WO2010051296A1 - Pharmaceutical compositions containing diacerein - Google Patents

Pharmaceutical compositions containing diacerein Download PDF

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Publication number
WO2010051296A1
WO2010051296A1 PCT/US2009/062302 US2009062302W WO2010051296A1 WO 2010051296 A1 WO2010051296 A1 WO 2010051296A1 US 2009062302 W US2009062302 W US 2009062302W WO 2010051296 A1 WO2010051296 A1 WO 2010051296A1
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WO
WIPO (PCT)
Prior art keywords
diacerein
weight
formulation
formulation according
controlied
Prior art date
Application number
PCT/US2009/062302
Other languages
French (fr)
Inventor
Danchen Gao
Jen-Sen Wu
Wei-Shu Lu
Shouchiung Chen
Pei-Chun Kuo
Chih-Ming Chen
Original Assignee
Anchen Laboratories, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to MX2011004395A priority Critical patent/MX2011004395A/en
Application filed by Anchen Laboratories, Inc. filed Critical Anchen Laboratories, Inc.
Priority to KR1020117012172A priority patent/KR101718347B1/en
Priority to BRPI0920255A priority patent/BRPI0920255A2/en
Priority to EP09824084.9A priority patent/EP2349289B1/en
Priority to CN2009801431098A priority patent/CN102202673B/en
Priority to RU2011121609/15A priority patent/RU2542461C2/en
Priority to NZ592376A priority patent/NZ592376A/en
Priority to AU2009308958A priority patent/AU2009308958B2/en
Priority to ES09824084.9T priority patent/ES2585904T3/en
Priority to CA2741846A priority patent/CA2741846C/en
Priority to JP2011534697A priority patent/JP5642691B2/en
Publication of WO2010051296A1 publication Critical patent/WO2010051296A1/en
Priority to IL212483A priority patent/IL212483A/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
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    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
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Definitions

  • Diacerein 5- bis(acetyloxy)-9, 10- dioxo ⁇ 2 -anthracene carboxylic acid
  • SYSADOA Symptomatic Slow-Acting Drug in Osteoarthritis
  • Diacerein has a log P value of 2.42 and is practically insoluble in water.
  • Diacerein is entirely converted into rhein before reaching the systemic circuiation.
  • Rhein itself is either eliminated by the renal route (20%) or conjugated in the liver to rhein giucuronide (60%) and rhein sulfate (20%). These metabolites are mainly eliminated by the kidney.
  • Oral bioavailability of diacerein is about 35-56%.
  • the incidence rate of diarrhea was dose proportional, in contrast to a dose disproportional nature of the other side effects (J, P. Pelletier et al., Arthritis & Rheumatism, 43(1 O) 1 2339-2348, 2000). This finding implies that minimizing the exposure of diacerein to the colon couid improve diarrhea symptoms by enhancing absorption in the intestine.
  • diacerein in addition to the treatment of osteoarthritis, diacerein may be considered for use in treating other inflammatory or autoimmune diseases, for example, type l/il diabetes and its comp ⁇ cations, such as nephropathy, retinopathy, neuropathy or foot ulcers, etc.
  • type l/il diabetes and its comp ⁇ cations such as nephropathy, retinopathy, neuropathy or foot ulcers, etc.
  • diacerein and rhein slow down the disease progression of diabetes and suppress the hyper-metabolism of the kidney in diabetic animals.
  • I diabetes and its comp ⁇ cations involves decreasing the expression and activity of pro-inflammatory cytokines, IL-1 ; downregulating the expression of IL-6, TNF- ⁇ and TGF- ⁇ ; and inhibiting iNOS expression; thereby decreasing the expression and function of GLUT-1 and decreasing the uptake of glucose.
  • An object of the present invention is to provide a once-daily controiled-release formulation of diacerein for treating inflammatory, autoimmune diseases or their complications, such as osteoarthritis, type l/il diabetes or diabetic nephropathy, with reduced adverse side effects.
  • the once-daily controiled-release formulations of diacerein of the present invention could be a membrane-controlled formulation, a matrix formulation or an osmotic pump formulation.
  • the contro ⁇ ed-release formulations of diacerein of the present invention could further provide increased bioavailability when compared to commercia! immediate release (IR) formulations. More specifically, said method reduces the adverse side effect of diarrhea caused by diacerein.
  • Yet another object of the invention is to provide a once-daily controlled-release formulation comprising diacerein and a second active ingredient for treating inflammatory, autoimmune diseases or their complications.
  • the second active ingredient could be an angiotensin converting enzyme inhibitor or an angiotensin Il receptor blocker for treating diabetic nephropathy, an antihypergiycemic drug for treating type I/I I diabetes, or a non-steroidal anti-inflammatory drug (NSAID) for treating osteoarthritis.
  • NSAID non-steroidal anti-inflammatory drug
  • diacerein The major adverse side effects of diacerein are diarrhea and soft stools.
  • non-absorbed diacerein is metabolized to rhein in the colon, Rhein in the colon induces a laxative effect via activating chloride secretion by excitation of submucosal neurons and release of acetylcholine and endogenous prostaglandins, but not by release of histamine or serotonin.
  • the present invention provides a once-daily controiled-release formulation of diacerein which can minimize the release of diacerein in the colon to reduce these adverse side effects.
  • An ideal control of diacerein release is when the drug release rate and the absorption rate are close to identical so that the adverse side effects caused by the contact of diacerein and the colon mucosa can be minimized.
  • Technologies for controlling the release of diacerein include, but are not ⁇ mited to, membrane-controlled technology, matrix-controlled technology and osmotic pump technology.
  • the diacerein, or other active ingredient that is utilized in the present invention may be prepared either through micronization alone or with a milling aid.
  • the diacerein utilized in the formulations of the present invention may be crystalline or in the amorphous state.
  • the sustained-release formulation may include common additives in addition to the active ingredient and a polymer.
  • the sustained-release core may include a diluent such as a microcrystalline cellulose, dextrose, starch, sucrose, lactose, sorbitol, mannito!
  • the sustained-release formulation may also include a disintegrating agent such as sodium starch glycoSate, starch, alginic acid or its sodium salt.
  • a pharmaceutical composition of the present invention can be formulated as various types of oral formulations having the above-described composition.
  • the pharmaceutical composition of the present invention can be formulated as tablets or beads.
  • the formulation of the invention may be surrounded by a controlied-release film that can isolate the drug core from the G! environment to minimize direct contact of diacerein with the colon mucosa.
  • the controiled-reiease film may contain a water-insoluble polymer which forms a membrane to avoid direct contact of diacerein and the colon mucosa.
  • the water-insoiubie polymer may include celiulose acetate, cellulose triacetate, agar acetate, amyiose triacetate, beta giucan acetate, acetaldehyde dimethyl acetate, cellulose acetate methyl carbamate, cellulose acetate phthafate, candose acetate succinate, cellulose acetate dimethylamino acetate, cellulose acetate ethyl carbonate, cellulose acetate chloroacetate, celiuiose acetate ethyl oxalate, cellulose acetate propionate, poly(vinyimethylether) copolymers, cellulose acetate butyl sulfonate, cellulose acetate octate, cellulose acetate
  • the controiled-reiease film can further contain a piasticizer or a pore-forming agent to obtain suitable film properties.
  • suitable plasticizers are dibutyl sebacate, triethyl citrate and polyethylene glycol (PEG).
  • suitable pore-forming agents are hydroxymethylpropylceliuiose (HPMC), polyvinylpyrrolidone (PVP) and hydroxypropyiceilulose (HPC).
  • the drug release rate of diacerein can be controlled by adjusting the weight gain of the controlied-release film. Suitable weight gain couid be 3-50% of the core tablet or bead.
  • the controiled-release formulation comprises an active layer, a sustained-release film layer and a deiayed-release film layer,
  • the active layer comprises between about 40.0% and about 50.0% by weight of microcrystaliine cellulose, between about 20.0% and about 30.0% by weight of dtacerein, between about 2.0% and about 5.0% by weight of povidone and between about 20.0% and about 30.0% by weight of mannitoi.
  • the active layer comprises about 50.0% by weight of microcrystaliine cellulose, about 25.0% by weight of diacerein, about 2.0% by weight of povidone and about 23.0% by weight of mannitoi.
  • the sustained-release film layer may comprise, but is not limited to, ethyl cellulose polymers, povidone, t ⁇ ethyl citrate and talc.
  • the delayed-reiease film layer may comprise, but is not limited to, Eudragit® polymers, triethyl citrate and talc.
  • the formulation of the invention may contain a controiied-release material, such as a hydrophiiic polymer, a hydrophobic polymer or wax to form a controlled-reiease matrix. Diacerein is trapped in the matrix to avoid contact of the diacerein and the colon mucosa.
  • a controiied-release material such as a hydrophiiic polymer, a hydrophobic polymer or wax to form a controlled-reiease matrix.
  • Diacerein is trapped in the matrix to avoid contact of the diacerein and the colon mucosa.
  • controlled release materials include hydroxypropyimethyi cellulose with a molecular weight of between 1 ,000 and 4,000,000, hydroxypropyl cellulose with a molecular weight of from 2,000 to 2,000,000, sodium alginate, carbomer (Carbopo!®), sodium carboxymethyl cellulose, xanthan gum, guar gum, locust bean gum, poly vinyl acetate, polyvinyl alcohol carboxyvinyl polymers, polyvinyl alcohois, giucans, scleroglucans, mannans, xanthans, aiginic acid and its derivatives, poiyanhydrides, poiyaminoacids, carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, polyvinyl pyrrolidone, cross-iinked polyvinyl pyrrolidone, carboxymethyiamide, potassium methacrySate/divinylbenzene copolymer, starches and their derivatives, ⁇
  • the controlled-reiease formulation comprises about 20.0% by weight of diacerein, between about 20.0% and 40.0% by weight of hydroxymethylpropylcellulose, between about 37.0% and about 57.0% by weight of mannitol, about 2.0% by weight of povidone and about 1.0% by weight of magnesium stearate.
  • the controlled-reiease formulation comprises about 20.0% by weight of diacerein, about 20.0% by weight of hydroxymethylpropyicellulose, about 57.0% by weight of mannitol, about 2.0% by weight of povidone and about 1.0% by weight of magnesium stearate.
  • the contro ⁇ ed-release formulation comprises about 20.0% by weight of diacerein, about 40.0% by weight of hydroxymethyipropyicelluiose, about 37.0% by weight of mannitoi, about 2.0% by weight of povidone and about 1.0% by weight of magnesium stearate.
  • the controlled-reiease formulation comprises about 20.0% by weight of diacerein, about 33.0% by weight of hydroxymethylpropylcellulose, about 46.0% by weight of mannitol and about 1.0% by weight of magnesium stearate.
  • the release rate of diacerein can be controlled by an osmotic pump system.
  • a drug-containing core is covered by a semipermeable membrane, allowing only water to permeate.
  • aqueous fluids are imbibed through the semipermeable membrane into the core by an osmotic pressure gradient, the drug is released from a passageway in the membrane.
  • Said passageway may be a hole, aperture, orifice, bore, weakened area or an erodible element that erodes to form an passageway for the release of diacerein.
  • the materials used for the semipermeable membrane in the invention are well-known in the pharmaceutical industry.
  • a controlied-release formulation of diacerein which is controlied by osmotic pump technology may utilize a formulation comprising a drug layer and a push iayer.
  • a push layer of an osmotic delivery dosage comprises an osmopolymer. The osmopolymer swells when aqueous liquids are absorbed.
  • osmopoiymers examples include poiy(hydroxyalkylmethacrylate with a molecular weight of 30,000-5,000,000, polyvinylpyrrolidone) with a molecular weight of 10,000-36,000, anion and cation hydrogels, polyelectrolyte complexes, poly(vinyi alcohol), polyethylene oxide, N-vinyi lactams, Carbopol® acidic carboxy polymers with a molecular weight of 4, 000 ⁇ 4, 500,000, Cyanamer® polyacryiamides, cross-linked water swellable indene-maleic anhydride polymers, aminopectin copolymer, Aqua-Keeps® acrylate polymer and polysaccharides.
  • the controlled-release formulation of the invention could further provide increased bioavailability of diacerein when compared to commercial immediate release formulations (ex. Arthrodar ®, TRB Pharma s.a.). It is believed that the increase in bioavailability could be heipful to decrease the adverse side effects.
  • Methods for increasing the bioavailability include, but are not limited to, (a) adding surfactants; (b) forming a solid dispersion; (c) utilizing micronized or nanonized diacerein, (d) adding acidifying or buffering agents and (e) complexation with cyclodextrins.
  • Suitable surfactants include, but are not limited to, sodium iauryl sulfate, polyethylene-polypropylene glycol, glycerol-poiyethylene glycol oxystearate, PEG-40 hydrogenated castor oil and stearoyi macrogolglycerides (polyoxylgiycerides).
  • Solid dispersions have been traditionally employed to enhance the dissolution rate of drugs, with a view to improve bioavailability.
  • the drug may be entrapped in a carrier in an amorphous form without undergoing recrystallization.
  • the process to prepare a solid dispersion is well known by a skilled artisan.
  • Controlling the particle size of diacerein is also considered to be helpful to improve its bioavailability.
  • the preferred particle size of diacerein is D50 less than 20 ⁇ m and, more preferably, D50 less than 5 ⁇ m.
  • the combination of co-micronized diacerein with hydrophiiic milling aids can facilitate drug dissolution and bioavailability.
  • Suitable hydrophiiic milling aids include, but are not limited to, HPMC, sucrose, iactose, surfactants and superdisintegrants.
  • the process may be practiced by utilizing a mill or a micronizer, such as an Aljet mill.
  • the co-micronized diacerein can then be mixed or granulated with other excipients.
  • the tables below indicate the solubility and stability of diacerein in buffer solutions with different pH values.
  • diacerein is stable and its solubility is relatively low.
  • the degradation products including rhein increase at a pH above 5.
  • the poor stability of diacerein in the intestinal environment may result in incomplete absorption and cause poor and variable bioavailability.
  • one of the increased degradants in the intestinal environment, rhein has been suspected to be a major factor in stimulating colon mucosa and results in diarrhea. Accordingly, methods to stabilize diacerein during gastro-intestinal absorption might improve its bioavailability as well as the side effect of diarrhea.
  • the stabilization methods for use with diacerein may include the addition of acidifying or buffering agents or complexation with cyclodextrins.
  • compositions of diacerein of the present invention can be used for treating inflammatory or autoimmune diseases, such as rheumatoid arthritis, osteoarthritis, osteoporosis, inflammatory bowel disease, inciuding ulcerative colitis and Crohn's disease, ulcerative colitis, multiple sclerosis, periodontitis, gingivitis, graft versus host reactions, psoriasis, scleroderma, atopic dermatitis, asthma, systemic lupus erythematosus (SLE), nephropathy and chronic obstructive pulmonary disease (COPD).
  • inflammatory or autoimmune diseases such as rheumatoid arthritis, osteoarthritis, osteoporosis, inflammatory bowel disease, inciuding ulcerative colitis and Crohn's disease, ulcerative colitis, multiple sclerosis, periodontitis, gingivitis, graft versus host reactions, psoriasis, scleroderma, atopic
  • Dermal conditions that may be treated include those given above, and also psoriatic arthritis, epidermolysis bullosa, atopic dermatitis and vasculitis.
  • Anti-angiogenic activity may allow the treatment of conditions such as age-related macular degeneration and cancer.
  • the pharmaceutical compositions of the invention are used for treating osteoarthritis, type I/I! diabetes or diabetic nephropathy, with fewer adverse side effects.
  • Suitable doses of diacerein for treating the above diseases are in the range of 5-200 mg/per day, preferably, 20-150 mg/per day.
  • a 50 mg commercial IR diacerein formulation administered twice daily only maintains the plasma concentration of rhein above 2 mg/ml for about 12 hours.
  • a 50 mg commercial IR diacerein formulation administered twice daily only maintains the plasma concentration of rhein above 2 mg/ml for about 12 hours.
  • a 50 mg diacerein formulation of the present invention maintains the plasma concentration of rhein above the concentration of 1 mg/ml for more than 12 hours in humans when orally administered to a human patient who has reached the steady state condition;
  • a 100 mg diacerein formulation of the present invention maintains the plasma concentration of rhein above the concentration of 2 mg/ml for more than 12 hours in humans when orally administered to a human patient who has reached the steady state condition;
  • a 150 mg diacerein formulation of the present invention maintains the plasma concentration of rhein above the concentration of 3 mg/ml for more than 12 hours in humans when orally administered to a human patient who has reached the steady state condition;
  • a 200 mg diacerein formulation of the present invention maintains the plasma concentration of rhein above the concentration of 4 mg/ml for more than 12 hours in humans when oraily administered to a human patient who has reached the steady state condition.
  • the controlied-reiease formulation of the invention can further comprise another active ingredient such as Angiotensin I! receptor blockers (ARBs), angiotensin converting enzyme inhibitors (ACEIs), ant ⁇ hyperglycemics or NSAIDs. More specifically, the formulations of diacerein according to the present invention can further contain an angiotensin converting enzyme inhibitor or a angiotensin Il receptor blocker for treating diabetic nephropathy, a antihypergiycemic drug for treating type i/il diabetes, or a non-steroidal anti-inflammatory drug (NSAID) for treating osteoarthritis.
  • ARBs Angiotensin I! receptor blockers
  • ACEIs angiotensin converting enzyme inhibitors
  • NSAID non-steroidal anti-inflammatory drug
  • ACEIs examples include captopril, benazepril, enalapril, lisinopril, fosinopril, ramip ⁇ i, perindopril, quinapril, moexipril and trandoiapril.
  • ARBs examples include candesartan, eprosartan, irbesartan, telmisartan, valsartan and losartan.
  • antihypergiycemics include sulfonylureas, such as glyburide, glipizide, and glimeptride; megiitinides such as repaglinide and nateglinide; biguanides such as metformin; thiazolidinediones such as piogiitazone and rosigiitazone; alpha glucosidase inhibitor such as acarbose.
  • NSAIDs examples include salicylates such as aspirin; aryialkanoic acids, such as acetaminophen; 2-Arylpropionic acids such as Ibuprofen, Ketorolac and Naproxen; n-aryianthranilic acids such as mefenamic acid, meclofenamic acid; Oxicams such as piroxicam, meloxicam; and COX-2 inhibitors such as Celecoxib.
  • salicylates such as aspirin
  • aryialkanoic acids such as acetaminophen
  • 2-Arylpropionic acids such as Ibuprofen, Ketorolac and Naproxen
  • n-aryianthranilic acids such as mefenamic acid, meclofenamic acid
  • Oxicams such as piroxicam, meloxicam
  • COX-2 inhibitors such as Celecoxib.
  • the second active ingredient may be in a controiled-release dosage form or in an immediate release dosage form.
  • Diacerein may be dissolved with suitable organic solvents to form a drug solution.
  • Carriers such as hydrophilic polymers, hydrophobic polymers, surfactants, water-soiuble excipients, or wax, or a combination of the above carriers are then dissolved or dispersed in the drug solution, Spray drying of the above solution may be used to obtain a solid dispersion, or the solution may be coated onto suitable excipients ⁇ water-soiuble materials that function as a second carrier) using a fiuidized bed.
  • Water solutions of cyciodextrins may be prepared with various percentages. Diacerein is added to the above solutions to yield saturated solutions. The solutions are stirred for at least 72 hours and then allowed to stand until ali undissolved material has precipitated. The supernatant solution is filtered and dried by oven, spray drying or freeze drying or coated onto suitable excipients (which function as diluents) using a fluidized bed.
  • the API part is prepared as described in the above examples.
  • the diacerein API part is physically mixed or granulated with controlled release materials and then the mixture is compressed to obtain matrix tablets.
  • an acidifying agent or buffering agent may be included in the tablet formulation.
  • Formula A ingredients mg % mg %
  • Granule I! was prepared by wet granulation. Granules I and Il were mixed with lubricants and then compressed to obtain matrix tablets. Example 5
  • Diacerein, HPMC, mannitol, cremophor and tartaric acid were granulated by wet granulation. The granules were mixed with lubricants and then compressed.
  • Diacerein is dissolved with suitable organic solvents to form a drug solution.
  • Carriers such as hydrophiiic polymers, hydrophobic polymers, surfactants, water-soluble excipients, wax or the combination of above carriers are then dissolved or dispersed in the drug solution. The sofution is sprayed onto seeds by fiuidized bed to obtain matrix beads. The beads are then encapsulated in a capsule with suitable size.
  • the API part is prepared as described in the above examples.
  • the Diacerein API part is physically mixed or granulated with suitable diluents and lubricants then compressed to obtain core tablets.
  • the acidifying agent or buffering agent may be included in the core tablet formuiation.
  • the controlled release materials are dissolved along with pore forming agents and plasticizer in organic solvents to obtain the coating solution for above core tablet. Then, the tablets are coated in a tablet coater.
  • the core tablet was manufactured by a soiid dispersion method as described in the above examples or by a wet granulation method. The core tablet was then coated with a seal coat and a sustained-reiease coat.
  • Diacerein is dissolved with suitable organic solvents to form a drug solution.
  • Carriers such as hydrophiiic polymers, hydrophobic polymers, surfactants, water-soluble excipients, wax or the combination of above carriers are then dissolved or dispersed in the drug solution.
  • the solution is sprayed onto seeds by a fluidized bed to obtain core beads.
  • the controlled release materials are dissolved along with pore forming agents and ptasticizer in organic solvents to obtain the coating solution for the core beads. Then, the beads are coated with a controiled-release membrane.
  • the extended-release beads are then encapsulated in a capsule with suitable size.
  • the formula H was prepared by the process described in Example 10.
  • the API part as described in the above examples is prepared by physically mixing or granulating the diacerein API part with PEO, an osmotic agent, a binder, and an antioxidant and then blending with a lubricant to obtain the drug layer.
  • the acidifying agent or buffering agent may be included in the drug layer formulation.
  • the push layer is also prepared by physically mixing or granulating.
  • the semipermeable membrane is introduced by dissolving cellulose acetate along with a pore forming agent and piasttcizer in organic solvents and then performing the coating process in a tablet coater
  • a passageway is formed by laser or mechanical drilling on the surface of the CA film next to the drug layer
  • Push Layer PEO (MW 7,000,000) 194 00 77 48
  • the API part is prepared as described in the above examples.
  • the diacerein AP! part is physically mixed or granulated with PEO, a binder, an osmotic agent and an antioxidant.
  • the mixture is blended with lubricants and then compressed to obtain the core tablet
  • the acidifying agent or buffering agent may be inciuded in the core tablet formulation.
  • a seal coating solution is prepared by dissolving or dispersing a hydrophilic polymer, an osmotic agent and iubricants in water, then spraying the coating solution onto the core tablets in a coater.
  • a semipermeable coating is prepared by dissolving cellulose acetate along with a pore forming agent and plasticizer in an organic solvent and then spraying the coating solution onto the seal-coated tablet in a coater. At least one passageway is formed during the dissolution of the dosage form Example 15
  • the sustained-release formulation of the present invention can be prepared by- direct compression, compaction-granulation, wet granulation or extrusion and spheronization.
  • the sustained-release formulation can be prepared in such a manner that the diacerein, a swellable polymer, a diluent, a disintegrating agent, a binder, and a lubricant are mixed, followed by granulation with a compaction granulator (e.g. roller compacter), screening through an about 20-mesh screen, and tabletting.
  • a compaction granulator e.g. roller compacter
  • the sustained-release formulation in the case of wet granulation, can be prepared in such a manner that the diacerein, a swellable polymer, a diluent, a disintegrating agent, and a binder are mixed in a high shear granuiator with the addition of water or solvent (e.g. ethanol or isopropyl alcohol).
  • the granules are further dried, milled and mixed with iubricant and tabletting.
  • the sustained-release formulation can be prepared in such a manner that the diacerein, a swellabie polymer, a diluent, a disintegrating agent, a binder, and a lubricant are mixed in a low shear granulator or mixer with the addition of water or solvent (e.g. ethanol or isopropyl alcohol).
  • water or solvent e.g. ethanol or isopropyl alcohol.
  • the wet mass is added to a single screw or twin screw extruder, the extrudate is spheronized in a marumerizer to obtain sustained release beads.
  • a representative matrix sustained release tablet formulation is shown in Table 17.
  • Formula K was prepared by the process described in Example 16.
  • the core tablet is prepared by direct compression, compaction-granulation is used, or wet granulation.
  • the core bead is prepared by fluid bed granulation.
  • the tablet core can be prepared in such a manner that the diacerein, a diluent, a binder, and a lubricant are mixed, followed by granulation with a compaction granuiator (e.g. roller compacter), screening through an about 20-mesh screen, and tabletting.
  • a compaction granuiator e.g. roller compacter
  • the core tablet can be prepared in such a manner that the diacerein, a diluent, and a binder are mixed in a high shear granuiator with the addition of water or solvent (e.g. ethanol or isopropyl alcohol).
  • water or solvent e.g. ethanol or isopropyl alcohol.
  • the granules are further dried, milled and blended with iubricant and tabietted.
  • the beads can be prepared in such a manner that the diacerein, a diluent, and a binder are granulated in a fluid bed granuiator with the addition of water or solvent (e.g. ethanol or isopropyl alcohol).
  • water or solvent e.g. ethanol or isopropyl alcohol.
  • the bead granules are further dried and sieved through an appropriate mesh.
  • the controlled release materials are dissolved along with pore forming agents and plasticizer in organic solvents to obtain the coating solution for the above core tablets or beads. Then, the tablets or beads are coated either in a tablet coater or a fluid bed coater.
  • Diacerein (Highsun) refers to diacerein produced by Taizhou Highsun Pharmaceutical
  • Diacerein refers to diacerein produced by TRB Chemedica.
  • HPMC K4MCR HPMC K100LVCR
  • HPMC E5LVCR various METHOCELTM hypromeliose products produced by the Dow Chemical Company.
  • Example 20 The dissolution tests were performed according to the so-caifed “basket” method and/or the “paddle and sinker” method.
  • the “basket method” uses USP apparatus 1. It is usually operated at 100 rpm (revolutions per minute) and is usually used for beads formulation.
  • the FDA guidances contain descriptions of the "basket” method.
  • the "paddle and sinker” method uses USP apparatus 2. It is usually operated at 50 rpm. A “sinker” can be some wires wrapped around the capsules before the capsules are put into dissolution vessels. The FDA guidances contain descriptions of the "paddle and sinker” method.
  • Both methods are usually used at 37° C + 0.5° C.
  • the samples are usually dissolved in 900 ml of aqueous media.
  • Table 23 contains the results of the dissolution tests performed on formulations DIAC-2002, DIAC-2005, DfAC-2017 and DIAC-2018. Ail tests were performed utilizing pH 6.0 PBS buffer. The tests on DIAC-2002 and DIAC-2005 formulations were performed utilizing the "basket” method at 100 rpm, and the tests on DIAC-2017 and DIAC-2018 formulations were performed utilizing the "paddle and sinker” method at 100 rpm.
  • Table 24 contains the results of the dissolution tests performed on formulations DIAC-2001 , DIAC-2002, DIAC-2005 and DIAC-2006. Ail tests were performed using pH 6.8 PBS buffer and the "basket" method at 100 rpm The tests were performed in triplicates, and the table shows the data for the mean of these triplicates
  • Tables 25-29 show compositions of active layers of formulations DIAC-3002, DIAC-3004, DIAC-3006, DlAC-3007, DIAC-3008, DIAC-3010, D1AC-3Q11 and DIAC-3012;
  • Tables 27 and 28 show compositions of Sustained-Release (SR) film layers of these formulations;
  • Table 29 shows compositions of Delayed-Release (DR) film layers of formulations DIAC-3007, DIAC-3008, DlAC-3011 and DIAC-3012 (the other formulations do not contain DR film layer).
  • Cellets® 350 and Celiets® 750 are neutral starter cores for controlled release formulation produced by the Glatt Group
  • Example 22 The dissolution tests were performed according to the "basket” method and/or the “paddle and sinker” method as described in Example 21.
  • Table 30 contains the results of the dissolution tests performed on formulations DIAC-3002, DiAC-3004, DlAC-3006 and DIAC-3007. All tests were performed utilizing pH 6.0 PBS buffer and utilizing the "basket" method at 100 rpm. Table 30
  • the % refers to the Sustained-Release (SR) or the Deiayed-Release (DR) poiymer percentage in each tested formuiation.
  • Table 31 contains the results of the dissolution tests performed on formulations
  • Table 32 contains the results of the dissolution tests performed on formulations DIAC-3004, DIAC-3006 and DIAC-3007. All tests were performed utilizing pH 6.8 PBS buffer and utilizing the "basket" method at 100 rpm.
  • Table 33 contains the results of the dissolution tests performed on formulations DIAC-3008, DIAC-3010, DlAC-3011 and DIAC-3012. AIi tests were performed utiiizing pH 6.8 PBS buffer and utiiizing the "basket" method at 100 rpm.

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Abstract

A once-daily controlted-release formulation of diacerein for treating inflammatory or autoimmune diseases or their complications, with reduced adverse side effects and methods of treating such diseases are disclosed.

Description

PHARMACEUTICAL COMPOSITIONS CONTAINING DiACERESN
BACKGROUND OF THE INVENTION
Diacerein (4, 5- bis(acetyloxy)-9, 10- dioxo~2 -anthracene carboxylic acid) is a highly purified anthraquinone derivative, it is known to inhibit interleukin-1 activity, and has been approved as a Symptomatic Slow-Acting Drug in Osteoarthritis (SYSADOA) in several countries.
Diacerein has a log P value of 2.42 and is practically insoluble in water.
Diacerein is entirely converted into rhein before reaching the systemic circuiation.
Rhein itself is either eliminated by the renal route (20%) or conjugated in the liver to rhein giucuronide (60%) and rhein sulfate (20%). These metabolites are mainly eliminated by the kidney.
There are two major adverse side effects of diacerein: diarrhea or soft stools and yellow-brown coloring of urine. The severity of diarrhea is mild-to-moderate and occurs within the first two weeks of treatment. Coloring of urine is due to the metabolites of diacerein present in the urine, in vitro and in vivo studies have showed that non- absorbed diacerein is metabolized to rhein in the colon. Rhein in the colon induces a iaxative effect via activating chloride secretion by excitation of submucosal neurons and release of acetylcholine and endogenous prostaglandins, but not by release of histamine or serotonin.
Oral bioavailability of diacerein is about 35-56%. A 3-year clinical study indicated that up to 30% diarrhea or soft stools occurred in the patients who took diacerein twice a day with meais (M. Dougados et ai,, Arthritis & Rheumatism, 44(11), 2539-2547, 2001 ), Even though feeding increases the bioavailability of diacerein to 43-70%, incomplete absorption still results in a local effect in the colon. The incidence rate of diarrhea was dose proportional, in contrast to a dose disproportional nature of the other side effects (J, P. Pelletier et al., Arthritis & Rheumatism, 43(1 O)1 2339-2348, 2000). This finding implies that minimizing the exposure of diacerein to the colon couid improve diarrhea symptoms by enhancing absorption in the intestine.
in addition to the treatment of osteoarthritis, diacerein may be considered for use in treating other inflammatory or autoimmune diseases, for example, type l/il diabetes and its compϋcations, such as nephropathy, retinopathy, neuropathy or foot ulcers, etc. There are non-clinical studies indicating that diacerein and rhein slow down the disease progression of diabetes and suppress the hyper-metabolism of the kidney in diabetic animals. The potential mechanism of diacerein and its metabolite, rhein, to decrease the progression of type I/! I diabetes and its compϋcations involves decreasing the expression and activity of pro-inflammatory cytokines, IL-1 ; downregulating the expression of IL-6, TNF-α and TGF-β; and inhibiting iNOS expression; thereby decreasing the expression and function of GLUT-1 and decreasing the uptake of glucose.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a once-daily controiled-release formulation of diacerein for treating inflammatory, autoimmune diseases or their complications, such as osteoarthritis, type l/il diabetes or diabetic nephropathy, with reduced adverse side effects. More specifically, the once-daily controiled-release formulations of diacerein of the present invention could be a membrane-controlled formulation, a matrix formulation or an osmotic pump formulation. In a preferred embodiment, the controϋed-release formulations of diacerein of the present invention could further provide increased bioavailability when compared to commercia! immediate release (IR) formulations. More specifically, said method reduces the adverse side effect of diarrhea caused by diacerein.
Yet another object of the invention is to provide a once-daily controlled-release formulation comprising diacerein and a second active ingredient for treating inflammatory, autoimmune diseases or their complications. More specifically, the second active ingredient could be an angiotensin converting enzyme inhibitor or an angiotensin Il receptor blocker for treating diabetic nephropathy, an antihypergiycemic drug for treating type I/I I diabetes, or a non-steroidal anti-inflammatory drug (NSAID) for treating osteoarthritis.
DETAILED DESCRIPTION QF THE INVENTION
The major adverse side effects of diacerein are diarrhea and soft stools. In vitro and in vivo studies have showed that non-absorbed diacerein is metabolized to rhein in the colon, Rhein in the colon induces a laxative effect via activating chloride secretion by excitation of submucosal neurons and release of acetylcholine and endogenous prostaglandins, but not by release of histamine or serotonin.
The present invention provides a once-daily controiled-release formulation of diacerein which can minimize the release of diacerein in the colon to reduce these adverse side effects. An ideal control of diacerein release is when the drug release rate and the absorption rate are close to identical so that the adverse side effects caused by the contact of diacerein and the colon mucosa can be minimized. Technologies for controlling the release of diacerein include, but are not ϋmited to, membrane-controlled technology, matrix-controlled technology and osmotic pump technology.
The diacerein, or other active ingredient that is utilized in the present invention, may be prepared either through micronization alone or with a milling aid.
The diacerein utilized in the formulations of the present invention may be crystalline or in the amorphous state.
The sustained-release formulation may include common additives in addition to the active ingredient and a polymer. For example, the sustained-release core may include a diluent such as a microcrystalline cellulose, dextrose, starch, sucrose, lactose, sorbitol, mannito! or caicium phosphate; a disintegrating agent such as talc, sodium carboxymethylceliuiose, L-hydroxypropySceliulose, cropovidone, or corn starch; a binder such as polyvinylpyrrolidone, starch, gelatin, tragacanth, methyicellulose, or hydroxypropylcelluiose; and a solvent such as water or a lower alcohol such as ethanoi or isopropanol; and a lubricant such as light anhydrous silicic acid, talc, stearic acid and its zinc, magnesium, or calcium salt or polyethyieneglycoi. In addition, the sustained-release formulation may also include a disintegrating agent such as sodium starch glycoSate, starch, alginic acid or its sodium salt.
A pharmaceutical composition of the present invention can be formulated as various types of oral formulations having the above-described composition. Preferably, the pharmaceutical composition of the present invention can be formulated as tablets or beads. Membrane-controlled Technoiogy
In one embodiment, the formulation of the invention may be surrounded by a controlied-release film that can isolate the drug core from the G! environment to minimize direct contact of diacerein with the colon mucosa.
The controiled-reiease film may contain a water-insoluble polymer which forms a membrane to avoid direct contact of diacerein and the colon mucosa. The water-insoiubie polymer may include celiulose acetate, cellulose triacetate, agar acetate, amyiose triacetate, beta giucan acetate, acetaldehyde dimethyl acetate, cellulose acetate methyl carbamate, cellulose acetate phthafate, ceiluiose acetate succinate, cellulose acetate dimethylamino acetate, cellulose acetate ethyl carbonate, cellulose acetate chloroacetate, celiuiose acetate ethyl oxalate, cellulose acetate propionate, poly(vinyimethylether) copolymers, cellulose acetate butyl sulfonate, cellulose acetate octate, cellulose acetate iaurate, cellulose acetate p-toluene sulfonate, triacetate of locust gum bean, hydroxyiated ethylene-vinyl acetate, celiulose acetate butyrate, ethyl cellulose and the like.
The controiled-reiease film can further contain a piasticizer or a pore-forming agent to obtain suitable film properties. Examples of suitable plasticizers are dibutyl sebacate, triethyl citrate and polyethylene glycol (PEG). Examples of suitable pore-forming agents are hydroxymethylpropylceliuiose (HPMC), polyvinylpyrrolidone (PVP) and hydroxypropyiceilulose (HPC).
The drug release rate of diacerein can be controlled by adjusting the weight gain of the controlied-release film. Suitable weight gain couid be 3-50% of the core tablet or bead. In one embodiment of the invention, the controiled-release formulation comprises an active layer, a sustained-release film layer and a deiayed-release film layer,
In one embodiment of the invention, the active layer comprises between about 40.0% and about 50.0% by weight of microcrystaliine cellulose, between about 20.0% and about 30.0% by weight of dtacerein, between about 2.0% and about 5.0% by weight of povidone and between about 20.0% and about 30.0% by weight of mannitoi.
in another embodiment of the invention, the active layer comprises about 50.0% by weight of microcrystaliine cellulose, about 25.0% by weight of diacerein, about 2.0% by weight of povidone and about 23.0% by weight of mannitoi.
The sustained-release film layer may comprise, but is not limited to, ethyl cellulose polymers, povidone, tπethyl citrate and talc.
The delayed-reiease film layer may comprise, but is not limited to, Eudragit® polymers, triethyl citrate and talc.
Matrix Technology
In another embodiment, the formulation of the invention may contain a controiied-release material, such as a hydrophiiic polymer, a hydrophobic polymer or wax to form a controlled-reiease matrix. Diacerein is trapped in the matrix to avoid contact of the diacerein and the colon mucosa.
Examples of controlled release materials include hydroxypropyimethyi cellulose with a molecular weight of between 1 ,000 and 4,000,000, hydroxypropyl cellulose with a molecular weight of from 2,000 to 2,000,000, sodium alginate, carbomer (Carbopo!®), sodium carboxymethyl cellulose, xanthan gum, guar gum, locust bean gum, poly vinyl acetate, polyvinyl alcohol carboxyvinyl polymers, polyvinyl alcohois, giucans, scleroglucans, mannans, xanthans, aiginic acid and its derivatives, poiyanhydrides, poiyaminoacids, carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, polyvinyl pyrrolidone, cross-iinked polyvinyl pyrrolidone, carboxymethyiamide, potassium methacrySate/divinylbenzene copolymer, starches and their derivatives, β-cyclodextrin, dextrin derivatives with linear or branched chains, ethyl cellulose, methyl cellulose and cellulose derivatives.
In one embodiment of the invention, the controlled-reiease formulation comprises about 20.0% by weight of diacerein, between about 20.0% and 40.0% by weight of hydroxymethylpropylcellulose, between about 37.0% and about 57.0% by weight of mannitol, about 2.0% by weight of povidone and about 1.0% by weight of magnesium stearate.
In a preferred embodiment of the invention, the controlled-reiease formulation comprises about 20.0% by weight of diacerein, about 20.0% by weight of hydroxymethylpropyicellulose, about 57.0% by weight of mannitol, about 2.0% by weight of povidone and about 1.0% by weight of magnesium stearate.
In another preferred embodiment of the invention, the controϋed-release formulation comprises about 20.0% by weight of diacerein, about 40.0% by weight of hydroxymethyipropyicelluiose, about 37.0% by weight of mannitoi, about 2.0% by weight of povidone and about 1.0% by weight of magnesium stearate.
In another preferred embodiment of the invention, the controlled-reiease formulation comprises about 20.0% by weight of diacerein, about 33.0% by weight of hydroxymethylpropylcellulose, about 46.0% by weight of mannitol and about 1.0% by weight of magnesium stearate.
Osmotic pump system
In another embodiment, the release rate of diacerein can be controlled by an osmotic pump system. A drug-containing core is covered by a semipermeable membrane, allowing only water to permeate. When externa! aqueous fluids are imbibed through the semipermeable membrane into the core by an osmotic pressure gradient, the drug is released from a passageway in the membrane. Said passageway may be a hole, aperture, orifice, bore, weakened area or an erodible element that erodes to form an passageway for the release of diacerein.
The materials used for the semipermeable membrane in the invention are well-known in the pharmaceutical industry. For example, commercially available non-plasticized cellulose acetate, piasticised cellulose triacetate, agar acetate, pentacglucose acetate, dextran acetate, cellulose acetate methylurethane, cellulose acetate phthalate, cellulose acetate ethylurethane, cellulose acetate succinate, cellulose acetate dimethylglycine, cellulose acetate ethanecarbonate, cellulose acetate methanesulfonate, cellulose acetate butanesulfonate, cellulose acetate propionate, vinyl methyl ether polymer, cellulose acetate coctanoate, cellulose acetate laurate, cellulose acetate p-toluenesulfonate, ethyl cellulose, locust bean gum triacetate, cellulose acetate with acetyl hydroxyethytcellulose, hydroxation ethylene vinyl acetate, membrane material made with expoxy polymer, alkylidene oxide-alkyl glycidyl ether, pofyurethane, polyglycolic acid, and the well-known polyoxygen-poiyanionic membrane may be used in the present invention. In one embodiment, a controlied-release formulation of diacerein which is controlied by osmotic pump technology may utilize a formulation comprising a drug layer and a push iayer. A push layer of an osmotic delivery dosage comprises an osmopolymer. The osmopolymer swells when aqueous liquids are absorbed. Examples of osmopoiymers include poiy(hydroxyalkylmethacrylate with a molecular weight of 30,000-5,000,000, polyvinylpyrrolidone) with a molecular weight of 10,000-36,000, anion and cation hydrogels, polyelectrolyte complexes, poly(vinyi alcohol), polyethylene oxide, N-vinyi lactams, Carbopol® acidic carboxy polymers with a molecular weight of 4, 000~4, 500,000, Cyanamer® polyacryiamides, cross-linked water swellable indene-maleic anhydride polymers, aminopectin copolymer, Aqua-Keeps® acrylate polymer and polysaccharides.
Methods for improving bioavailability
In another embodiment, the controlled-release formulation of the invention could further provide increased bioavailability of diacerein when compared to commercial immediate release formulations (ex. Arthrodar ®, TRB Pharma s.a.). It is believed that the increase in bioavailability could be heipful to decrease the adverse side effects. Methods for increasing the bioavailability include, but are not limited to, (a) adding surfactants; (b) forming a solid dispersion; (c) utilizing micronized or nanonized diacerein, (d) adding acidifying or buffering agents and (e) complexation with cyclodextrins.
The addition of suitable surfactants into pharmaceutical compositions of diacerein can enhance the in vitro dissolution rate and in vivo bioavailability. Suitable surfactants include, but are not limited to, sodium iauryl sulfate, polyethylene-polypropylene glycol, glycerol-poiyethylene glycol oxystearate, PEG-40 hydrogenated castor oil and stearoyi macrogolglycerides (polyoxylgiycerides).
Solid dispersions have been traditionally employed to enhance the dissolution rate of drugs, with a view to improve bioavailability. The drug may be entrapped in a carrier in an amorphous form without undergoing recrystallization. The process to prepare a solid dispersion is well known by a skilled artisan.
Controlling the particle size of diacerein is also considered to be helpful to improve its bioavailability. The preferred particle size of diacerein is D50 less than 20 μm and, more preferably, D50 less than 5 μm. In addition, the combination of co-micronized diacerein with hydrophiiic milling aids can facilitate drug dissolution and bioavailability. Suitable hydrophiiic milling aids include, but are not limited to, HPMC, sucrose, iactose, surfactants and superdisintegrants. The process may be practiced by utilizing a mill or a micronizer, such as an Aljet mill. The co-micronized diacerein can then be mixed or granulated with other excipients.
The tables below indicate the solubility and stability of diacerein in buffer solutions with different pH values. At a pH below 4.17, diacerein is stable and its solubility is relatively low. The degradation products including rhein increase at a pH above 5. The poor stability of diacerein in the intestinal environment may result in incomplete absorption and cause poor and variable bioavailability. Moreover, one of the increased degradants in the intestinal environment, rhein, has been suspected to be a major factor in stimulating colon mucosa and results in diarrhea. Accordingly, methods to stabilize diacerein during gastro-intestinal absorption might improve its bioavailability as well as the side effect of diarrhea. The stabilization methods for use with diacerein may include the addition of acidifying or buffering agents or complexation with cyclodextrins.
Table 1
Solubility and stability pH profile of diacerein at ambient temperature for 48 hours
Figure imgf000012_0001
Table 2
Soiubiiity and stability of diacerein at ambient temperature for one hour
Figure imgf000012_0002
Use of the Formulations of the Invention
The pharmaceutical compositions of diacerein of the present invention can be used for treating inflammatory or autoimmune diseases, such as rheumatoid arthritis, osteoarthritis, osteoporosis, inflammatory bowel disease, inciuding ulcerative colitis and Crohn's disease, ulcerative colitis, multiple sclerosis, periodontitis, gingivitis, graft versus host reactions, psoriasis, scleroderma, atopic dermatitis, asthma, systemic lupus erythematosus (SLE), nephropathy and chronic obstructive pulmonary disease (COPD). Dermal conditions that may be treated include those given above, and also psoriatic arthritis, epidermolysis bullosa, atopic dermatitis and vasculitis. Anti-angiogenic activity may allow the treatment of conditions such as age-related macular degeneration and cancer. Preferably, the pharmaceutical compositions of the invention are used for treating osteoarthritis, type I/I! diabetes or diabetic nephropathy, with fewer adverse side effects.
Suitable doses of diacerein for treating the above diseases are in the range of 5-200 mg/per day, preferably, 20-150 mg/per day.
When administered to a patient who has reached the steady state of plasma concentration, a 50 mg commercial IR diacerein formulation administered twice daily only maintains the plasma concentration of rhein above 2 mg/ml for about 12 hours. However, in a preferred embodiment of the invention:
a 50 mg diacerein formulation of the present invention maintains the plasma concentration of rhein above the concentration of 1 mg/ml for more than 12 hours in humans when orally administered to a human patient who has reached the steady state condition;
a 100 mg diacerein formulation of the present invention maintains the plasma concentration of rhein above the concentration of 2 mg/ml for more than 12 hours in humans when orally administered to a human patient who has reached the steady state condition;
a 150 mg diacerein formulation of the present invention maintains the plasma concentration of rhein above the concentration of 3 mg/ml for more than 12 hours in humans when orally administered to a human patient who has reached the steady state condition;
and a 200 mg diacerein formulation of the present invention maintains the plasma concentration of rhein above the concentration of 4 mg/ml for more than 12 hours in humans when oraily administered to a human patient who has reached the steady state condition.
Com bo tou lations
The controlied-reiease formulation of the invention can further comprise another active ingredient such as Angiotensin I! receptor blockers (ARBs), angiotensin converting enzyme inhibitors (ACEIs), antϊhyperglycemics or NSAIDs. More specifically, the formulations of diacerein according to the present invention can further contain an angiotensin converting enzyme inhibitor or a angiotensin Il receptor blocker for treating diabetic nephropathy, a antihypergiycemic drug for treating type i/il diabetes, or a non-steroidal anti-inflammatory drug (NSAID) for treating osteoarthritis.
Examples of ACEIs include captopril, benazepril, enalapril, lisinopril, fosinopril, ramipπi, perindopril, quinapril, moexipril and trandoiapril. Examples of ARBs include candesartan, eprosartan, irbesartan, telmisartan, valsartan and losartan. Examples of antihypergiycemics include sulfonylureas, such as glyburide, glipizide, and glimeptride; megiitinides such as repaglinide and nateglinide; biguanides such as metformin; thiazolidinediones such as piogiitazone and rosigiitazone; alpha glucosidase inhibitor such as acarbose. Examples of NSAIDs include salicylates such as aspirin; aryialkanoic acids, such as acetaminophen; 2-Arylpropionic acids such as Ibuprofen, Ketorolac and Naproxen; n-aryianthranilic acids such as mefenamic acid, meclofenamic acid; Oxicams such as piroxicam, meloxicam; and COX-2 inhibitors such as Celecoxib.
The second active ingredient may be in a controiled-release dosage form or in an immediate release dosage form.
It should be noted that the present embodiments are to be considered as illustrative and the invention is not to be limited to the details given herein.
EXAMPLES
Example 1 Preparation of soiid dispersion
Acceptable ranges for the components of representative soiid dispersions are shown in Table 3.
Table 3
Figure imgf000015_0001
Figure imgf000016_0001
Process:
Diacerein may be dissolved with suitable organic solvents to form a drug solution. Carriers, such as hydrophilic polymers, hydrophobic polymers, surfactants, water-soiuble excipients, or wax, or a combination of the above carriers are then dissolved or dispersed in the drug solution, Spray drying of the above solution may be used to obtain a solid dispersion, or the solution may be coated onto suitable excipients {water-soiuble materials that function as a second carrier) using a fiuidized bed.
Example 2
Complexation with cvciodextrins
Acceptable ranges for the components of representative complexes with cyclodextrins are shown in Table 4.
Table 4
Figure imgf000017_0001
Process:
Water solutions of cyciodextrins may be prepared with various percentages. Diacerein is added to the above solutions to yield saturated solutions. The solutions are stirred for at least 72 hours and then allowed to stand until ali undissolved material has precipitated. The supernatant solution is filtered and dried by oven, spray drying or freeze drying or coated onto suitable excipients (which function as diluents) using a fluidized bed.
Example 3
Matrix system (tablet) Acceptable ranges for the components of representative tablet matrix systems are shown in Table 5.
Table 5
Figure imgf000017_0002
Process: The API part is prepared as described in the above examples. The diacerein API part is physically mixed or granulated with controlled release materials and then the mixture is compressed to obtain matrix tablets. Optionally, an acidifying agent or buffering agent may be included in the tablet formulation.
Example 4
Matrix system (tablet)
Two representative matrix tablet formulations are shown in Table 6.
Table 6
Formula A Formula B ingredients mg % mg %
Granuϊe I Diacerein 100 20 0 100 20 0
HPC 100 20 0 - --
HPMC - - 179 35 8
Mannitol 204 40 8 -- --
SLS 10 2 0 - --
Cremophor - -- 10 2 0
Granule El HPMC 80 16 0 -- -
Mannitol - - 180 36 0
PVP 3 0 6 3 0.6
Tartaric acid 25 5.0
Lubricant Mg stearate 3 0 6 - -
S)O2 - - 3 0 6
Total 500 100 0 500 100 0
Process: A solid dispersion of granule I was prepared as described in Example 1.
Granule I! was prepared by wet granulation. Granules I and Il were mixed with lubricants and then compressed to obtain matrix tablets. Example 5
Matrix system (tablet)
A further representative matrix tabiet formuiation is shown in Table 7.
Table 7
Formula C
Ingredients mg %
Granule Diacerein 100 20.0
HPMC 175 35.0
Mannitof 147 29,4
Cremophor 50 10 0
Tartaric acid 25 5.0
Lubricant Mg. stearate 3 0.6
Total 500 100.0 Process:
Diacerein, HPMC, mannitol, cremophor and tartaric acid were granulated by wet granulation. The granules were mixed with lubricants and then compressed.
Example 6
Matrix system (beads)
Acceptable ranges for the components of representative bead matrix systems are shown in Table 8.
Table 8
Figure imgf000019_0001
Figure imgf000020_0001
Process:
Diacerein is dissolved with suitable organic solvents to form a drug solution. Carriers such as hydrophiiic polymers, hydrophobic polymers, surfactants, water-soluble excipients, wax or the combination of above carriers are then dissolved or dispersed in the drug solution. The sofution is sprayed onto seeds by fiuidized bed to obtain matrix beads. The beads are then encapsulated in a capsule with suitable size.
Example 7
Matrix system (beads)
A representative bead matrix formulation is shown in Table 9. Table 9
Formula D
Ingredients mg %
Core Bead API 100 20 0
HPC 100 20 0
EC 50 10 0
MCC sphere 240 48 0
Cremophor 10 2 0
Total 500 0 100 0
The formula D was prepared by the process described in Example 6
Example 8
Membrane-controiied system (tablet)
Acceptable ranges for the components of representative membrane controlled tablet formulations are shown in Table 10.
Table 10
Figure imgf000021_0001
The API part is prepared as described in the above examples. The Diacerein API part is physically mixed or granulated with suitable diluents and lubricants then compressed to obtain core tablets. Optionally, the acidifying agent or buffering agent may be included in the core tablet formuiation. The controlled release materials are dissolved along with pore forming agents and plasticizer in organic solvents to obtain the coating solution for above core tablet. Then, the tablets are coated in a tablet coater.
Example 9
Membrane-controlled system (tablet)
Three representative membrane controlled tablet formulations are shown in Table 11 ,
Table 11
Formula E FormuSa F Formula G
Ingredients mg % mg % mg %
Core Tablet Diacerein 100 22 7 100 23 0 100 23 0
Manmtol 304 69 1 274 5 63 0 289 5 66 5
SLS 20 4 5 .. 30 6 9
Cremophor - - 20 4 6 -- -
PVP 14 3 2 14 3 2 14 3 2
Tartaric acid - - 25 5 7 -- -
Mg stearate 2 0 5 2 0 5 2 0 5
Subtotal 440 100 435 5 100 435 5 100
Seal Coat Core tablet 440 97 3 435 5 97 3 435 5 97 3
HPMC 8 1 8 8 1 8 8 1 8
Taic 4 0 9 4 0 9 4 0 9
Subtotal 452 0 100 0 447 5 100 0 447 5 100 0
SR Coat Seal-coated tablet 452 0 90 4 447 5 89 5 447 5 89.5
EC 30 6 0 25 5 0 25 5 0
PVP 15 3 0 25 5 0 25 5 0 TEC 3 0.6 2 5 0 5 2 5 0 5 Total 500 0 100 0 500 0 100 0 500.0 100.0
Process:
The core tablet was manufactured by a soiid dispersion method as described in the above examples or by a wet granulation method. The core tablet was then coated with a seal coat and a sustained-reiease coat.
Example 10
Membrane-controJled system (beads)
Acceptable ranges for the components of representative bead membrane-controlled systems are shown in Tabfe 12.
Table 12
of
Figure imgf000023_0001
Figure imgf000024_0001
Process
Diacerein is dissolved with suitable organic solvents to form a drug solution. Carriers such as hydrophiiic polymers, hydrophobic polymers, surfactants, water-soluble excipients, wax or the combination of above carriers are then dissolved or dispersed in the drug solution. The solution is sprayed onto seeds by a fluidized bed to obtain core beads. The controlled release materials are dissolved along with pore forming agents and ptasticizer in organic solvents to obtain the coating solution for the core beads. Then, the beads are coated with a controiled-release membrane. The extended-release beads are then encapsulated in a capsule with suitable size.
Example 11
Membrane-controlled system (beads)
Representative bead membrane-controlled system formulations are shown in Table 13.
Table 13
Formula H
Ingredients mg %
Core Bead API 100 22 8 HPC 100 22 8 MCC sphere 228 5 52 1 SLS 10 2 3 Subtotal 438 5 100
Sea! Coat Core bead 438 5 98 0
HPMC 6 1 3
Talc 3 0 7
Subtotal 447 5 100 0
CR Coat Seal-coated bead 447 5 89 5
EC 25 5 0
PVP 25 5 0
TEC 2 5 0 5
Total 500 0 100 0
The formula H was prepared by the process described in Example 10.
Example 12
Osmotic pump (Push puil) system
Acceptable ranges for the components of representative osmotic pump (push pull) formulations are shown in Table 14.
Table 14
Figure imgf000025_0001
Figure imgf000026_0001
The API part as described in the above examples is prepared by physically mixing or granulating the diacerein API part with PEO, an osmotic agent, a binder, and an antioxidant and then blending with a lubricant to obtain the drug layer. Optionally, the acidifying agent or buffering agent may be included in the drug layer formulation. The push layer is also prepared by physically mixing or granulating. The semipermeable membrane is introduced by dissolving cellulose acetate along with a pore forming agent and piasttcizer in organic solvents and then performing the coating process in a tablet coater A passageway is formed by laser or mechanical drilling on the surface of the CA film next to the drug layer
Example 13
Osmotic pump (Push puil) system
A representative push pull osmotic pump formulation is shown tn Table 15.
Table 15
Formula I
Ingredients mg %
Drug Layer Diacerein 100 00 20 00 PEO (MW 200,000} 282 25 56 45 NaCI 100 00 20 00
HPMC E5 15 00 3 00
BHT {Butylated hydroxytotuene} 0 25 0 05
Glyceryl monostearate 2 50 0 50 subtotal 500 00 100 00
Push Layer PEO (MW 7,000,000) 194 00 77 48
NaCI 50 00 19 97
HPMC E5 5 00 2 00
BHT 0 125 0 05
Glyceryl monostearate 1 25 0 50 subtotal 250 38 100
Semi- Bi-layer tablet 750 38 83 34 permeable Cellulose acetate (CA-398) 112 5 12 49
Membrane PEG 4000 7 5 0 83
HPC (Klυceϊ EF) 30 3 33
Acetone / water* qs qs
Totai 900 38 100 00
* Which are evaporated dunng pi oceswng
The formula i was prepared by the process described in Example 12.
Example 14
Osmotic pump system (in-situ hole)
Acceptable ranges for the components of representative osmotic pump(ιn-situ hole) formulations are shown in Table 16.
Table 16
Figure imgf000027_0001
Figure imgf000028_0001
Process
The API part is prepared as described in the above examples. The diacerein AP! part is physically mixed or granulated with PEO, a binder, an osmotic agent and an antioxidant. The mixture is blended with lubricants and then compressed to obtain the core tablet Optionally, the acidifying agent or buffering agent may be inciuded in the core tablet formulation. A seal coating solution is prepared by dissolving or dispersing a hydrophilic polymer, an osmotic agent and iubricants in water, then spraying the coating solution onto the core tablets in a coater. A semipermeable coating is prepared by dissolving cellulose acetate along with a pore forming agent and plasticizer in an organic solvent and then spraying the coating solution onto the seal-coated tablet in a coater. At least one passageway is formed during the dissolution of the dosage form Example 15
Osmotic pump system {in-situ hole)
A representative osmotic pump {in-situ ho!e) formulation is shown in Table 17.
Table 17
Formula J ingredients mg %
Drug Layer Diaceresπ 100 00 19 93
PEO (MW 5,000,000) 48 00 9 57
PEO (MW 200,000) 192 00 38 27
NaCI 139 00 27 70
Sodium lauryl sulfate 15 00 2 99
8HT (Butylated hydroxytoluene) 0.25 0.05
SfO2 2 50 0 50
Glyceryl monostearate 5 00 1.00 subtotal 501 75 100 00
Seal Coat Core tablet 501.75 97.29
Opadry 10.50 2 04
NaCI 3 50 0 67
Water* qs qs subtotal 515 75 100 00
Semi- Seal-coated tablet 515 75 97 06 permeable Cellulose acetate (CA-398) 9 30 1 75
Membrane PEG 400 0 80 0 15
Tπacetin 0 80 0 15
Manπitol 4 70 0 88
Acetone / water* qs qs
Total 531 35 100 00
* Evaporated during piocessing.
The formula J was prepared by the process described in Example 14. Example 16
Sustained-release formulation (Matrix System)
Acceptable ranges for the components of representative matrix sustained release formulations are shown in Table 18.
Table 18
Figure imgf000030_0001
Process:
The sustained-release formulation of the present invention can be prepared by- direct compression, compaction-granulation, wet granulation or extrusion and spheronization. In the case of using direct compression or compaction-granulation, the sustained-release formulation can be prepared in such a manner that the diacerein, a swellable polymer, a diluent, a disintegrating agent, a binder, and a lubricant are mixed, followed by granulation with a compaction granulator (e.g. roller compacter), screening through an about 20-mesh screen, and tabletting.
in the case of wet granulation, the sustained-release formulation can be prepared in such a manner that the diacerein, a swellable polymer, a diluent, a disintegrating agent, and a binder are mixed in a high shear granuiator with the addition of water or solvent (e.g. ethanol or isopropyl alcohol). The granules are further dried, milled and mixed with iubricant and tabletting.
In the case of using extrusion and sphernoization, the sustained-release formulation can be prepared in such a manner that the diacerein, a swellabie polymer, a diluent, a disintegrating agent, a binder, and a lubricant are mixed in a low shear granulator or mixer with the addition of water or solvent (e.g. ethanol or isopropyl alcohol). The wet mass is added to a single screw or twin screw extruder, the extrudate is spheronized in a marumerizer to obtain sustained release beads.
Example 17
A representative matrix sustained release tablet formulation is shown in Table 17.
Table 19
Formula K
Ingredients mg %
Granule Diaceresn 100 20.0 HPMC 175 35.0 MCC 147 29 4
SLS 50 10.0
L-HPC 25 5 0
Lubricant Mg stearate 3 0.6
Total 500 100.0
Formula K was prepared by the process described in Example 16.
Example 18
Membrane Controiled System
Acceptable ranges for the components of representative sustained release membrane-controlied system formulations are shown in Table 20.
Table 20
Figure imgf000032_0001
Process:
The core tablet is prepared by direct compression, compaction-granulation is used, or wet granulation. The core bead is prepared by fluid bed granulation.
When direct compression or compaction-granulation is used, the tablet core can be prepared in such a manner that the diacerein, a diluent, a binder, and a lubricant are mixed, followed by granulation with a compaction granuiator (e.g. roller compacter), screening through an about 20-mesh screen, and tabletting.
When wet granulation is used, the core tablet can be prepared in such a manner that the diacerein, a diluent, and a binder are mixed in a high shear granuiator with the addition of water or solvent (e.g. ethanol or isopropyl alcohol). The granules are further dried, milled and blended with iubricant and tabietted.
For bead core preparation, the beads can be prepared in such a manner that the diacerein, a diluent, and a binder are granulated in a fluid bed granuiator with the addition of water or solvent (e.g. ethanol or isopropyl alcohol). The bead granules are further dried and sieved through an appropriate mesh.
The controlled release materials are dissolved along with pore forming agents and plasticizer in organic solvents to obtain the coating solution for the above core tablets or beads. Then, the tablets or beads are coated either in a tablet coater or a fluid bed coater.
Example 19
Bead formulation for a membrane-controiled system
A representative bead formulation for a membrane-controlled system is shown in Table 21. Table 21
Formula L ingredients mg %
Core bead Diacerein 100 22 7
Lactose 302.6 68.8
SLS 13 2 3
PVP 22 5 0
Mg stearate 2.2 0.5
Subtotal 440 100
Sea! Coat Core beads 440 97.3
HPMC 8 1 8
Talc 4 0 9
Subtotal 452 0 100 0
SR Coat Seal-coated
452 0 90 4 beads
EC 30 6 0
PVP 15 3 0
TEC 3 0 6
Total 500 0 100.0
Example 20
Hydroqel Matrix Formulations
Representative hydroge! matrix formulations are shown in Table 22.
Table 22
Figure imgf000034_0001
Figure imgf000035_0001
Diacerein (Highsun) refers to diacerein produced by Taizhou Highsun Pharmaceutical
Co., Ltd.
Diacerein (TRB) refers to diacerein produced by TRB Chemedica. "HPMC K4MCR," "HPMC K100LVCR," and "HPMC E5LVCR" are various METHOCEL™ hypromeliose products produced by the Dow Chemical Company.
Example 21
Dissolution Data for Hydrogel Matrix Formulations
Dissolution tests were performed on diacerein hydrogei matrix formuiations of
Example 20. The dissolution tests were performed according to the so-caifed "basket" method and/or the "paddle and sinker" method.
"Basket" Method
The "basket method" uses USP apparatus 1. It is usually operated at 100 rpm (revolutions per minute) and is usually used for beads formulation. The FDA guidances contain descriptions of the "basket" method.
"Paddle and Sinker Method"
The "paddle and sinker" method uses USP apparatus 2. It is usually operated at 50 rpm. A "sinker" can be some wires wrapped around the capsules before the capsules are put into dissolution vessels. The FDA guidances contain descriptions of the "paddle and sinker" method.
Both methods are usually used at 37° C + 0.5° C. The samples are usually dissolved in 900 ml of aqueous media.
Table 23 contains the results of the dissolution tests performed on formulations DIAC-2002, DIAC-2005, DfAC-2017 and DIAC-2018. Ail tests were performed utilizing pH 6.0 PBS buffer. The tests on DIAC-2002 and DIAC-2005 formulations were performed utilizing the "basket" method at 100 rpm, and the tests on DIAC-2017 and DIAC-2018 formulations were performed utilizing the "paddle and sinker" method at 100 rpm.
Table 23
Figure imgf000037_0001
"St. dev." stands for "standard deviation."
Table 24 contains the results of the dissolution tests performed on formulations DIAC-2001 , DIAC-2002, DIAC-2005 and DIAC-2006. Ail tests were performed using pH 6.8 PBS buffer and the "basket" method at 100 rpm The tests were performed in triplicates, and the table shows the data for the mean of these triplicates
Table 24
Figure imgf000037_0002
Figure imgf000038_0001
Example 22 Sustained-Release Formulations
Representative sustained release formulations are shown in Tables 25-29 as follows. Tables 25 and 26 show compositions of active layers of formulations DIAC-3002, DIAC-3004, DIAC-3006, DlAC-3007, DIAC-3008, DIAC-3010, D1AC-3Q11 and DIAC-3012; Tables 27 and 28 show compositions of Sustained-Release (SR) film layers of these formulations; and Table 29 shows compositions of Delayed-Release (DR) film layers of formulations DIAC-3007, DIAC-3008, DlAC-3011 and DIAC-3012 (the other formulations do not contain DR film layer).
Tab!e 25
Figure imgf000038_0002
Figure imgf000039_0001
Cellets® 350 and Celiets® 750 are neutral starter cores for controlled release formulation produced by the Glatt Group
Table 26
ACTIVE LAYER
Figure imgf000039_0002
Table 27
Figure imgf000040_0001
Table 28
Figure imgf000040_0002
Table 29
Figure imgf000041_0001
Example 23
Dissolution Data for Sustained-Release FormuJations
Dissolution tests were performed on diacerein sustained-release formulations of
Example 22. The dissolution tests were performed according to the "basket" method and/or the "paddle and sinker" method as described in Example 21.
Table 30 contains the results of the dissolution tests performed on formulations DIAC-3002, DiAC-3004, DlAC-3006 and DIAC-3007. All tests were performed utilizing pH 6.0 PBS buffer and utilizing the "basket" method at 100 rpm. Table 30
Figure imgf000042_0001
*The % refers to the Sustained-Release (SR) or the Deiayed-Release (DR) poiymer percentage in each tested formuiation.
Table 31 contains the results of the dissolution tests performed on formulations
DIAC-3010 and D1AC-3011. Ail tests were performed utilizing pH 6.0 PBS buffer and utilizing the "basket" method at 100 rpm.
Table 31
Figure imgf000042_0002
Figure imgf000043_0001
Table 32 contains the results of the dissolution tests performed on formulations DIAC-3004, DIAC-3006 and DIAC-3007. All tests were performed utilizing pH 6.8 PBS buffer and utilizing the "basket" method at 100 rpm.
Tabie 32
Figure imgf000043_0002
Table 33 contains the results of the dissolution tests performed on formulations DIAC-3008, DIAC-3010, DlAC-3011 and DIAC-3012. AIi tests were performed utiiizing pH 6.8 PBS buffer and utiiizing the "basket" method at 100 rpm.
Table 33
Figure imgf000044_0001

Claims

WHAT IS CLAIMED IS:
1 , A once-daily controtled-reiease formulation of diacerein for treating inflammatory diseases, autoimmune diseases or their complications with reduced adverse side effects.
2. The controlled-release formulation according to claim 1 , wherein the formulation is a membrane-controlled formulation, matrix formulation or osmotic pump formulation.
3. The controiied-release formulation according to claim 2, wherein the formulation provides increased bioavailability when compared to an immediate release formulation.
4. The controiied-release formulation according to claim 3, wherein the formulation comprises a surfactant, acidifying agent or a buffering agent.
5. The controiled-reiease formulation according to claim 3, wherein the particle size of diacerein is less than 2000 μm.
6. The controlled-release formulation according to claim 3, wherein the diacerein is presented as an amorphous state in a solid carrier.
7, The controiied-release formulation according to claim 3, wherein the diacerein is formed as a complex with cyclodextrins.
8. The controlled release formulation according to claim 3, wherein the diacerein is crystalline.
9. The confrolSed release formulation according to claim 1 wherein a formulation containing 50 mg diacerein maintains the plasma concentration of rhein above the concentration of 1 mg/ ml for more than 12 hours in humans, when orally administered to a human patient who has reached the steady state condition
10. The controlled release formulation according to claim 1 wherein a formulation containing 100 mg diacerein maintains the plasma concentration of rhein above the concentration of 2 mg/ ml for more than 12 hours in humans, when orally administered to a human patient who has reached the steady state condition.
11. The controlled release formulation according to claim 1 wherein a formulation containing 150 mg diacerein maintains the plasma concentration of rhein above the concentration of 3 mg/ ml for more than 12 hours in humans, when orally administered to a human patient who has reached the steady state condition,.
12. The controlled release formulation according to claim 1 wherein a formulation containing 200 mg diacerein maintains the plasma concentration of rhein above the concentration of 4 mg/ ml for more than 12 hours in humans, when oraliy administered to a human patient who has reached the steady state condition.
13. A method of treating inflammatory diseases, autoimmune diseases or their complications comprising administering to a subject in need thereof a once-daiiy controlied-reiease formulation of diacerein according to claim 1 , wherein said method results in fewer adverse side effects as compared to administering immediate release formulations of diacerein.
14. The method according to claim 13, wherein said adverse side effect is diarrhea.
15. The method of claim 13, wherein the controlied-reiease formulation is administered to treat type [/type El diabetes or osteoarthritis.
16. The method of claim 13, wherein the controlied-reiease formulation is administered to treat complications from type I/type El diabetes.
17. The method of claim 16 wherein the complications from type I/type Ii diabetes are nephropathy, retinopathy, neuropathy or foot ulcers.
18. A once-daiiy controlied-reiease formulation according to claim 1 comprising a first active of diacerein and a second active ingredient for treating inflammatory diseases, autoimmune diseases or their complications.
19. The controlied-reiease formulation according to claim 18, wherein said second active ingredient is an angiotensin converting enzyme inhibitor, a angiotensin Il receptor blockers, a antihypergiycemic drug, or a Non-steroidal anti-inflammatory drug.
20. The controlied-reiease formulation according to claim 1 comprising about 20.0% by weight of diacerein, about 20.0% by weight of hydroxymethylpropyicelluiose, about 57.0% by weight of mannitol, about 2.0% by weight of povidone and about 1.0% by weight of magnesium stearate.
21. The controlied-reiease formulation according to claim 1 comprising about 20.0% by weight of diacerein, about 40.0% by weight of hydroxymethylpropylceiiulose, about 37.0% by weight of mannitol, about 2.0% by weight of povidone and about 1.0% by weight of magnesium stearate.
22. The controlied-release formulation according to claim 1 comprising about 20.0% by weight of diacerein, about 33.0% by weight of hydroxymethylpropylceiluiose, about 46.0% by weight of mannitol and about 1.0% by weight of magnesium stearate.
23. The controlied-release formulation according to claim 1 , comprising an active layer, a sustained-release film layer, and a delayed-reiease fiim layer.
24. The controlied-release formulation according to claim 23, wherein said active layer comprises between about 40.0% and about 50.0% by weight of microcrystalline ceϋuiose, between about 20.0% and about 30.0% by weight of diacerein, between about 2.0% and about 5.0% by weight of povidone and between about 20.0% and about 30.0% by weight of mannitoi.
25. The controlied-release formulation according to claim 22, wherein said active layer comprises about 50.0% by weight of microcrystalline cellulose, about 25.0% by weight of diacerein, about 2.0% by weight of povidone and about 23.0% by weight of mannitol.
PCT/US2009/062302 2008-10-28 2009-10-28 Pharmaceutical compositions containing diacerein WO2010051296A1 (en)

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BRPI0920255A BRPI0920255A2 (en) 2008-10-28 2009-10-28 controlled release formulation, and method for treating inflammatory diseases, autoimmune diseases or their complications
EP09824084.9A EP2349289B1 (en) 2008-10-28 2009-10-28 Pharmaceutical compositions containing diacerein
CN2009801431098A CN102202673B (en) 2008-10-28 2009-10-28 Pharmaceutical compositions containing diacerein
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