EP1830811A2 - Verfahren zur herstellung einer festen pharmazeutischen zusammensetzung mit längerer und kontrollierter freisetzung durch hochdruckbehandlung - Google Patents

Verfahren zur herstellung einer festen pharmazeutischen zusammensetzung mit längerer und kontrollierter freisetzung durch hochdruckbehandlung

Info

Publication number
EP1830811A2
EP1830811A2 EP05850552A EP05850552A EP1830811A2 EP 1830811 A2 EP1830811 A2 EP 1830811A2 EP 05850552 A EP05850552 A EP 05850552A EP 05850552 A EP05850552 A EP 05850552A EP 1830811 A2 EP1830811 A2 EP 1830811A2
Authority
EP
European Patent Office
Prior art keywords
derivatives
active ingredient
polymer
solid
composition
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP05850552A
Other languages
English (en)
French (fr)
Inventor
Vassilios Kaltsatos
Patrick Forget
Eliane Boivin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ceva Sante Animale SA
Original Assignee
Ceva Sante Animale SA
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 Ceva Sante Animale SA filed Critical Ceva Sante Animale SA
Publication of EP1830811A2 publication Critical patent/EP1830811A2/de
Withdrawn legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0048Eye, e.g. artificial tears
    • A61K9/0051Ocular inserts, ocular implants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38Cellulose; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • A61P27/02Ophthalmic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

  • the present invention relates to a process for the manufacture of a solid sustained-release and controlled-release pharmaceutical composition, by treatment under high pressures of a composition comprising at least one composition comprising at least one composition. at least one active ingredient and at least one polymer.
  • compositions having the property of prolonged and controlled release of the active ingredients is very common in the human and veterinary pharmaceutical fields. This allows, with a single dose, to obtain a prolonged effect of several hours up to several months for certain implantable forms, in particular ophthalmic inserts.
  • the active ingredients are mixed with polymers.
  • said polymers will form a matrix containing said active ingredients.
  • the property of prolonged and controlled release of the active ingredients (release kinetics) will therefore be closely correlated, on the one hand, to the nature of the polymers used to form the matrix and, on the other hand, to the manufacturing process used.
  • the process used makes it possible to reach the glass transition temperature of the polymers so that the polymer molecules melt with each other and arrange spatially to form a homogeneous plastic matrix.
  • Glass transition temperature refers to the temperature at which a polymer changes from a soft, flexible state to a hard (plastic) or even brittle state.
  • the manufacturing process must implement a heat treatment at a temperature above the glass transition temperature, to soften the polymer, to make the matrix by making the polymer a densified form, free of holes or pores, then the temperature must be decreased below this glass transition temperature, to harden the polymer and make it resistant to external aggressions ie gas, water vapor, oxygen, water, etc.
  • High pressure treatments are used for sterilization processes of active ingredients or compositions.
  • the French application FR 00 01059 describes a process for sterilizing at least one active ingredient by treatment at high pressures between 3.10 8 and 6.10 8 Pa.
  • the French application FR 02 05458 describes a sterilization process. without degradation of a pharmaceutical composition in micronized or nanodispersed form comprising at least one active principle by treatment at high pressures of between 200 and 1000 MPa.
  • High pressure treatments to sterilize food, drugs, etc. are already well known to those skilled in the art. Conversely, a high pressure treatment has never been used in a process for producing a composition allowing a sustained and controlled release of the active ingredient.
  • the subject of the invention is a process for producing solid sustained-release and controlled-release pharmaceutical compositions of at least one active principle, said process comprising the treatment under high pressures of a solid composition comprising at least one active principle and at least one polymer.
  • composition is meant any composition in solid form.
  • the compositions in solid form comprise, on the one hand, unitary solid forms such as tablets, implants, inserts, dragees, suppositories, etc. and on the other hand, powdery solid forms such as powders.
  • insert is meant in particular a sterile solid or semi-solid preparation, of suitable size and shape, intended to be inserted into the conjunctival sac for action on the eye (see for example Inserenda Ophthalmica,
  • Extended release means the provision of the active ingredient (s) to the body, in a constant or programmed manner, lasting from 8 to 12 hours to several months (for implants).
  • controlled release characterizes a release of the active principle according to linear kinetics (kinetics of zero order), that is to say that the active ingredient is released at a constant speed. in the middle as a function of time.
  • high pressures is meant a treatment carried out at pressures generally above 100 MPa (10 8 Pa).
  • thermosensitive an active ingredient whose biological activity is diminished, partially or totally, following a high temperature treatment applied for several hours, for example a treatment at 100 ° C. for 15 hours.
  • the present invention thus relates to a process for the manufacture of a solid sustained release pharmaceutical composition controlled by high pressure treatment of a composition comprising at least one active ingredient and at least one polymer.
  • said method comprises the step of subjecting a solid composition comprising at least one active ingredient and at least one polymer to a pressure greater than 10 8 Pa and to a heat treatment for a predetermined period.
  • Heat treatment is usually done at a temperature greater than +10 ° C.
  • the duration of said step is generally equal to or greater than one minute.
  • the solid composition is subjected to a pressure of between 10 8 and 10 9 Pa, preferentially still between 10 8 and 6.10 8 Pa, more preferably between 2.5 ⁇ 10 8 and 5 ⁇ 10 8 Pa.
  • the temperature of the heat treatment is between +10 ° C. and + 150 ° C., more preferably between +20 ° C. and + 120 ° C., more preferably between + 45 ° C. and +100 ° C. more preferably between +60 ° C. and + 90 ° C.
  • the duration of said step is between one minute and one hour, more preferably between 1 and 30 minute (s).
  • said method comprises the step of subjecting a solid composition comprising at least one active ingredient and at least one polymer to a pressure of between 10 8 and 6.10 8 Pa, and at a temperature of between + 20 ° C. and + 120 ° C. for a period of between one minute and 30 minutes.
  • the glass transition temperature of the polymer (s) be reached during the manufacturing process. Indeed, when the glass transition temperature is reached, the polymers "melt” and become malleable with a plastic behavior and then form a homogeneous matrix devoid of (or weakly provided) intergranular pore. This temperature depends on the nature of the polymer (s) used.
  • the glass transition temperatures of the polymers are given by the documents of the polymer supplier. Indeed, these temperatures depend strongly on the nature of the polymer used (molecular weight, crosslinking, groups and their attachment, sequences), and the process of obtaining used (solvents used, manufacturing process).
  • composition subjected to the process according to the invention may contain an active ingredient of any kind.
  • the composition may comprise at least one active ingredient which may belong, in particular, to the class of antibiotics, to the class of nonsteroidal anti-inflammatory drugs and corticosteroids, to the class of hormones or hormonal analogs, to the class of anticancer drugs, the class of antivirals, the class of drugs of the central nervous system (anti-migraine, sedatives, hypnotics, anti-Parkinson's, anti-epileptics, antidepressants).
  • the composition comprises at least one active ingredient belonging in particular to the class of antibiotics.
  • this composition comprises fusidic acid.
  • the composition further comprises at least one polymer that is a biocompatible polymer.
  • the biocompatible polymers may be water-soluble or non-water-soluble.
  • Different types of polymers are particularly suitable for carrying out the process according to the invention, namely the polymers belonging in particular to acrylic derivatives, to polycarbophilic derivatives, to cellulose derivatives, to vinyl derivatives (vinyl acetate, vinyl alcohol, vinyl acetate phthalate).
  • gums lacquer, tragacanth, xanthan, guar, arabic, tragacanth, scleroglucans, carrageenans
  • derivatives of polysaccharides polyoxyethylene derivatives, polyethylene derivatives polypropylene glycol (poloxamers), dextran derivatives, gelatin derivatives, derivatives of sugars and polyols, derivatives of alginic acid, silicone derivatives, derivatives of lactic and glycolic acids, derivatives of polyanhydrides, polybutadiene derivatives, glutamic acid derivatives, polyorthoesters derivatives and or the derivatives of ion exchange resins.
  • the polymers belong to the family of cellulose derivatives.
  • the polymers are chosen from hydroxyethylcellulose, hydroxymethylpropylcellulose or ethylcellulose.
  • the respective proportions of active principle (s) and polymer (s) depend on the nature of the active ingredients and the polymers used.
  • the dissolution rate of a solid active ingredient in a medium is proportional to its solubility in said medium. Consequently, a weakly soluble active ingredient in a medium will have a low dissolution rate in this medium, the release of the active ingredient then being prolonged in time.
  • the composition further comprises a variety of pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipient is meant any compound which facilitates the shaping of the composition and does not modify the nature of the biological activity of the active principle.
  • a pharmaceutically acceptable excipient can be a solvent, plasticizer, lubricant, dispersion medium, absorption delay agents, flow agent, etc.
  • the composition further comprises plasticizers, lubricants and / or flow agents.
  • the composition furthermore optionally comprises at least one plasticizer, in particular when the polymer is difficult to compress.
  • plasticizers are particularly suitable for carrying out the process according to the invention, namely polyethylene glycol derivatives, vegetable or mineral oils, phthalic or sebacic derivatives, triacetin, triethylcitrate and fatty substances.
  • the plasticizers are vegetable oils.
  • the plasticizer is castor oil.
  • the composition furthermore optionally comprises at least one lubricant.
  • lubricants are particularly suitable for the implementation of the method according to the invention, namely magnesium stearate, stearic acid, leucine, glycine, sodium lauryl sulfate, sodium benzoate, benzoate of potassium, sodium stearyl fumarate, glycerol behenate, hydrogenated vegetable oil, polyethylene glycol, silicone, talc, zinc stearate, glycerine mono-stearate and glycerol palmitea stearate.
  • the lubricant is a hydrogenated vegetable oil.
  • the solid composition comprises, by weight relative to the total weight of the composition:
  • polymer (s) - 50 to 90% of polymer (s) and optionally one or more pharmaceutically acceptable excipients.
  • the solid composition comprises, by weight relative to the total weight of the composition:
  • polymer (s) - 60 to 80% of polymer (s) and optionally one or more pharmaceutically acceptable excipients.
  • said solid composition subjected to the process according to the invention comprises 25% of fusidic acid, 1% of hydroxyethylcellulose, 65.5% of hydropropylmethylcellulose, 5% of ethylcellulose, 3% of hydrogenated vegetable oil and 0.5% of castor oil, the percentages being expressed by weight relative to the total weight of the composition.
  • said solid composition is an ophthalmic insert. Said insert can then be inserted directly into the conjunctival sac. Nevertheless, prior to any use in animals of the solid composition treated at high pressures, this composition may optionally be sterilized (by radiation or otherwise) and / or may be packaged (sachet, blister).
  • the composition comprising at least one active ingredient, at least one polymer and optionally one or more excipients, which is subjected to the process according to the invention, is in solid form.
  • the various compounds (at least one active ingredient, at least one polymer and optionally the excipients) forming the composition are mixed to form a solid powdery form.
  • the pulverulent solid form is optionally granulated by granulation techniques well known to those skilled in the art, to form a granular solid form.
  • the pulverulent solid forms or granulated solid forms are optionally compressed, molded or cast by the techniques well known to those skilled in the art in order to obtain a unitary solid form.
  • the various compounds forming the composition are mixed and granulated before being converted into unitary solid form.
  • the solid form (pulverulent, granulated or unit) is then treated with high pressures in order to obtain a composition allowing a sustained and controlled release of the active ingredient.
  • the high pressure treatment is applied in such a way as to induce a homothetic reduction of the dimensions of the composition.
  • homothetic reduction or reduction of scale
  • This homothetic reduction does not entail any change of form.
  • Such a reduction without modification of shape is obtained by applying an isostatic pressure, that is to say during the treatment the pressure applied is identical at any point on the surface of the solid form.
  • the high pressure treatment can be carried out using isostatic press equipment, preferably hot so that heat treatment can also be applied.
  • isostatic press equipment preferably hot so that heat treatment can also be applied.
  • an industrial scale hot isostatic press marketed by NovaSwiss® is suitable for implementing the invention.
  • the use of high pressures is usually combined with specified temperatures.
  • the choice of temperature is directly correlated to the nature of the polymer (s) used.
  • the application of a suitable temperature allows a modification of the polymers used and, in particular, a modification of their physical characteristics. Indeed, the application of a temperature above the glass transition temperature of the polymer allows the formation of a homogeneous and sealed matrix by melting the polymers and condensing them around the active ingredient.
  • the inventors have observed that the application of high pressures makes it possible to lower the glass transition temperature of the polymers compared with the hot extrusion process of the prior art. This lowering is important because it makes it possible to work with heat-sensitive active principles and thus to apply the method according to the invention to the manufacture of compositions comprising at least one thermosensitive active principle.
  • the combined application of high pressures and an adequate temperature results in a large reduction in the porosity of the composition obtained.
  • the decrease in the number of intra-granular and inter-granular pores, the reduction in the surface / volume ratio and the increase in the density of the composition are observed.
  • the process according to the invention after incorporating the active ingredient by mixing optionally followed by granulation and / or compaction and optionally compression, in a matrix formed essentially of polymers, will, under the effect of high pressure treatment, close a large number of intra-granular pores and ensure the continuity and tightness of the polymer matrix.
  • These continuity and sealing give the polymeric matrix the qualities allowing regulation and prolongation of the dissolution of the active principle.
  • the concept obtained allows dissolutions at least as prolonged as those of products obtained by fusion-extrusion.
  • Another object of the invention relates to the sustained-release and controlled-release pharmaceutical compositions that can be obtained by the process according to the invention.
  • said solid pharmaceutical composition comprises at least one thermosensitive active ingredient and at least one polymer.
  • the pharmaceutical composition provides a sustained and controlled release of said at least one active ingredient for a period of at least 8 hours, preferably at least 12 hours or more preferably for one, two or more months.
  • the pharmaceutical composition according to the invention comprises fusidic acid as active principle.
  • the pharmaceutical composition comprises at least one polymer which is selected from the group consisting of hydroxymethylcellulose, hydroxymethylpropylcellulose and ethylcellulose.
  • the pharmaceutical composition comprises 25% fusidic acid, 1% hydroxyethylcellulose, 65.5% hydroxymethylpropylcellulose, 5% ethylcellulose, 3% hydrogenated vegetable oil and 0.5% hydrogenated oil. castor.
  • FIG. 1 shows the analysis of the release profile, by dissolution in a phosphate buffer medium, of the active ingredient contained in a composition not treated with high pressures and in a composition according to the invention.
  • the solid forms are obtained by successive granulations of 25% of fusidic acid with 65.5% of hydroxymethylpropylcellulose, 5% of ethylcellulose, 1% of hydroxyethylcellulose, 3% of hydrogenated vegetable oil and 0.5% of castor oil, by weight relative to the total weight of the mixture, then by compression in order to obtain a unitary solid form of fusidic acid of cylindrical form, the dimensions of which are indicated in the table below.
  • the granulation and compression steps are carried out with conventional equipment.
  • the solid forms are treated according to the present invention, by using the device "Pilot HP all stainless steel 7000 bars" (reference 7-1000-097, marketed by Novaswiss®).
  • the solid forms are placed in waterproof plastic envelopes and are immersed in water contained in the isostatic enclosure.
  • the solid forms are then treated by applying an isostatic pressure of 5.10 8 Pa at a temperature of 80 ° C. for 10 minutes.
  • said method implemented comprises a first phase of steady increase in pressure of 5 minutes, followed by a second phase of plateau by applying an isostatic pressure of 5.10 8 Pa at a temperature of 80 0 C for 10 minutes and a decompression phase of 50 seconds.
  • the characteristics of the treated solid forms obtained are compared with those of the untreated solid forms.
  • the mass, the thickness, the diameter, the surface, the volume and the surface / volume ratio of the treated and untreated solid forms have been calculated from methods well known to those skilled in the art.
  • the measurement of the surface and the volume shows that the ratio of these two parameters is greater for the treated solid forms than the untreated solid forms. Therefore, the increase in the area / volume ratio shows that the volume decreases faster than the surface.
  • This augmentation characterizes the significant contraction of the polymer matrix on the active ingredient.
  • the increase in the surface / volume ratio thus leads to a decrease in the contact between the external medium and the treated solid form. This contact surface being reduced, this delays and prolongs the release of the active ingredient.
  • the concomitant effects of contraction of the polymer on the active ingredient and reduction of the contact surface with the external medium lead to an increase in the dissolution time. This is necessarily due to the disappearance of the inter-granular pores, the temperature applied during the treatment having modified the polymer, said polymer having then perfectly isolated the active ingredient in a sealed polymer film.
  • the dosage of the active ingredient was carried out by HPLC.
  • the assay is performed on a Kromasil® C18 inverted phase column with a mobile phase consisting of a mixture of 9 volumes of methanol, 9 volumes of water, 16.4 volumes of phosphoric acid at 10 g / l and 65, 6 volumes of acetonitrile.
  • the detection is carried out using an ultraviolet spectrophotometer set at 235 nm (the retention time of the fusidic acid is 5.98 min).
  • the "Sink” conditions have been verified for fusidic acid.
  • the term “Sink conditions” denotes the experimental conditions for dissolving a pharmaceutical form, without this dissolution being slowed down by the saturation of the medium and the dissolution of the active ingredient. Thus, under these conditions, one must be able to solubilize in the defined volume of medium, three times the amount of active ingredient normally present in the pharmaceutical form. The results obtained are illustrated in FIG. 1 appended to the present application.
  • the release of the active ingredient contained in the treated solid forms is prolonged by at least 2h relative to the untreated solid forms. Similarly, it is observed that this prolonged release is accompanied by a transformation of the dissolution into a profile of order 0. In other words, it means that the amount of active ingredient released from the solid form treated is linear as a function of time (controlled release) unlike the untreated solid form for which the release profile is irregular as a function of time. Likewise, when the release rate of the active principle as a function of time is expressed (quantity of active ingredient released as a function of time), this rate is constant in the case of a zero-order release form and the we thus obtain a horizontal line.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP05850552A 2004-12-30 2005-12-20 Verfahren zur herstellung einer festen pharmazeutischen zusammensetzung mit längerer und kontrollierter freisetzung durch hochdruckbehandlung Withdrawn EP1830811A2 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0414099A FR2880273B1 (fr) 2004-12-30 2004-12-30 Procede de separation d'une composition pharmaceutique solide a liberation prolongee et controlee sous hautes pressions
PCT/FR2005/003203 WO2006072685A2 (fr) 2004-12-30 2005-12-20 Procede de preparation d'une composition pharmaceutique solide a liberation prolongee et controlee par traitement sous hautes pressions

Publications (1)

Publication Number Publication Date
EP1830811A2 true EP1830811A2 (de) 2007-09-12

Family

ID=34954133

Family Applications (1)

Application Number Title Priority Date Filing Date
EP05850552A Withdrawn EP1830811A2 (de) 2004-12-30 2005-12-20 Verfahren zur herstellung einer festen pharmazeutischen zusammensetzung mit längerer und kontrollierter freisetzung durch hochdruckbehandlung

Country Status (6)

Country Link
US (1) US20090281070A1 (de)
EP (1) EP1830811A2 (de)
JP (1) JP2008526719A (de)
CA (1) CA2594273A1 (de)
FR (1) FR2880273B1 (de)
WO (1) WO2006072685A2 (de)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2163240A1 (de) * 2008-09-12 2010-03-17 Universita' Degli Studi Di Genova Verfahren zur Herstellung von bioadhesiven Kompaktmatrizen
WO2010123563A2 (en) * 2009-04-23 2010-10-28 Sustained Nano Systems Llc Controlled release dispensing device
JP2011026212A (ja) * 2009-07-21 2011-02-10 Sawai Pharmaceutical Co Ltd 保存安定性に優れ、良好な打錠性を有するフルボキサミンマレイン酸塩錠剤
AU2018300071B2 (en) 2017-07-11 2024-09-19 Sustained Nano Systems Llc Radiation sterilization of hypercompressed polymer dosage forms
JP7493796B2 (ja) 2017-07-11 2024-06-03 サステインドナノシステムズエルエルシー 超圧縮医薬製剤

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2872429A1 (fr) * 2004-07-02 2006-01-06 Ellipse Pharmaceuticals Sa Procede de fabrication d'une forme pharmaceutique a liberation controlee contenant au moins un principe actif

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4591496A (en) * 1984-01-16 1986-05-27 Massachusetts Institute Of Technology Process for making systems for the controlled release of macromolecules
US5456917A (en) * 1993-04-12 1995-10-10 Cambridge Scientific, Inc. Method for making a bioerodible material for the sustained release of a medicament and the material made from the method
US5958458A (en) * 1994-06-15 1999-09-28 Dumex-Alpharma A/S Pharmaceutical multiple unit particulate formulation in the form of coated cores
US6465002B1 (en) * 2000-03-13 2002-10-15 Brown University Research Foundation Liquid crystalline polymers

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2872429A1 (fr) * 2004-07-02 2006-01-06 Ellipse Pharmaceuticals Sa Procede de fabrication d'une forme pharmaceutique a liberation controlee contenant au moins un principe actif

Also Published As

Publication number Publication date
JP2008526719A (ja) 2008-07-24
CA2594273A1 (fr) 2006-07-13
WO2006072685A2 (fr) 2006-07-13
FR2880273A1 (fr) 2006-07-07
WO2006072685A3 (fr) 2006-08-31
FR2880273B1 (fr) 2007-03-30
US20090281070A1 (en) 2009-11-12

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