WO2009034409A2 - Compositions pharmaceutiques de rheine ou de diacereine - Google Patents

Compositions pharmaceutiques de rheine ou de diacereine Download PDF

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Publication number
WO2009034409A2
WO2009034409A2 PCT/IB2007/003224 IB2007003224W WO2009034409A2 WO 2009034409 A2 WO2009034409 A2 WO 2009034409A2 IB 2007003224 W IB2007003224 W IB 2007003224W WO 2009034409 A2 WO2009034409 A2 WO 2009034409A2
Authority
WO
WIPO (PCT)
Prior art keywords
diacerein
pharmaceutical composition
rhein
salts
pharmaceutically acceptable
Prior art date
Application number
PCT/IB2007/003224
Other languages
English (en)
Other versions
WO2009034409A3 (fr
Inventor
Cyril Estanove
François PRUVOST
Girish Kumar Jain
Original Assignee
Wockhardt Research Centre
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
Application filed by Wockhardt Research Centre filed Critical Wockhardt Research Centre
Publication of WO2009034409A2 publication Critical patent/WO2009034409A2/fr
Publication of WO2009034409A3 publication Critical patent/WO2009034409A3/fr

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Classifications

    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol

Definitions

  • the present invention relates to pharmaceutical compositions of rhein or diacerein, or salts thereof.
  • the invention also relates to processes for the preparation of such compositions.
  • Rhein is chemically 9, 10-dihydro-4, 5-dihydroxy-9, 10-dioxo-2-anthracene carboxylic acid and diacerein, (Formula II), is chemically 4,5-bis (acetyloxy) 9,10- dihydro-4, 5-dihydroxy-9, 10-dioxo-2-anthracenecarboxylic acid.
  • Diacerein is used particularly in the treatment of osteoarthritis. Diacerein has a unique mode of action that differentiates it from non-steroidal anti-inflammatory drugs (NSAIDs) and other conventional forms of drug therapy. It has a melting point of 217-218°C. It has a molecular weight of 368.29 and molecular formula is C 19 H 12 O 8 .
  • Diacerein is practically insoluble in the solvents compatible with a pharmaceutical use, such as water, alcohols, acetone, dichloromethane and chloroform. Further, diacerein can be administered by oral route but it cannot be completely absorbed by the digestive tract, and this incomplete absorption may result in undesirable side effects such as laxatives effects.
  • EP 243,968 describes a diacerein potassium salt, which is water-soluble and can be used in the preparation of compositions for parenteral administration.
  • solubility and/or wettability of a substance can be improved by treatment with a surface-active agent, which results in promoting the bioavailability of the active principle.
  • EP243968B1 provides parenteral preparations of diacerein salts.
  • U.S. Patent No. 6,124,358 and European Patent No EP904060B1 provides pha ⁇ naceutical composition comprising co-micronized rhein or diacerein, with sodium lauryl sulfate.
  • U.S. Patent No. 5,952,383 and European Patent No EP 862423B1 provides pharmaceutical compositions of diacerein, rhein and their salts along with excipients.
  • the present invention addresses and overcomes these commonly encountered * problems of low solubility, incomplete absorption and soft stools effect.
  • a pharmaceutical composition comprising rhein or diacerein, or salts thereof along with sugar alcohols.
  • the pharmaceutical composition may further include one or more pharmaceutically acceptable excipients.
  • composition comprising rhein or diacerein, or salts thereof along with sugar alcohols, optionally with one or more pharmaceutically acceptable excipients, wherein diacerein is present in admixture with sugar alcohol.
  • the one or more pharmaceutically pharmaceutically acceptable excipients may include one or more of fillers, lubricants, disintegrants, and glidants.
  • composition comprising rhein or diacerein, or salts thereof along with sugar alcohols, optionally with one or more pharmaceutically acceptable excipients, wherein diacerein is present in the form of complex with sugar alcohol.
  • a pharmaceutical composition comprising rhein or diacerein, or salts thereof along with sugar alcohols, optionally with one or more pharmaceutically acceptable excipients, wherein diacerein is adsorbed on sugar alcohol.
  • the pharmaceutical composition may include one or more of the following features.
  • the pharmaceutical composition may include one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients may include one or more of fillers, lubricants, glidants, disintegrants, and the like.
  • a pharmaceutical composition comprising rhein or diacerein, or salts thereof characterized by the crystallographic data shown in fig 1.
  • a a pha ⁇ naceutical composition comprising rhein or diacerein, or salts thereof having X-ray diffraction peaks at angle 2 theta of 9.6 and 13.52 degrees.
  • Embodiments of the pharmaceutical composition may include one or more of the following features.
  • the pharmaceutical composition may include one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients may include one or more of fillers, lubricants, glidants, disintegrants, and the like.
  • a pharmaceutical composition which comprises of rhein or diacerein, or salts thereof along with sugar alcohols optionally with one or more pharmaceutically acceptable excipients; and wherein the formulation exhibits a dissolution profile such that within 30 minutes more than 75% of diacerein is released, wherein the release rate is measured in Apparatus 2 (USP, Dissolution, paddle, 75 rpm) using 1000 ml of pH 5.7 phosphate buffer at 37 0 C ⁇ 0.5 0 C
  • a process of preparation of pharmaceutical composition comprises of spraying an organic solution of rhein or diacerein, or salts thereof optionally with sugar alcohols or one or more pharmaceutically acceptable excipients in a flow of a fluid under supercritical pressure to form particles and collecting the said particles.
  • composition for oral administration to mammals and refers to tablets, capsules, granules, beads, caplets, disc, pills, sachet, suspension, spheroids, minitablets, granules in a capsule, beads in a capsule, minitablets in a capsule, and the like.
  • Embodiments of the pharmaceutical composition may include one or more of the following features.
  • the pharmaceutical composition may include one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients may include one or more of fillers, lubricants, glidants, disintegrants, and the like.
  • sugar alcohols like mannitol or sorbitol when used along with other known water insoluble drugs like fenofibrate, irbesartan, aripiprazole, entacapone, either as physical mixture or in the form of complex, does not result in any significant increase in solubility of above mentioned poorly soluble drugs. It was observed that it does not make any significant difference either in solubility or percent release of these poorly soluble drugs, whether these drugs are present alone in formulation or along with sugar alcohols.
  • the present inventors while working on the diacerein formulation have surprisingly found when diacerein is present along with sugar alcohols, either as physical mixture or in form of any sort of complex or any other physical or chemical association, it results in significant increase in solubility of diacerein and percent drug release of diacerein as compared to Art 50 (Marketed formulation of diacerein). Art 50 releases about 14% of diacerein in 60 minutes,- whereas pharmaceutical composition of the present invention releases about 80-100% diacerein in 60 minutes.
  • X-ray diffraction pattern of the pharmaceutical composition of the present invention comprising diacerein or salts thereof is shown in Figure 1.
  • X-ray diffraction pattern of plain Diacerein is shown in Figure 2.
  • the X-ray spectroscopic analysis of the samples obtained demonstrated the presence of a new crystallographically different entity, as shown on Fig. 1 representing the spectrum of the samples of the present invention (Example 4) compared with a plain diacerein (Fig 2).
  • the pharmaceutical composition may be prepared by spraying an organic solution of diacerein or salts thereof in a flow of fluid under supercritical pressure to form microparticles, which may be collected on suitable sugar alcohol bed. Collected particles may be mixed with other pharmaceutically acceptable excipients and may be converted into suitable dosage form. , . •
  • the pharmaceutical composition may be prepared by spraying an organic solution of diacerein or salts thereof and suitable sugar alcohol in a flow of fluid under supercritical pressure to form microparticles, which may be collected mixed with other pharmaceutically acceptable excipients and converted into suitable dosage form.
  • the pharmaceutical composition of the present invention may also be prepared by triturating diacerein with sugar alcohol, drying the triturate, mixing the dried triturate with other pharmaceutically acceptable excipients and converting the mixture into suitable dosage form.
  • the pharmaceutical composition of the present invention may also be prepared by triturating diacerein with sugar alcohol along with one or more surfactants, drying the triturate, mixing the dried triturate with other pharmaceutically acceptable excipients and converting the mixture into suitable dosage form.
  • diacerein in the pharmaceutical composition of the present invention, can be present in an_ amount relative to the sugar alcohol, such that such that a molar ratio between the diacerein and the sugar alcohol is from about 1 : 1 to 1: 10.
  • the diacerein-sugar alcohol composition can be prepared by various processes including anti-solvent technique, solvent evaporation, kneading, spray drying, colloidal milling, high speed mixing, trituration.
  • the diacerein-sugar alcohol composition prepared by anti-solvent method using supercritical fluid results in better increase in solubility and percent release of diacerein as compared to composition containing mere diacerein-sugar alcohol mixture.
  • Suitable fluid used under supercritical pressure may include but not limited to carbon dioxide, water, ethane, xenon and the like.
  • Suitable organic solvents used for preparing organic solution of diacerein or salts thereof are those known to ordinary skill in the art and may include one or more of N-methyl- pyrrolidone, dimethyl sulfoxide, dimethylacetamide, tetrahydrofuran, ketones and the like.
  • Suitable sugar alcohols may include one or more of mannitol, maltitol, maltol, sorbitol, lactitol, xylitol and the like.
  • the pharmaceutical composition comprises of pharmaceutically acceptable excipients wherein excipients may include fillers, lubricants, disintegrants, and glidants.
  • Suitable filler may include one or more of microcrystalline cellulose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar and the like.
  • Suitable lubricant may include one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl behenate and the like.
  • Suitable glidant may include one or more of colloidal silicon dioxide, talc or cornstarch and the like.
  • Suitable disintegrant may include one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
  • Suitable surfactants are those known to ordinary skilled in the art and may include but not limited to amphoteric, non-ionic, cationic or anionic surfactants.
  • Suitable surfactants comprises one or more of sodium lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or another ester of polyoxyethylene sorbitane, sodium dioctylsulfosuccinate (DOSS), lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamer, cremophore RH 40 and the like.
  • DOSS sodium dioctylsulfosuccinate
  • Table 1 provides the composition of batches of the present invention.
  • Table 2 provides the dissolution data for diacerein capsules (50mg) prepared as per the fonnula given in Table 1.
  • USP Type 2 Apparatus rpm 75
  • 1000 ml of pH 5.7 phosphate buffer at 37 0 C ⁇ 0.5 0 C was used as medium.
  • Diacerein is mixed with sorbitol and triturated with minimum amount of water to form a pasty mass.
  • Pasty mass is dried, sieved to form granules and mixed with microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The final mixture is filled into hard gelatin capsules.
  • Table 3 provides the composition of batches of the present invention.
  • Table 4 provides the dissolution data for diacerein capsules (50mg) prepared as per the formula given in Table 3.
  • USP Type 2 Apparatus rpm 75
  • 1000 ml of pH 5.7 phosphate buffer at 37 0 C ⁇ 0.5 0 C was used as medium.
  • Diacerein is mixed with sorbitol, sodium docusate, sodium lauryl sulfate and triturated with minimum amount of water to form a pasty mass.
  • Pasty mass is dried, sieved to form granules and mixed with glycine, lactose and crospovidone. The final mixture is filled into hard gelatin capsules.
  • Example 3 Table 5 provides composition of batches of the present invention.
  • Table 6 provides the dissolution data for diacerein capsules (50mg) prepared as per the formula given in Table 5.
  • USP Type 2 Apparatus rpm 75
  • 1000 ml of pH 5.7 phosphate buffer at 37 0 C ⁇ 0.5 0 C was used as medium.
  • Diacerein is dissolved in N-methyl pyrrolidone and sprayed (Spray rate: 3ml/min) in a flow of carbon dioxide (15 Kg/h) under supercritical pressure (100 bars, 40 0 C) on bed of mannitol placed into spray reactor.
  • the particles thus formed are recovered on bed of mannitol and mixed with microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.
  • the final mixture is filled into hard gelatin capsules.
  • Table 7 provides composition of batches of the present invention.
  • Table 8 provides the dissolution data for diacerein capsules prepared as per the formula given in Table 7.
  • USP Type 2 Apparatus rpm 75
  • 1000 ml of pH 5.7 phosphate buffer at 37 0 C ⁇ 0.5 0 C was used as medium.
  • Diacerein and mannitol are dissolved in N-methyl pyrrolidone and sprayed (Spray rate: 3ml/min) in a flow of carbon dioxide (15 Kg/h) under supercritical pressure (100 bars, 40 0 C) in spray reactor.
  • the particles thus formed are recovered and mixed with microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.
  • the final mixture is filled into hard gelatin capsules.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne une composition pharmaceutique contenant de la diacéréine, ou des sels pharmaceutiquement acceptables de celle-ci, des alcools de sucre et facultativement au moins un excipient pharmaceutiquement acceptable. L'invention concerne également des procédés de préparation de ces compositions. La composition selon l'invention peut présenter une biodisponibilité améliorée, ainsi que de effets secondaires indésirables réduits.
PCT/IB2007/003224 2007-09-14 2007-10-26 Compositions pharmaceutiques de rheine ou de diacereine WO2009034409A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1766MU2007 2007-09-14
IN1766/MUM/2007 2007-09-14

Publications (2)

Publication Number Publication Date
WO2009034409A2 true WO2009034409A2 (fr) 2009-03-19
WO2009034409A3 WO2009034409A3 (fr) 2009-08-27

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2943543A1 (fr) * 2009-03-31 2010-10-01 Separex Sa Procede de preparation de compositions pharmaceutiques comprenant des particules fines de substance active.
EP2865371A1 (fr) * 2013-10-22 2015-04-29 Disphar International B.V. Granules à dissolution rapide
CN106236729A (zh) * 2016-07-31 2016-12-21 合肥远志医药科技开发有限公司 一种双醋瑞因胶囊制剂及其制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4721709A (en) * 1984-07-26 1988-01-26 Pyare Seth Novel pharmaceutical compositions containing hydrophobic practically water-insoluble drugs adsorbed on pharmaceutical excipients as carrier; process for their preparation and the use of said compositions
US20020128317A1 (en) * 2001-01-23 2002-09-12 Laboratories Negma Treatment of pathological conditions characterized by an increased IL-1 level
US6566347B1 (en) * 2001-08-22 2003-05-20 Duquesne University Of The Holy Ghost Controlled release pharmaceutical
US6974593B2 (en) * 1995-10-17 2005-12-13 Jagotec Ag Insoluble drug delivery
US20060210640A1 (en) * 1999-12-20 2006-09-21 Kerkhof Nicholas J Process for producing nanoparticles by spray drying

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4721709A (en) * 1984-07-26 1988-01-26 Pyare Seth Novel pharmaceutical compositions containing hydrophobic practically water-insoluble drugs adsorbed on pharmaceutical excipients as carrier; process for their preparation and the use of said compositions
US6974593B2 (en) * 1995-10-17 2005-12-13 Jagotec Ag Insoluble drug delivery
US20060210640A1 (en) * 1999-12-20 2006-09-21 Kerkhof Nicholas J Process for producing nanoparticles by spray drying
US20020128317A1 (en) * 2001-01-23 2002-09-12 Laboratories Negma Treatment of pathological conditions characterized by an increased IL-1 level
US6566347B1 (en) * 2001-08-22 2003-05-20 Duquesne University Of The Holy Ghost Controlled release pharmaceutical

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2943543A1 (fr) * 2009-03-31 2010-10-01 Separex Sa Procede de preparation de compositions pharmaceutiques comprenant des particules fines de substance active.
WO2010112702A1 (fr) * 2009-03-31 2010-10-07 Separex Procédé de préparation de compositions pharmaceutiques comprenant des particules fines de substance active
US8765184B2 (en) 2009-03-31 2014-07-01 Stanipharm Method for preparing pharmaceutical compositions comprising fine particles of active substance
EP2865371A1 (fr) * 2013-10-22 2015-04-29 Disphar International B.V. Granules à dissolution rapide
CN106236729A (zh) * 2016-07-31 2016-12-21 合肥远志医药科技开发有限公司 一种双醋瑞因胶囊制剂及其制备方法

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Publication number Publication date
WO2009034409A3 (fr) 2009-08-27

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