated sorbitan esters (TWEEN™), esters of polyethylene glycol glycerides aliphatic alcohols and PEG ethers, phenol and PEG ethers.

Polyoxyethylene castor oil derivatives are materials obtained by reacting varying amounts of ethylene oxide with either castor oil or hydrogenated castor oil. Several different types of material are commercially available, the best-known being the CREMOPHOR™ products (BASF Corp.) For example, polyoxyl 35 castor oil (CREMOPHOR EL), polyoxyl 40 hydrogenated castor oil (CREMOPHOR RH 40), etc. Mixtures of mono-, di- and th-glycehdes with polyethylene glycol (PEG) esters of fatty acids are sold as GELUCIRE™ products. GELUCIRE products are available with a range of preperties depending on their hydrophilic lipophilic balance and melting point range such as GELUCIRE 50/13 and GELUCIRE 44/14. The products containing only PEG esters are generally used in the preparation of fast release compositions, while products containing only glycehdes or a mixture of glycerides and PEG esters are used in the preparation of sustained release formulations.

Examples of useful cationic surfactants include, but are not limited to, polymers, biopolymers, polysaccharides, cellulosics, alginates, poly-n- methylpyridinium, anthryl pyhdinium chloride, cationic phospholipids, chitosan, polylysine, polyvinylimidazole, polybrene, polymethylmethacrylate, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate, lysozyme, long-chain polymers such as alginic acid, carrageenan (FMC Corp.), and POLYOX™ (Dow Chemical Co., Midland, Ml); cationic lipids, sulfonium, phosphonium, and quarternary ammonium compounds, such as stearylthmethylammonium chloride, and benzyl-di (2-chloroethyl) ethylammonium bromide, quaternary ammonium salts (e.g. cetylthmethylammonium bromide) and amine salts (e.g. octadecylamine hydrochloride).

Examples of amphoteric and zwittehonic surfactants include but are not limited to carboxy, sulfonate, sulfate, phosphate, or phosphonate compounds. Examples are alkylimino acetates and iminodialkanoates and aminoalkanoates, imidazolinium and ammonium derivatives, betaines, sultaines, hydroxysultaines, alkyl sarcosinates and alkanoyl sarcosinates, and the like.

Natural surface active agents may also be used, such as for example phospholipids, e.g. diacylphosphatidyl glycerols, diaceylphosphatidyl cholines, and diaceylphosphatidic acids, the precursors and derivatives thereof, such as for example soybean lecithin and egg yolk. Coloring Agents:

Coloring agents can be used to color code the composition, for example, to indicate the type and dosage of the therapeutic agent therein. Suitable coloring agents include, without limitation, natural and/or artificial compounds such as FD&C coloring agents, natural juice concentrates, pigments such as titanium oxide, iron oxides, silicon dioxide, and zinc oxide, combinations thereof, and the like. Sweeteners:

Compositions of the present invention may include a sweetener. Useful sweeteners include, but are not limited to: sugars such as sucrose, glucose (corn syrup), dextrose, invert sugar, fructose, and mixtures thereof; acid saccharin and its various salts such as the sodium or calcium salt; cyclamic acid and its various salts such as the sodium salt; the dipeptide sweeteners such as aspartame and alitame; natural sweeteners such as dihydrochalcone compounds; glycyrrhizin; Stevia rebaudiana (Stevioside); sugar alcohols such as sorbitol, sorbitol syrup, mannitol (Pearlitol™ SD200), xylitol and the like, synthetic sweeteners such as acesulfame-K and sodium and calcium salts thereof and other synthetic sweeteners and mixtures thereof. Flavoring Agents: Flavoring agents can also be used to improve the palatability of the composition. Examples of suitable flavoring agents include, without limitation, natural and/or synthetic (i.e., artificial) flavoring compounds such as orange or mix fruit flavor. Lubricants: An effective amount of any generally accepted pharmaceutical tableting lubricant can be added to assist with compressing tablets. Useful tablet lubricants include magnesium stearate, glyceryl monostearates, palmitic acid, talc, carnauba wax, calcium stearate sodium, sodium or magnesium lauryl sulfate, calcium soaps, zinc stearate, polyoxyethylene monostearates, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid, and combinations thereof. Glidants:

One or more glidant materials, which improve the flow of powder blends and minimize the dosage form weight variation, can be used. Useful glidants include but are not limited to silicone dioxide, talc and combinations thereof. Solvents:

Various solvents used in the processes of preparation of pharmaceutical compositions of the present invention include but are not limited to water, methanol, ethanol, acidified ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, N,N-dimethylformamide, tetrahydrofuran and mixtures thereof.

The final formulation may comprise one or more layers and may be coated or uncoated. For coating, one or more additional excipients such as film forming agents, plasticizers, antiadherents, and opacifiers are frequently used. Film-forming Agents:

Various film-forming agents include but are not limited to cellulose derivatives such as soluble alkyl- or hydroxyalkyl-cellulose derivatives such as methyl celluloses, hydroxymethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxymethyethyl celluloses, hydroxypropyl methylcelluloses, sodium carboxymethyl celluloses, etc., acidic cellulose derivatives such as cellulose acetate phthalates, cellulose acetate trimellitates and methylhydroxypropylcellulose phthalates, polyvinyl acetate phthalates, etc., insoluble cellulose derivatives such as ethylcelluloses and the like, dextrins, starches and starch derivatives, materials based on carbohydrates and derivatives thereof, natural gums such as gum Arabic, xanthans, alginates, polyacrylic acid, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidones, polymethacrylates and derivatives thereof (Eudragit™), chitosan and derivatives thereof, shellac and derivatives thereof, waxes, and fat substances.

If desired, the films may contain additional adjuvants for the coating process such as plasticizers, polishing agents, colorants, pigments, antifoam agents, opacifiers, antisticking agents, and the like. Plasticizers:

Various plasticizers include but are not limited to substances such as castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, triethyl citrate. Also mixtures of plasticizers may be utilized. The type of plasticizer depends upon the type of coating agent. A plasticizer is normally present in an amount ranging from about 5% (w/w) to 30 (w/w) based on the total weight of the film coating.

An opacifier like titanium dioxide may also be present in an amount ranging from about 10% (w/w) to about 20% (w/w) based on the total weight of the coating. When colored tablets are desired then the color is normally applied in the coating. Consequently, coloring agents and pigments may be present in the film coating. Various coloring agents include but are not limited to iron oxides, which can be red, yellow, black or blends thereof.

Anti-adhesives are normally used in the film coating process to avoid sticking effects during film formation and drying. An example of a useful anti- adhesive for this purpose is talc. The anti-adhesive and especially talc is present in the film coating in an amount of about 5% (w/w) to 15% (w/w) based upon the total weight of the coating.

Suitable polishing agents include polyethylene glycols of various molecular weights or mixtures thereof, talc, surfactants (e.g. glycerol monostearate and poloxamers), fatty alcohols (e.g., stearyl alcohol, cetyl alcohol, lauryl alcohol and myhstyl alcohol) and waxes (e.g., carnauba wax, candelilla wax and white wax). In an embodiment, polyethylene glycols having molecular weights about 3,000- 20,000 are employed. As alternatives to the above coating ingredients, sometimes premixed coating products such as those sold as OPADRY™ (supplied by Colorcon) are employed, requiring only dispersion in a liquid before use. OPADRY compositions generally comprise polymer, plasticizer and, if desired, pigment in a dry concentrate. OPADRY formulas produce attractive, elegant coatings on a variety of tablet cores and can be used in both aqueous and organic coating procedures The compositions of the present invention may be prepared using process steps including wet granulation, melt granulation, dry granulation such as slugging or compaction, direct compression, and various coating processes, and are formulated into solid unit dosage forms including tablets and capsules. The invention includes various processes for preparing the pharmaceutical formulations comprising compositions of diacerein. Some of the processes are described below.

In one embodiment, the present invention includes methods for preparing pharmaceutical formulations comprising diacerein, wherein an embodiment comprises:

1 . Sifting diacerein and alkalizing agent through a suitable sieve and mixing.

2. Sifting other optional excipients through a suitable sieve and mixing with the blend of step 1 , and optionally filling the mixture into capsules or compressing into tablets.

3. Granulating the blend of step 2 using a granulating agent followed by drying.

4. Sifting other excipients such as glidants, lubricants etc through a suitable sieve and blending with dried granules of step 3.

5. Filling the blend of step 4 into empty hard gelatin capsules of a suitable size or compressing into tablets.

In another embodiment, the present invention includes methods for preparing pharmaceutical formulations comprising diacerein and at least one alkalizing agent, wherein an embodiment comprises preparation of separate granules for diacerein and at least one alkalizing agent, and filling both granules into empty hard gelatin capsules of suitable size.

In an embodiment the invention includes pharmaceutical formulations wherein diacerein and alkalizing agent are in multiparticulate form, e.g., powders, granules, pellets, beads, etc.

In another embodiment the invention includes pharmaceutical formulations wherein diacerein in the form of powders, granules, pellets, beads, or tablets is encapsulated within a capsule containing an alkalizing agent in the form of powder, granules, pellets, beads, or tablets. In yet another embodiment compositions comprising diacerein and compositions comprising alkalizing agent may be combined in the form of multilayered tablets or coated tablets.

In an embodiment the invention includes pharmaceutical compositions wherein diacerein and alkalizing agent are in an intimate mixture. In an embodiment the invention includes pharmaceutical compositions wherein diacerein and alkalizing agent are not in an intimate mixture.

In one embodiment, the present invention includes methods for preparing gastro-retentive pharmaceutical formulations comprising diacerein, wherein an embodiment comprises: a) dispersing drug together with at least one pharmaceutically acceptable excipient into a suitable solvent, optionally including heating to suitable temperatures; b) homogenizing the dispersion for a suitable time to get a uniform dispersion; c) loading drug dispersion from step b) onto inert materials in suitable equipment; d) optionally, film-coating the drug loaded particles; e) optionally, blending the drug loaded particles from step c) or d) with one or more excipients such as glidants and/or lubricants; f) sifting the desired gastro-retentive excipients through a suitable sieve and mixing; g) mixing drug loaded particles form step c) or d) or e) with that of gastroretentive blend of step f). h) blending material from step g) with suitable glidants and lubricant; and i) filling step h) material into capsules or compressing into tablets, multilayered tablets, or inlay tablets.

In further embodiments the invention includes methods of treating patients suffering arthritic disorders and other such disorders, using the pharmaceutical compositions of the present invention.

The dosage forms can be subjected to in vitro dissolution testing according to Test 71 1 "Dissolution" in United States Pharmacopeia 29, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 2005, to determine the rate at which the active substance is released from the dosage forms, and content of active substance can be determined in dissolution media using techniques such as high performance liquid chromatography (HPLC). An example of a useful HPLC analytical method for determining diacerein concentrations and impurity content utilizes a 250x4.6 mm, 5 μm lnertsil ODS 3V C-18 column and the following parameters:

Flow: 1.0 ml/minute.

Detector wavelength: 254 nm.

Column temperature: 50±2°C.

Injection volume: 20 μl_.

Run time: 60 minutes.

Buffer: Mix 1 ml of orthophosphoric acid with 1 L of milli-

Q water, filter through a 0.45 μm nylon membrane and degas with sonication.

Program: Gradient, as follows:

A standard is prepared by dissolving 30.0 mg of diacerein in 10 ml of dimethylacetamide, with sonication, and diluting to 200 ml with diluent (1 ml of orthophosphoric acid in 1 L of methanol). A 1 ml aliquot is diluted to 100 ml with diluent.

Sample is prepared for analysis by adding a quantity containing 50 mg of diacerein to 10 ml of dimethylacetamide and sonicating, then diluting to 100 ml with diluent. A portion is centhfuged and clear liquid is injected into the chromatograph.

A blank is prepared by dissolving 10 ml of dimethylacetamide in diluent, and diluting to 100 ml.

For the analysis, a blank is injected, followed by two injections of diluted standard, then a sample. Among the observed peaks are those having the following relative retention times (diacerein=1 ):

The pharmaceutical dosage forms of the present invention are intended for oral or buccal or sublingual administration to a patient in need thereof.

In an embodiment the invention includes use of packaging materials such as containers and lids of high-density polyethylene (HDPE), low-density polyethylene (LDPE) and or polypropylene and/or glass, and blisters or strips composed of aluminium or high-density polypropylene, polyvinyl chloride, polyvinyl idene dichlohde, etc.

The following examples will further describe certain specific aspects and embodiments of the invention. The examples are provided solely for the purpose of illustration, and should not be construed as limiting the scope of the invention in any manner. In the examples describing dissolution testing, the following buffer solutions were used: pH 5.5 phosphate buffer: 6.8 g of potassium dihydrogen phosphate was dissolved in water, pH was adjusted with 0.2M NaOH, and the solution was diluted to 1 L. pH 6.0 phosphate buffer: same as for pH 5.5 buffer, except that NaOH solution was added to obtain pH 6.0. pH 4.5 acetate buffer: 2.99 g of sodium acetate trihydrate was dissolved in water, the pH was adjusted to 4.5 with dilute acetic acid, and the solution was diluted to 1 L.

X-ray powder diffraction patterns reported herein were generated using copper Kα-1 radiation.

All percentages are expressed on a weight basis, unless the context clearly dictates a different basis.

EXAMPLE 1 : Formulation for diacerein 50 mg capsules.

Manufacturing process:

1 ) Diacerein and sodium lauryl sulphate were mixed.

2) The mixture from step 1 ) was geometrically mixed with sodium bicarbonate.

3) The blend from step 2) was filled into empty size '0' hard gelatin capsule shells.

The capsules were tested using the in vitro dissolution conditions USP apparatus I, 100 rpm stirring, 900 ml_ of pH 4.5 acetate buffer, and the data are tabulated below:

EXAMPLE 2: Formulation for diacerein 50 mg capsules.

t Evaporates during processing. Manufacturing process: Part 1 (Drug granules)

1. Diacerein and poloxamer 407 were mixed together.

2. Crospovidone and microcrystalline cellulose were mixed geometrically with the mixture of step 1.

3. The blend of step 2 was granulated using water, and the granules were dried.

Part 2 (Sodium bicarbonate granules)

4. Sodium bicarbonate and microcrystalline cellulose were mixed

5. Crospovidone was mixed geometrically with the mixture of step 4.

6. HPMC 3 cps was dissolved in water and used to granulate the blend of step 5, then the granules were dried.

7. The dried granules of step 3 and step 6, together with HPMC 15 cps, were filled into empty hard gelatin capsules size ¹O'.

The capsules were tested using the following in vitro dissolution conditions: USP apparatus I, 100 rpm stirring, 900 ml_ of pH 4.5 Acetate buffer + 2% SLS. Results are below:

Alternate process: diacerein granules and sodium bicarbonate granules prepared as above may be alternatively compressed together into bilayer tablets, or into thlayer tablets with an intermediate layer of HPMC 15 cps.

EXAMPLE 3: Formulation for diacerein 50 mg capsules.

$ Evaporates during processing.

Manufacturing process:

1 ) Diacerein granules were prepared as described in Example 2, steps

1 -3. 2) Weighed quantity of diacerein granules was filled into empty hard gelatin capsules (size '3').

3) A filled capsule was placed into an empty hard gelatin capsule (size ¹OO') together with weighed quantities of sodium bicarbonate and HPMC 15 cps.

EXAMPLE 4: Formulation comprising diacerein and hydrophilic polymer.

Manufacturing process:

Weighed quantities of diacerein and polyvinylpyrrolidone were introduced into a ball mill and milled for about 1 hour until a homogeneous powder was obtained.

The X-ray powder diffraction pattern of the composition prepared was shown to be amorphous, as represented in Figure 2.

Formulation comprising composition of diacerein.

Manufacturing process: 1 ) Mix composition of diacerein with microcrystalline cellulose PH 102.

2) Mix crospovidone geometrically with the mixture of step 1 ).

3) Fill the mixture of step 2) into empty hard gelatin capsules size '1 '.

EXAMPLE 5: Formulation for diacerein coprecipitate.

*Evaporates during processing. Manufacturing process:

1 ) Weighed quantities of diacerein and polyvinylpyrrolidone were dissolved in 1 ,4 dioxane.

2) The solvent was evaporated using a spray drying process.

3) The spray dried powder is directly filled into hard gelatin capsules. Diacerein was dissolved in 1 ,4-dioxane at 70-75⁰C, the solvent was evaporated under vacuum and the resulting solid was dried. The X-ray powder diffraction pattern of the obtained product is represented by Figure 1. Amorphous material was not obtained.

The X-ray powder diffraction pattern of the spray dried composition, i.e., diacerein-PVP K-30 coprecipitate prepared in step 3 was shown to be amorphous, as represented by the X-ray powder diffraction pattern of Figure 3.

Formulation comprising the spray-dried diacerein-PVP K-30 coprecipitate:

Manufacturing process:

1 ) Mix composition of diacerein prepared above and microcrystalline cellulose.

2) Mix crospovidone geometrically with the mixture of step 1. 3) Fill the mixture of step 2 into empty hard gelatin capsules of size 2.

EXAMPLE 6: Formulation for diacerein coprecipitate.

t Evaporates during processing. Manufacturing process:

1 ) Tween 80 and Poloxamer 188 were dissolved in water.

2) Gelucire 50/13 was dispersed into the step 1 solution with stirring.

3) Lactose and diacerein were added to step 2 and stirred well to produce a uniform dispersion. 4) The dispersion of step 3 was spray dried.

5) 380 mg of spray dried product was filled into a size '0' capsule, to provide 50 mg of diacerein per capsule.

Diacerein powder (50 mg, placed into size '2' gelatin capsules) and the capsules prepared above were tested for drug dissolution characteristics using a USP type Il apparatus, 100 rpm stirring, and 900 ml of pH 4.5 buffer. The test data are tabulated below:

The spray dried formulation demonstrated more than a two-fold enhancement in drug dissolution, with respect to pure diacerein.

EXAMPLE 7: Diacerein 50 mg core-in-cup inlay tablet formulation.

t Evaporates during processing.

@ Opadry White is a composition of hydroxypropyl methylcellulose, polyethylene glycol, talc, and titanium dioxide, supplied by Colorcon. Manufacturing process: A. Core Tablets. 1 ) Measured amounts of diacerein and poloxamer 407 were triturated together using a mortar and pestle.

2) Lactose was added to the above mixture and was mixed uniformly by shaking in a polyethylene bag. 3) The blend of step 2 was granulated with an aqueous solution of hydroxypropyl methylcellulose 3 cps.

4) Wet granules obtained from step 3 were dried at 50-60⁰C.

5) Granules were sieved through an ASTM #25 mesh sieve.

6) Step 5 was blended with magnesium stearate, talc and Aerosil, and compressed to form core tablets.

B. Coating of compressed tablets.

7) The tablets from step 6 were film-coated with Opadry White to obtain a weight gain of 10% of the core tablet weight.

C. Preparation of inlay tablets. 8) Citric acid was ground using a mortar and pestle.

9) Xanthan gum, citric acid, and sodium bicarbonate were mixed by shaking in a polyethylene bag.

10) Step 9 was blended uniformly with microcrystalline cellulose and SLS in a polyethylene bag. 1 1 ) Step 10 was granulated with a solution of polyvinylpyrolidone in isopropyl alcohol.

12) Step 1 1 was dried in an oven at 50-60⁰C.

13) Step 12 was sifted through an ASTM #25 mesh sieve and was blended uniformly with magnesium stearate, talc and Aerosil. 14) Core-in-cup tablets were manufactured by compressing together core tablets and a weighed quantity of granules from step 13.

The tablets prepared above were subjected to dissolution testing with the following conditions: 900 ml of pH 4.5 acetate buffer with 2% SLS, USP type Il apparatus and 100 rpm stirring.

Pharmacokinetic parameters were determined in a single dose oral pharmacokinetic study using diacerein tablets prepared in Example 6 administered to male beagle dogs, and compared with the commercial product ARTRODAR 50 mg tablets.

The following parameters were calculated:

AUCo-_t = area under plasma concentration versus time curve, from time zero to the last measurable concentration.

AUCo-∞ = area under the plasma concentration versus time curve, from time zero to infinity.

C_max = maximum plasma concentration. tmax = time after administration to the maximum measured plasma concentration.

K_ei = elimination rate constant. ti/2 = half life.

EXAMPLE 8: Modified release bio-adhesive pellet formulation of diacerein.

t Evaporates during processing.

^** Celphere is a microcrystalline cellulose spherical seed core manufactured by Asahi Kasei in Japan. Manufacturing process:

1 ) Dissolve diacerein in a mixture of isopropyl alcohol and methylene chloride, and disperse HPMC 5 cps in the solution with stirring.

2) Coat the dispersion of step 1 ) onto Celphere pellets using a fluid bed coater.

3) Further coat the drug coated pellets of step 2) with a dispersion of ethyl cellulose and dibutyl phthalate in isopropyl alcohol and methylene chloride, using a fluid bed coater.

4) Dissolve HPMC 6 cps and propylene glycol in water to form polymer solution.

5) Coat modified release pellets from step 3) using the polymer solution of step 4).

6) Fill the pellets from step 5) into hard gelatin capsules or compress to form tablets. EXAMPLE 9: Formulation of diacerein using xanthan gum and guar gum.

$ Evaporates during processing.

^**Eudragit is an anionic polymer of methacrylic acid and methacrylates and is supplied by Evonik Industries, Germany. Manufacturing Process:

1 ) Sift diacerein, xanthan gum, guar gum, and lactose monohydrate through an ASTM #40 mesh sieve and mix for uniformity.

2) Sift magnesium stearate through a #60 mesh sieve.

3) Mix steps 1 ) and 2) to produce a final blend.

4) Compress the blend of step 3) into tablets.

5) Mix acetone and water, add Eudragit S 100 and triethyl citrate and dissolve.

6) Add talc to step 5) and stir well to get a uniform coating dispersion.

7) Coat step 4) tablets with step 6) coating dispersion.

EXAMPLE 10: Pharmaceutical formulation of diacerein.

t Evaporates during processing.

@ Cremophor RH 40 is supplied by BASF and is the reaction product of 45 moles of ethylene oxide and 1 mole of hydrogenated castor oil.

$ Opadry AMB is a composition of polyvinyl alcohol, titanium dioxide, talc, lecithin, and xanthan gum, supplied by Colorcon. Manufacturing process:

1 ) Cremophor was dissolved in water heated to about 40⁰C.

2) HPMC 3 cps and SLS were dissolved into step 1 ) with stirring.

3) Diacerein was dispersed into step 2) and homogenized for about 30 minutes to produce a uniform dispersion.

4) The dispersion of step 3, under continuous stirring, was coated onto sugar spheres in a Wurster coater.

5) Opadry AMB was dispersed in water with stirring and stirring was continued for about 45 minutes. The drug coated pellets of step 4 were barrier coated with Opadry dispersion.

6) The pellets from step.5 were blended with previously sifted talc and magnesium stearate and the blend was filled into size 2 hard gelatin capsules.

The prepared capsules, and the commercial ART 50 capsules, were tested for dissolution in 900 ml of various buffers with 2% sodium lauryl sulfate (except as noted) in USP type Il apparatus with 100 rpm stirring (except as noted), giving the following results where values are cumulative percentages of the drug that dissolved.

* 50 rpm stirring.

$ Without sodium lauryl sulfate.

Samples of capsules prepared in Example 10 were packaged in closed high-density polyethylene bottles with a desiccant pouch, and in blisters formed from PVC/PVDC 90 gsm (polyvinylchloride film coated with 90 grams per square meter of polyvinylidene dichloride), and the packages were stored at 40⁰C and 75% relative humidity for one month. Moisture content was analyzed by the Karl Fischer method and diacerein-related impurities were analyzed by HPLC at the time of preparation and after storage, and the results are shown below. Values for impurities in the table are weight percentages of the label diacerein content.

EXAMPLE 11 : Pharmaceutical formulation of diacerein.

$ Evaporates during processing.

Manufacturing process:

1 -5) Same as corresponding steps in Example 8.

6) Xanthan gum, sodium bicarbonate, sodium alginate, Polyplasdone, and Avicel were sifted through a BSS #60 mesh sieve and homogenously mixed.

7) The pellets from step 5 and blend from step 6 were mixed uniformly.

8) Talc and Aerosil were sifted through a BSS #36 mesh sieve. Step 7 blend was blended with talc and Aerosil for about 10 minutes. 9) Magnesium stearate was sifted through a BSS #60 mesh sieve and step 8 blend was blended with magnesium stearate.

10) Blend of step 9 was filled into size '0' capsules.

The capsules were tested for dissolution characteristics in USP Type Il apparatus, 50 rpm stirring, 900 ml of pH 5.5 buffer + 2% SLS. The data are given below:

EXAMPLE 12: Pharmaceutical formulation of diacerein.

$ Evaporates during processing.

$ Gelucire 50/13 chemically is stearoyl macrogolglycehdes and supplied by Gattafosse, France.

Manufacturing process: Diacerein layer

1 ) Melt Gelucire 50/13 at 50⁰C and disperse in hot water.

2) Dissolve Tween 80, poloxamer 188 and lactose into step.1

3) Add crospovidone and diacerein into step 2) and homogenize to produce a uniform dispersion.

4) Spray dry step 3) under continuous stirring to form a dry powder.

5) Blend the spray dried powder of step 4) with previously sifted Avicel PH102 and DCL21.

6) Blend step 5) with talc and magnesium stearate. Intermediate Layer

7) Sift together xanthan gum, crospovidone, lactose, and MCC through a BSS #60 sieve, and mix thoroughly.

8) Compact into slugs the blend of step 7) and pass the compacted mass through a 1 mm screen.

9) Blend the mass of step 8) with talc and Aerosil. Alkaline Layer

10) Sift together sodium bicarbonate, xanthan gum, crospovidone, lactose, and microcrystalline cellulose through a BSS #60 sieve, and mix thoroughly.

11 ) Compact into slugs the blend of step 10 and screen the compacted mass through a 1 mm screen.

12) Blend the mass of step 11 ) with talc and Aerosil. Compression

13) Compress thlayer tablets, consisting of a diacerein layer and an alkaline layer, separated by an intermediate layer.

EXAMPLE 13: Pharmaceutical formulation of diacerein.

@ Gelucire 44/14 chemically is lauroyl macrogolglycerides and supplied by Gattafosse, France.

$ Capmul GMS 50 K chemically is glyceryl monostearate and supplied by Abitec Corporation, USA. Manufacturing process:

1 ) Add diacerein into molten Cremophor RH 40 and mix thoroughly.

2) Sequentially add molten Gelucire 44/14, Gelucire 50/13 and Capmul GMS K50 into step 1 ) and triturate well after each addition.

3) Allow the mixture to solidify at room temperature for 30 minutes.

4) Add sodium aluminum silicate and colloidal silicon dioxide into step 3) to produce a free-flowing powder, then add Avicel PH102 and mix well.

5) Blend step 4) with talc and magnesium stearate, and fill into size'0' hard gelatin capsules

EXAMPLE 14: Pharmaceutical formulation of diacerein.

Manufacturing process:

1 ) Sift diacerin, mannitol and microcrystalline cellulose through a BSS #22 sieve, sift glycine carbonate through a BSS #60 sieve, and mix the ingredients together.

2) Add croscarmellose sodium and crospovidone to step 1 ) and mix thoroughly.

3) Sift Orange mixed fruit flavor and magnesium stearate through a BSS #60 sieve.

4) Blend the mixture from step 2) with step 3) materials.

5) Compress the step 4) mixture into tablets.

Claims

CLAIMS:

1. A pharmaceutical formulation comprising diacerein, together with one or more of: a) an alkalizing agent; b) a surfactant; and c) a hydrophilic polymer; wherein a dissolution rate of diacerein from the formulation in aqueous media at pH values about 4 to about 14 is at least about twice the dissolution rate of powdered diacerein.

2. The pharmaceutical formulation of claim 1 , wherein an alkalizing agent comprises at least one carbonate or bicarbonate of an alkali metal or alkaline earth metal.

3. The pharmaceutical formulation of claim 1 , wherein a surfactant comprises at least one non-ionic, cationic, or anionic surface-active agent.

4. The pharmaceutical formulation of claim 1 , wherein a surfactant comprises at least one of sodium lauryl sulphate, polyoxyl 40 hydrogenated castor oil, polysorbate 80, mixtures of mono-, di- and th-glycerides with polyethylene glycol (PEG) esters of fatty acids, and block copolymers of ethylene oxide and propylene oxide.

5. The pharmaceutical formulation of claim 1 , comprising more than one surfactant.

6. The pharmaceutical formulation of claim 1 , wherein a hydrophilic polymer comprises a polyvinylpyrrolidone, cellulose derivative, sugar, sugar alcohol, polyhydric alcohol, polyethylene glycol, polyethylene oxide, polyoxyethylene derivative, polyvinyl alcohol, propylene glycol derivative, oxide, cyclodexthn, gelatin, or a mixture of any two or more thereof.

7. The pharmaceutical formulation of any of claims 1 -6, further comprising a gastro-retentive polymer.

8. The pharmaceutical formulation of claim 7, wherein a gastro-retentive polymer comprises at least one hydrocolloid.

9. The pharmaceutical formulation of claim 8, wherein a hydrocolloid comprises at least one of a cellulose derivative, a polycarbopil, a polyacrylate, xanthan gum, guar gum, carrageenan gum, locust bean gum, sodium alginate, agar-agar, gelatin, a modified starch, and a co-polymer of ethylene oxide and propylene oxide.

10. The pharmaceutical formulation of claim 9, wherein a cellulose derivative comprises a methylcellulose, a hydroxyalkylcellulose, a carboxymethylcellulose, or a mixture of any two or more thereof.

11. The pharmaceutical formulation of any of claims 1 -10, comprising at least one gas generating component.

12. The pharmaceutical formulation of claim 11 , wherein a gas generating component comprises a bicarbonate or carbonate of an alkali metal or alkaline earth metal.

13. The pharmaceutical formulation of any of claims 1 -12, further comprising a component that modifies diacerein dissolution.

14. The pharmaceutical formulation of claim 13, wherein a component that modifies diacerein dissolution comprises a polyurethane, polypropylene, polyvinyl alcohol, polyvinyl acetate, polyacrylic acid or derivative, polymethylmethacrylic acid or derivative, polycarbonate, polyvinylidene difluohde, polytetrafluoro ethylene, waxe, oil, or a mixture of any two or more thereof.

15. The pharmaceutical formulation of any of claims 1 -14, wherein a portion of diacerein is in an immediate release form and a portion is in a modified release form.

16. The pharmaceutical formulation of any of claims 1 -14, wherein more than about 50 percent of contained diacerein is released into the upper gastrointestinal tract, following administration.

17. The pharmaceutical formulation of any of claims 1 -16, wherein the formulation comprises a multiparticulate component.

18. The pharmaceutical formulation of claim 17, wherein a multiparticulate component comprises at least one of formulated granules, beads, spheroids and a minitablet.

19. A pharmaceutical formulation comprising diacerein that releases at least about 50 percent of contained diacerein into 900 ml of pH 5.5 phosphate buffer containing 2 percent sodium lauryl sulphate, in USP type Il apparatus with 50 rpm stirring, within about two hours.

20. A pharmaceutical formulation comprising diacerein and having a moisture content less than about 8 percent by weight.