WO2004009059A1 - Composition orale de telithromycine possedant un gout agreable - Google Patents

Composition orale de telithromycine possedant un gout agreable Download PDF

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Publication number
WO2004009059A1
WO2004009059A1 PCT/EP2002/008670 EP0208670W WO2004009059A1 WO 2004009059 A1 WO2004009059 A1 WO 2004009059A1 EP 0208670 W EP0208670 W EP 0208670W WO 2004009059 A1 WO2004009059 A1 WO 2004009059A1
Authority
WO
WIPO (PCT)
Prior art keywords
telithromycin
composition
ethylcellulose
microcapsules
coating
Prior art date
Application number
PCT/EP2002/008670
Other languages
English (en)
Inventor
Philippe Becourt
Luigi Boltri
Nicoletta Cioloca
Stefano De Luigi Bruschi
Luigi Giovanni Mapelli
Leonardo Rabaglia
Detlev Schwabe
Original Assignee
Aventis Pharma S.A.
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 CA2492874A priority Critical patent/CA2492874C/fr
Application filed by Aventis Pharma S.A. filed Critical Aventis Pharma S.A.
Priority to PCT/EP2002/008670 priority patent/WO2004009059A1/fr
Priority to BR0215806-0A priority patent/BR0215806A/pt
Priority to DE60234539T priority patent/DE60234539D1/de
Priority to US10/198,115 priority patent/US20040013737A1/en
Priority to AU2002321289A priority patent/AU2002321289B8/en
Priority to AT02754972T priority patent/ATE449598T1/de
Priority to MXPA05000322A priority patent/MXPA05000322A/es
Priority to JP2004522150A priority patent/JP2005533121A/ja
Priority to EP02754972A priority patent/EP1524966B1/fr
Priority claimed from US10/198,115 external-priority patent/US20040013737A1/en
Publication of WO2004009059A1 publication Critical patent/WO2004009059A1/fr
Priority to IL166140A priority patent/IL166140A/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins

Definitions

  • the invention relates to an oral composition comprising telithromycin that have taste masking properties, and the process for the preparation thereof.
  • Telithromycin is an already known antibacterial active described in EP 680,967. Unfortunately it has an unpleasant taste and therefore it cannot be formulated in a simple oral composition, mainly for paediatric use, and so far it has not be found how to overcome the problem of preparing a composition that could be acceptable.
  • the international application WO 01/14393 describes spherical agglomerates of telithromycin which are obtained by direct transformation of cristals into spherical forms. These agglomerates have a size of between 30 and 400 ⁇ m and preferentially 80 to 150 ⁇ m.
  • the described agglomerates are used to prepare micro-capsules for the preparation of oral suspensions, with using a coacervation process. Unfortunately when using the general methods of micro-encapsulation and coacervation it is impossible to obtain a composition with sufficient properties of taste masking.
  • the composition comprise microcapsules having a 2 layers coating.
  • a first coating comprising ethylcellulose and a second coating comprising a layer of an acrylic polymer.
  • This provides thus improved pharmaceutical formulations where the umpleasant taste is masked and that can give an immediate delivery on the stomach.
  • the composition can be administered in the form of a suspension for oral administration.
  • composition comprises
  • the composition comprises : spherical agglomerates of telithromycin ethylcellulose, acrylic polymer, anti-agglomeration agent,
  • the acrylic polymer can be chosen for instance among Eudragit® E.
  • the anti-agglomeration agent can be talc.
  • xanthan gum can be cited for instance, the aromatization agents can be chosen from sugars and for instance maltitol, the antimicrobial preservation agent can be chosen from parabens and the sweetening agent can be chosen for instance from sodium saccharinate.
  • the composition comprises : spherical agglomerates of telithromycin : 40 to 65% ethylcellulose : 8 to 18%, acrylic polymer 18 to 35%, • talc 4.5 to 10%, D(-) N-methylglucamine : 0.8 to 1.8% aluminium and magnesium silicate : 4 to 9% and optionally xanthan gum : 0.3 to 0.7% • maltitol : 40 to 90% sodium saccharinate : 0.6 to 1.4% flavouring agent : 0.6 to 1.4%
  • the composition comprises from 45 to 63% of telithromycin agglomerates ; from 9 to 15% of ethylcellulose ; from 18 to 33% of the acrylic polymer; from 5 to 8% of talc, D(-) N-methylglucamine from 0.8 to 1.8%, aluminium and magnesium silicate from 4 to 9% and optionally the above mentioned additives.
  • the ratio acrylic polymer / anti-agglomeration agent is advantageously chosen around 2 to 4, preferably 4.
  • the mean size of the telithromycin agglomerates used as starting material is comprised between 30 and 500 ⁇ m. In a prefered embodiment the mean size is comprised between 60 and 250 ⁇ m (light scattering analysis).
  • composition is prepared from telithromycin in the form of spherical agglomerates (as described in WO 01/14393) using 2 main steps of encapsulation :
  • first step microencapsulation with ethylcellulose
  • second step fluid bed coating of the microcapsules with the acrylic polymer.
  • composition comprises D(-) N-methylglucamine, aluminium and magnesium silicate and optionally suspending agents, aromatization agents, sweetening agents and/or antimicrobial preservation agents these additives are added in a third step of the process after the 2 encapsulation steps.
  • composition comprises D(-) N-methylglucamine, aluminium and magnesium silicate and optionally xanthane gum, maltitol, sodium saccharinate and flavouring agent, these additives are also added in a third step of the process after the 2 encapsulation steps.
  • the 2 main steps of encapsulation can be advantageously conducted as follows :
  • microencapsulation in ethylcellulose can be made by coacervation according to the method described in US 6,139,865 and EP 38585 (incorporated here as a references), with ethylcellulose in cyclohexane and polyethylen wax, followed by separation of the microcapsules from the liquid phase and drying on a fluid bed.
  • the encapsulation in an acrylic polymer can be made using fluid bed coating technics, in the presence of an anti-agglomeration agent.
  • the process is carried out in a hydro alcoholic medium (for example in hydro-ethanolic medium).
  • the polyethylen wax can be Epolen® ; for instance, the acrylic polymer can be chosen among Eudragit E (Eudragit® E100) ; the anti-agglomeration agent is preferably talc and more preferably a micronized talc or talc of less than 75 ⁇ m.
  • the amount of the primary coating with ethylcellulose is defined such as to get a optimal particule size distribution, residual solvents complying with the regulatory acceptance and such as the microcapsules are suitable to be coated using a fluid bed technic. Usually an amount between 15 and 30% of coating level is suitable ; preferably a coating level between 18 and 25% is advantageously chosen, and more prefered is 18%.
  • the microcapsules prepared with the primary coating comprise 50 to 95 % of telithromycin agglomerates and 5 to 50% of ethylcellulose. After the first coating the mean particule size is acceptable and is for example less than 250 ⁇ m for more than 90% of the resulting microcapsules.
  • the secondary coating made of acrylic polymer in the presence of an anti- agglomeration agent is made in an amount that allows a narrow particule size distribution, together with the properties of satisfactory taste-masking and fast dissolution rate for the preparation of the suspension.
  • an amount between 20 and 45% of coating level is suitable ; preferably a coating level between 25 and 40% is advantageously chosen.
  • the mean particule size is less than 300 ⁇ m for more than 90% of the resulting microcapsules.
  • suspensions comprising from 5 to 250 mg/ml and more preferably 100 mg/ml.
  • the prepared microcapsules have the capability of forming a sufficiently stable suspension, and have a fast dissolution rate : equal or superior to 80% over 2 to 10 minutes and in some preferential aspects of the invention : 90% within 2 mn.
  • the first step of coating was carried out using a 5 liter reactor with a pneumatic stirring, introducing spherical agglomerates of telithromycin with ethylcellulose in cyclohexane and Epolene®, with agitation at a temperature of 80°C, according to the coacervation method described in US 6,139,865.
  • the second coating was performed over 75mn, with using a Glatt GPCG1 fluid bed equipped with Wurster insert (4 "), bottom plate « A » type, filter « T165P » type, 1mm spraying nozzle and adding to 456 g of the first coated microcapsules, Eudragit® E100 10%, talc ⁇ 75 ⁇ m 5.0%, ethanol 51 %, purified water 34%.
  • the coating layer was applied at a spraying rate of 2.5 to 5.5 g/mn.
  • the temperature of the air was 45 to 52°C and the air speed 1.0 to 1.5 m/s.
  • the atomisation pressure was 1.8 bars.
  • the temperature of the product during the coating was between 30 and 33°C.
  • the coating is performed with an amount of membrane of 25%. After drying on the fluid bed and sieving the corresponding 2 coatings microcapsules are obtained.
  • the resulting composition comprises telithromycin agglomerates 58.5%, ethylcellulose 6.5%, Eudragit® E 23.3%, talc 11.7%.
  • the coated samples were easily dispersible in aqueous medium without any agglomeration or segregation phenomena.
  • the second coating was performed over 92mn, with using a Glatt GPCG1 fluid bed equipped with Wurster insert (4 "), bottom plate « A » type, filter « T165P » type, 1mm spraying nozzle and adding to 456 g of the first coated microcapsules, Eudragit® E100 10%, talc ⁇ 75 ⁇ m 5.0%, ethanol 51 %, purified water 34%.
  • the coating layer was applied at a spraying rate of 2.0 to 5.0 g/mn.
  • the temperature of the air was 54 to 55°C and the air speed 1.0 to 1.5 m/s.
  • the atomisation pressure was 1.8 bars.
  • the temperature of the product during the coating was between 30 and 33°C.
  • the coating is performed with an amount of membrane of 35%. After drying on the fluid bed and sieving the corresponding 2 coatings microcapsules are obtained.
  • the resulting composition comprises telithromycin agglomerates 67.5%, ethylcellulose 7.5%, Eudragit® E 16.7%, talc 8.3%.
  • the coated samples were easily dispersible in aqueous medium without any agglomeration or segregation phenomena.
  • the second coating was performed over 92mn, with using a Glatt GPCG1 fluid bed equipped with Wurster insert (4 "), bottom plate « A » type, filter « T165P » type, 1mm spraying nozzle and adding to 456 gof the first coated microcapsules, Eudragit® E100 10%, micronized talc 2.5%, ethanol 52.5%, purified water 35%.
  • the first part of the coating layer was applied at a lower spraying rate : 2.0 to 3.0 g/mn.
  • the temperature of the air was 55 to 60°C and the air speed 1.0 to 1.8 m/s.
  • the atomisation pressure was 1.8 bars.
  • the temperature of the product during the first part of the coating was between 33 and 38°C.
  • the temperature of the product during the second part of the coating was between 30 and 32°C.
  • the coating is performed with an amount of membrane of 20.9%. After drying on the fluid bed and sieving the corresponding 2 coatings microcapsules are obtained.
  • the resulting composition comprises telithromycin agglomerates 71.6%, ethylcellulose 7.5%, Eudragit® E 16.7%, talc 4.2%.
  • the coated samples were easily dispersible in aqueous medium without any agglomeration or segregation phenomena. The release is 97 + 1 after 2 mn.

Abstract

Composition de télithromycine conçue pour être administrée oralement et contenant: des agglomérés sphériques de télithromycine, éthylcellulose, un polymère acrylique et un agent anti-agglomérant. Cette composition se présente sous la forme de microgélules possédant un revêtement bicouche.
PCT/EP2002/008670 2002-07-19 2002-07-19 Composition orale de telithromycine possedant un gout agreable WO2004009059A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
AU2002321289A AU2002321289B8 (en) 2002-07-19 2002-07-19 Taste masked oral composition of telithromycin
PCT/EP2002/008670 WO2004009059A1 (fr) 2002-07-19 2002-07-19 Composition orale de telithromycine possedant un gout agreable
BR0215806-0A BR0215806A (pt) 2002-07-19 2002-07-19 Composição oral de telitromicina com paladar mascarado
DE60234539T DE60234539D1 (de) 2002-07-19 2002-07-19 Geschmacksmaskierte orale zubereitung von telithromycin
US10/198,115 US20040013737A1 (en) 2002-07-19 2002-07-19 Taste masked oral composition of telithromycin
CA2492874A CA2492874C (fr) 2002-07-19 2002-07-19 Composition orale de telithromycine possedant un gout agreable
AT02754972T ATE449598T1 (de) 2002-07-19 2002-07-19 Geschmacksmaskierte orale zubereitung von telithromycin
EP02754972A EP1524966B1 (fr) 2002-07-19 2002-07-19 Composition orale de telithromycine possedant un gout agreable
JP2004522150A JP2005533121A (ja) 2002-07-19 2002-07-19 テリスロマイシンの味覚マスキングされた経口組成物
MXPA05000322A MXPA05000322A (es) 2002-07-19 2002-07-19 Composicion oral de telitromicina con sabor enmascarado.
IL166140A IL166140A (en) 2002-07-19 2005-01-04 Taste masked oral composition of telithromycin, process for its preparation and use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/EP2002/008670 WO2004009059A1 (fr) 2002-07-19 2002-07-19 Composition orale de telithromycine possedant un gout agreable
US10/198,115 US20040013737A1 (en) 2002-07-19 2002-07-19 Taste masked oral composition of telithromycin

Publications (1)

Publication Number Publication Date
WO2004009059A1 true WO2004009059A1 (fr) 2004-01-29

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2002/008670 WO2004009059A1 (fr) 2002-07-19 2002-07-19 Composition orale de telithromycine possedant un gout agreable

Country Status (1)

Country Link
WO (1) WO2004009059A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2882522A1 (fr) * 2005-02-25 2006-09-01 Aventis Pharma Sa Composition pharmaceutique solide comprenant de la telithromycine
EP1978936B1 (fr) * 2006-02-03 2013-07-10 Evonik Röhm GmbH Compositions pharmaceutiques contenant des mélanges de polymères et d'agents actifs peu solubles dans l'eau
WO2014047496A3 (fr) * 2012-09-20 2014-08-21 The Procter & Gamble Company Microcapsules à séchage par pulvérisation

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0293885A2 (fr) * 1987-06-05 1988-12-07 Abbott Laboratories Compositions contenant une association antibiotique-polymère
US5635485A (en) * 1994-05-03 1997-06-03 Roussel Uclaf Erythromycin compounds
US5945124A (en) * 1995-07-05 1999-08-31 Byk Gulden Chemische Fabrik Gmbh Oral pharmaceutical composition with delayed release of active ingredient for pantoprazole
WO2001014393A2 (fr) * 1999-08-26 2001-03-01 Aventis Pharma S.A. Agglomerats spheriques de telithromycine, leur procede de preparation et leur application dans la preparation de formes pharmaceutiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0293885A2 (fr) * 1987-06-05 1988-12-07 Abbott Laboratories Compositions contenant une association antibiotique-polymère
US5635485A (en) * 1994-05-03 1997-06-03 Roussel Uclaf Erythromycin compounds
US5945124A (en) * 1995-07-05 1999-08-31 Byk Gulden Chemische Fabrik Gmbh Oral pharmaceutical composition with delayed release of active ingredient for pantoprazole
WO2001014393A2 (fr) * 1999-08-26 2001-03-01 Aventis Pharma S.A. Agglomerats spheriques de telithromycine, leur procede de preparation et leur application dans la preparation de formes pharmaceutiques

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2882522A1 (fr) * 2005-02-25 2006-09-01 Aventis Pharma Sa Composition pharmaceutique solide comprenant de la telithromycine
EP1978936B1 (fr) * 2006-02-03 2013-07-10 Evonik Röhm GmbH Compositions pharmaceutiques contenant des mélanges de polymères et d'agents actifs peu solubles dans l'eau
WO2014047496A3 (fr) * 2012-09-20 2014-08-21 The Procter & Gamble Company Microcapsules à séchage par pulvérisation
WO2014047486A3 (fr) * 2012-09-20 2014-08-28 Appvion, Inc. Microcapsules à séchage par pulvérisation
AU2013317851B2 (en) * 2012-09-20 2017-04-13 Encapsys, Llc Spray drying microcapsules

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