WO2001002087A1 - Methode de production de dispersions colloidales aqueuses de nanoparticules - Google Patents

Methode de production de dispersions colloidales aqueuses de nanoparticules Download PDF

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Publication number
WO2001002087A1
WO2001002087A1 PCT/EP1999/004677 EP9904677W WO0102087A1 WO 2001002087 A1 WO2001002087 A1 WO 2001002087A1 EP 9904677 W EP9904677 W EP 9904677W WO 0102087 A1 WO0102087 A1 WO 0102087A1
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Prior art keywords
water
producing
colloidal dispersion
aqueous colloidal
nanoparticles
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PCT/EP1999/004677
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English (en)
Inventor
David Quintanar-Guerrero
Eric Allemann
Robert Gurny
Hatem Fessi
Eric Doelker
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Universite De Geneve Laboratoire De Pharmacie Galenique
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Priority to AU51567/99A priority Critical patent/AU5156799A/en
Priority to PCT/EP1999/004677 priority patent/WO2001002087A1/fr
Publication of WO2001002087A1 publication Critical patent/WO2001002087A1/fr

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    • 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
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/04—Making microcapsules or microballoons by physical processes, e.g. drying, spraying
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/07—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media from polymer solutions

Definitions

  • the invention pertains to the area of dispersions in a liquid phase of water- insoluble materials, and more particularly the invention relates to a method for producing aqueous colloidal dispersions of nanoparticles, using an emulsification-diffusion type technique.
  • Aqueous colloidal dispersions of nanoparticles, and in particular pseudolatexes which are aqueous colloidal, dispersions containing nanoparticles of water insoluble preformed polymers, are currently offered for use as aqueous coating means or as pharmaceutical vectors.
  • aqueous colloidal dispersions containing nanoparticles and in particular pseudolatexes.
  • These techniques include emulsification-evaporation, nanoprecipitation, salting-out and emulsification-diffusion, which have in common that they involve the use of an organic solution, containing the nanoparticle components, which functions as an internal phase during preparation, and of an aqueous solution, containing stabilizers which will constitute the dispersion medium for the nanoparticles.
  • the emulsification-evaporation technique is a well- established technique based on the classical procedure disclosed in US-A-4.177.177 (Vanderhoff) .
  • a polymer solution in a water- immiscible organic solvent such as chloroform or methylene chloride is emulsified in an aqueous phase containing emulsifiers.
  • This crude emulsion is then submitted to a high energy mixing step using a high energy source such as ultrasounds, homogenizers, high pressure dispersers, colloid mills or microfluidizers, in order to reduce the droplet size.
  • the polymer emulsion resulting from such a treatment is very fine and contains very small droplets (below 0.5 ⁇ m in diameter) .
  • each emulsion droplet will form one polymer particle when the solvent is removed. Consequently, the homogenization step is the determining factor in obtaining submicronic particles.
  • a lipophilic stabilizer e.g., phospholipids
  • a semipolar water-miscible solvent such as acetone or ethanol
  • This solution is poured or injected into an aqueous solution containing a stabilizer (e.g., poly (vinyl alcohol) (PVAL) or poloxamer 188) under magnetic stirring.
  • PVAL poly (vinyl alcohol)
  • Nanoparticles are formed instantaneously by the rapid diffusion of the solvent, which is then eliminated from the suspension under reduced pressure.
  • the polymer and the drug are dissolved in acetone and this solution is emulsified under vigorous mechanical stirring in an aqueous gel containing the salting-out agent and a colloidal stabilizer.
  • This oil-in-water emulsion is diluted with a sufficient volume of water or of aqueous solution, in order to enhance the diffusion of acetone into the aqueous phase, thus inducing the formation of nanospheres.
  • the utility of this technique is however generally limited to drugs soluble in water-miscible solvents, in particular acetone-soluble drugs, to salting-out agents that enable phase separation without precipitation and to soluble stabilizers which are compatible with saturated aqueous solutions and which do not coacervate or precipitate in the presence of the solvent.
  • a major drawback is the use of a high quantity of salt which gives to the aqueous phase a fixed pH and which must be eliminated in a subsequent purification step.
  • Another drawback is that it is necessary to remove the solvent and a considerable amount of water to obtain a high polymer concentration in the final dispersion.
  • the acetone is mixed in the water which renders recycling of acetone problematic.
  • the method involves the emulsification of a partially water-soluble (partially water-miscible) solvent, previously saturated with water and containing a polymer, in an aqueous phase previously saturated with the solvent and containing a stabilizer.
  • the subsequent addition of water to the system causes the solvent to diffuse into the external phase, resulting in the aggregation of polymer in nanoparticles.
  • the object of the present invention is achieved by a method for producing an aqueous colloidal dispersion of nanoparticles, characterized in that it comprises : a) the emulsification of a partially water-soluble organic solvent, containing a water-insoluble material in a weight/volume percentage at which nanoparticles are formed in step b) , in an aqueous solution containing optionally a stabilizing agent, using a low energy source ; b) the distillation of the organic solvent from the oil-in-water emulsion formed in step a) to cause the formation of nanoparticles in suspension in the aqueous phase .
  • a method effective for producing aqueous colloidal dispersions containing a high concentration of nanoparticles which is based on the emulsification-diffusion technique, which does not require the use of high energy source for homogenization, which does not require the removing of a considerable amount of water, in which pharmaceutically acceptable organic solvents may be used with a possibility of solvent reuse, in which pharmaceutically acceptable stabilizers may be used or not, and which is simple to., implement, easy to scale up, of a low cost and reproducible.
  • aqueous colloidal dispersions having a high concentration of nanoparticles obtained by the method of the present invention are that they can be used directly for coatings or as pharmaceutical vectors without additional purification step.
  • the method of the present invention can be advantageously applied for producing aqueous colloidal dispersions of nanoparticles with ingredients entrapped therein, when the partially water-soluble organic solvent further contains additional ingredients.
  • a partially water-soluble organic solvent or "a partially water-miscible organic solvent” mean an organic solvent at least sparingly soluble in water in the sense of the European Pharmacopoeia or a mixture of organic solvents containing at least one organic solvent at least sparingly soluble in water in the sense of the
  • nanoparticles means particles having a mean particle size not greater than 1 ⁇ m.
  • the first steps are to prepare the organic phase, also named internal phase, and the aqueous phase, also named external phase.
  • the organic phase is prepared by dissolving the selected water-insoluble material, and optionally additional ingredients, in a partially water-soluble organic solvent.
  • the aqueous phase is prepared separately, by providing water and optionally dissolving the selected stabilizing agent in water.
  • the partially water-soluble organic solvent is previously added with a certain amount of water extending up to saturation and in a particularly preferred embodiment of the invention, the partially water-soluble organic solvent is previously saturated with water in order to ensure initial thermodynamic equilibrium in the subsequent step.
  • the water is previously added with a certain amount, extending up to saturation, of the same or another partially water-soluble organic solvent, and more preferably the water is previously saturated with the same or the other partially water-soluble organic solvent in order to ensure initial thermodynamic equilibrium in the subsequent step.
  • the partially water-soluble organic solvent added to water may be identical or different to the partially water-soluble organic solvent in which water- insoluble material is to be dissolved.
  • the water is previously added with a certain amount of a water-soluble organic solvent (for example ethanol) .
  • a water-soluble organic solvent for example ethanol
  • the water-insoluble material may be, for example, a polymer, a lipid, a wax and the like, or a mixture of two or more polymers and/or lipids and/or waxes and the like.
  • the water- " insoluble material is a polymer or a mixture of polymers, and in a particularly preferred embodiment, the water- insoluble material is a polymer selected from biodegradable polymer such as poly (D, L-lactic acid) (PLA) and poly( ⁇ - caprolactone) (PCL) and non-biodegradable polymers such as Eudragit®E, Eudragit ⁇ RS, Eudragit®RL, cellulose acetate phthalate (CAP) , cellulose acetate trimellitate (CAT) , and ethylene vinyl acetate copolymer (EVAC) .
  • biodegradable polymer such as poly (D, L-lactic acid) (PLA) and poly( ⁇ - caprolactone) (PCL)
  • non-biodegradable polymers such as Eudragit®E, Eudragit ⁇ RS, Eudragit®RL, cellulose acetate phthalate (CAP) , cellulose acetate trimellitate (CAT) , and ethylene vinyl acetate copolymer (EV
  • the partially water-soluble organic solvents should be selected on the basis of their volatility and low toxicity, in particular when a pharmaceutical application for the resulting aqueous colloidal dispersion is considered.
  • partially water-soluble organic solvents particularly preferred are ethyl acetate (AcEt) , methyl acetate (MeAc) , isopropyl acetate and 2-butanone, because of their widely recognized low toxicity, good solubilizing properties and low boiling points.
  • the additional ingredients may be any ingredients which can be entrapped in the nanoparticles or adsorbed at the surface of the nanoparticles, such as for example drugs, cosmetics, products for veterinary and agricultural use, food products or additives, colorants or any other ingredients which can be useful when they are entrapped in nanoparticles or adsorbed at the surface of nanoparticles .
  • stabilizing agents particularly preferred for 5 the emulsification and for stabilizing the final dispersion are poly (vinyl alcohol) (PVAL) and poloxamer 407 because of their good water solubility, suitability for ingestion and compatibility with the system.
  • PVAL poly (vinyl alcohol)
  • poloxamer 407 because of their good water solubility, suitability for ingestion and compatibility with the system.
  • the stabilizing agent is contained in the aqueous phase preferably in an amount of not more than 5 % w/v, and more preferably in an amount of not more than 1.25 % w/v.
  • aqueous phase is then mixed with the organic solution of the material, using a low energy source such as, for example, a propeller, a magnetic stirrer, a shaker and the like, to produce, when the addition is finished, an emulsion of the ⁇ il-in-water type.
  • a low energy source such as, for example, a propeller, a magnetic stirrer, a shaker and the like.
  • a particularly advantageous stirring rate for the propeller is from 1500 to 2000 rpm.
  • stirring rate up to 5000 rpm may be acceptable -5
  • the emulsification step is advantageously carried out at room temperature, but other temperatures may be used.
  • distillation of the 0 organic solvent from the oil-in-water emulsion is then carried out, to cause the displacement of the partially water-soluble organic solvent of the internal phase into the external phase and, consequently, to cause the formation of the particles in suspension in the aqueous 5 phase.
  • the distillation is a vacuum distillation.
  • the formation of nanoparticles is highly dependent on the water-insoluble material concentration in the internal phase and a transition from nano- to microparticles is observed at high water-insoluble material concentration.
  • the amount of water-insoluble material in the organic phase is critical for achieving the mean particle size desired for the final particles.
  • the weight/volume percentage of the water- insoluble material in the organic solvent should be not greater than the critical weight/volume percentage at which the particles formed during distillation have a mean particle size of 1 ⁇ m.
  • This critical percentage varies depending on the material/solvent/stabilizer system or material/solvent system and on the stirring rat"e of the propeller, in view of the known effect of an increased stirring rate on decreasing the particle size.
  • the critical percentage at which the particles formed during distillation have a mean particle size of 1 ⁇ m is easily obtained by an optimization for each material/solvent/stabilizer system or material/solvent system at a specific stirring rate.
  • Figure 1 represents the influence of the percentage of Eudragit E in the internal phase (ethyl acetate) on the mean particle size, when the external phase contains 5 % w/v of PVAL as stabilizer and the rate of stirring is 1500 rpm.
  • Figure 2 represents scanning electron micrographs
  • Figure 3 represents the influence of the percentage of cellulose acetate phthalate in the internal phase (2-butanone) on mean particle size when the external phase contains 5 % w/v of poloxamer 407 and the stirring rate is 1500 rpm.
  • Figure 4 represents the influence of the percentage of Eudragit E in the internal phase (methyl acetate) on mean particle size when the external phase contains no stabilizing agent and the stirring rate is 2000 rpm.
  • the particle sizes were determined using a Coulter® Nanosizer (Coulter Electronics, Harpenden (UK)).
  • a concentrated dispersion of nanoparticles was finely spread over a slab and dried under vacuum.
  • the sample was shadowed in a cathodic evaporator with a gold layer ( ⁇ 20 nm thick) .
  • the surface morphology of the nanoparticles was observed by SEM using a JSM-6400 scanning electron microscope (JEOL, Tokyo, Japan) .
  • Eudragit®E to ethyl acetate to obtain a mean particle size of 1000 nm is about 28 % w/v. However, in slightly different experimental conditions, this percentage varies.
  • Another non-biodegradable polymer preferred for the present invention is cellulose acetate phthalate (CAP) .
  • CAP cellulose acetate phthalate
  • 2-butanone to obtain a mean particle size of 1000 nm is about 38 % w/v. However, in slightly different experimental conditions, this percentage varies.
  • Fig. 4 an example of a Eudragit®E/methyl acetate system when the internal phase contains no stabilizing agent and the stirring rate is about 2000 rpm.
  • the critical weight/volume percentage of Eudragit®E to methyl acetate to obtain a mean particle size of 1000 nm is about 21 % w/v.
  • this percentage varies.
  • the water-insoluble materials are not limited to water-insoluble polymers.
  • Water insoluble polymers used in the Examples were Eudragit®E, Eudragit®RS and Eudragit®RL (obtained from Rohm (GmbH Darmstadt, Germany); poly ( ⁇ -caprolactone) (PCL)
  • Stabilizing agents used in the present Examples were poly (vinyl alcohol) (PVAL) (Mw 26 000) (Mowiol®4-88 , Hoechst, Frankfurt-am-Main, Germany) and poloxamer 407 (Pluronic®F-127, BASF, Ludwigshafen, Germany) .
  • Distilled water used in the present examples was purified using a Milli-Q system (millipore, USA-Bedford, MO) .
  • the average particle size and polydispersity index (scale from 0 to 9) were determined using a Coulter® Nanosizer (Coulter Electronics, Harpenden (UK). The measurements were made in triplicate for all the batches prepared.
  • Ethyl acetate and water were mutually saturated for 1 min before use, in order to ensure initial thermodynamic equilibrium of both liquids.
  • 4 g of Eudragit E were dissolved in 40 ml of water-saturated ethyl acetate and this organic solution (internal phase) was emulsified at room temperature with 80 ml of a 5 % w/v PVAL ethyl acetate saturated aqueous solution (external phase) , using a propeller stirrer (Heidolph-Elektro, KG type E-60, propeller : IKA 1381, Germany) at 1500 rpm for ten minutes.
  • a propeller stirrer Heidolph-Elektro, KG type E-60, propeller : IKA 1381, Germany
  • the oil-in-water emulsion formed was subjected to vacuum distillation at 35°C and 60 mmHg until complete solvent evaporation. Generally, the solvent was recovered and used to prepare new batches.
  • the mean particle size of the particles obtained by this method as well as the polydispersity are indicated in Table 1 below.
  • Example 2 The method was repeated in the same manner as in Example 1, except that 1.25 % w/v of PVAL was used in the external phase, instead of 5.0 % w/v of PVAL.
  • the mean particle size of the particles obtained by this method and the polydispersity are indicated in Table 1 below.
  • Example 1 The method was repeated in the same manner as in Example 1, except that 8 g of Eudragit E was used instead of 4 g of Eudragit E.
  • the mean particle size of the particles obtained by this method and the polydispersity are indicated in Table 1 below.
  • Example 5 The method was repeated in the same manner as in Example 1, except that EVAC was used, instead of Eudragit E.
  • EVAC was used, instead of Eudragit E.
  • the mean particle size of the particles obtained by this method and the polydispersity are indicated in Table 1 below.
  • Example 7 The method was repeated in the same manner as in Example 1, except that PLA was used, instead of Eudragit E.
  • the mean particle size of the particles obtained by this method and the polydispersity are indicated in Table 1 below.
  • 2-butanone and water were mutually saturated for 1 min before use, in order to ensure initial thermodynamic equilibrium of both liquids.
  • 4 g of CAP were dissolved in 40 ml of water-saturated 2-butanone and this organic solution (internal phase) was emulsified at room temperature with 80 ml of a 5 % w/v poloxamer 407 2- butanone saturated aqueous solution (external phase) , using a propeller (Heidolph-Elektro, KG type E-60, propeller : IKA 1381, Germany) at 1500 rpm for ten minutes.
  • a propeller Heidolph-Elektro, KG type E-60, propeller : IKA 1381, Germany
  • the oil-in- water emulsion formed was subjected to vacuum distillation at 35°C and 60 mmHg until complete solvent evaporation. Generally, the solvent was recovered and used to prepare new batches.
  • the mean particle size of the particles obtained by this method as well as the polydispersity are indicated in Table 1 below.
  • Example 7 The method was repeated in the same manner as in Example 7, except that 1.25 % w/v of poloxamer 407 was used, instead of 5.00 % w/v of poloxamer 407.
  • the mean particle size of the particles obtained by this method as well as the polydispersity are indicated in Table 1 below.
  • Example 7 The method was repeated in the same manner as in Example 7, except that 8 g of CAP was used, instead of 4 g of CAP.
  • the mean particle size of the particles obtained by this method as well as the polydispersity are indicated in Table 1 below.
  • Example 7 The method was repeated in the same manner as in Example 7, except that 12 g of CAP was used, instead of 4 g of CAP.
  • the mean particle size of the particles obtained by this method as well as the polydispersity are indicated in Table 1 below.
  • Example 11 The method was repeated in the same manner as in Example 7, except that CAT was used, instead of CAP.
  • the mean size of the particles obtained by this method as well as the polydispersity are indicated in Table 1 below.
  • Ethyl acetate and water were mutually saturated for 1 min before use, in order to ensure initial thermodynamic equilibrium of both liquids.
  • 4 g of Eudragit E were dissolved in 40 ml of water-saturated ethyl acetate and this organic solution (internal phase) was emulsified at room temperature with 100 ml of a 80 : 20 v/v water- ethanol mixture containing 0.21 % w/v of poloxamer 407 (external phase) , using a propeller stirrer (Heidolph- Elektro, KG type E-60, propeller : IKA 1381, Germany) at 1500 rpm for ten minutes.
  • a propeller stirrer Heidolph- Elektro, KG type E-60, propeller : IKA 1381, Germany
  • the oil-in-water emulsion formed was subjected to vacuum distillation at 35°C and 60 mmHg until complete solvent evaporation. Generally, the solvent was recovered and used to prepare new batches.
  • the mean particle size of the particles obtained by this method as well as the polydispersity are indicated in Table 1 below.
  • the oil-in-water emulsion formed was subjected to vacuum distillation at 35°C and 60 mmHg until complete solvent evaporation. Generally, the solvent was recovered and used to prepare new batches.
  • the mean particle size of the particles obtained by this method as well as the polydispersity are indicated in Table 1 below.
  • Example 14 The method was repeated in the same manner as in Example 14, except that propeller stirrer was used at 1500 rpm instead of 2000 rpm.
  • the mean particle size of the particles obtained by this method as well as the polydispersity are indicated in Table 1 below.
  • Example 17 The method was repeated in the same manner as in Example 14, except that 6 g of Eudragit E was used, instead of 4 g of Eudragit.
  • the mean particle size of the particles obtained by this method as well as the polydispersity are indicated in Table 1 below.
  • Example 14 The method was repeated in the same manner as in Example 14, except that 8 g of Eudragit E was used, instead of 4 g of Eudragit.
  • the mean particle size of the particles obtained by this method as well as the polydispersity are indicated in Table 1 below.
  • Example 18 The method was repeated in the same manner as in Example 18, except that Eudragit RL was used, instead of Eudragit RS.
  • the mean particle size of the particles obtained by this method as well as the polydispersity are indicated in Table 1 below.
  • the method of the present invention thus makes it possible to prepare aqueous colloidal dispersions containing high concentration of nanoparticles of water-insoluble material, for example pseudolatexes, from a conventional oil-in-water emulsion with an ordinary mechanical stirring without requiring homogenization, without requiring dilution with water, with or without stabilizing agent, by direct displacement of a partially water-soluble solvent during distillation. Further, the dispersion obtained by the method of the present invention may be used directly for coatings without additional treatments.

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Abstract

L'invention concerne une méthode de production de dispersions colloïdales aqueuses de nanoparticules. La méthode consiste à émulsionner, dans une première étape, un solvant organique partiellement soluble dans l'eau, qui contient un polymère insoluble dans l'eau, selon un certain pourcentage poids/volume permettant d'obtenir les nanoparticules dans une seconde étape, dans une solution aqueuse contenant éventuellement un agent stabilisant, au moyen d'une faible source d'énergie, et, dans une seconde étape, à distiller le solvant organique depuis l'émulsion de type huile dans l'eau obtenue à la première étape, afin de provoquer la production de nanoparticules en suspension dans la phase aqueuse.
PCT/EP1999/004677 1999-07-06 1999-07-06 Methode de production de dispersions colloidales aqueuses de nanoparticules WO2001002087A1 (fr)

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AU51567/99A AU5156799A (en) 1999-07-06 1999-07-06 Method for producing aqueous colloidal dispersions of nanoparticles
PCT/EP1999/004677 WO2001002087A1 (fr) 1999-07-06 1999-07-06 Methode de production de dispersions colloidales aqueuses de nanoparticules

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Cited By (5)

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Publication number Priority date Publication date Assignee Title
EP2109443A1 (fr) * 2007-02-09 2009-10-21 AstraZeneca AB Procédé de préparation d'une dispersion stable de particules submicroniques amorphes solides dans un milieu aqueux
EP2407150A1 (fr) * 2010-07-16 2012-01-18 Justus-Liebig-Universität Gießen Nano- et microparticules polymèriques pour maintenir la tension de surface dans les poumons et pour la protection de les tensioactifs pulmonaire
WO2012059936A1 (fr) 2010-11-03 2012-05-10 Padma Venkitachalam Devarajan Compositions pharmaceutiques destinées à l'administration de médicaments colloïdaux
WO2012107694A1 (fr) * 2011-02-10 2012-08-16 Alpol Cosmetique Microparticules cationiques et utilisation dans le domaine des cosmeto - textiles
WO2021083989A1 (fr) 2019-10-31 2021-05-06 Evonik Operations Gmbh Procédé de préparation de nano ou microparticules comprenant un polymère porteur et un ou plusieurs principes biologiquement actifs

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US5766635A (en) * 1991-06-28 1998-06-16 Rhone-Poulenc Rorer S.A. Process for preparing nanoparticles
WO1999033558A1 (fr) * 1997-12-29 1999-07-08 Universite De Geneve Procede servant a preparer une dispersion colloidale aqueuse de nanoparticules

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EP0275796A1 (fr) * 1986-12-31 1988-07-27 Centre National De La Recherche Scientifique Procédé de préparation de systèmes colloidaux dispersibles d'une substance, sous forme du nanoparticules
US5766635A (en) * 1991-06-28 1998-06-16 Rhone-Poulenc Rorer S.A. Process for preparing nanoparticles
WO1999033558A1 (fr) * 1997-12-29 1999-07-08 Universite De Geneve Procede servant a preparer une dispersion colloidale aqueuse de nanoparticules

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LEROUW J -C ET AL: "NEW APPROACH FOR THE PREPARATION OF NANOPARTICLES BY AN EMULSIFICATION-DIFFUSION METHOD", EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS,NL,ELSEVIER SCIENCE PUBLISHERS B.V., AMSTERDAM, vol. 41, no. 1, 1 January 1995 (1995-01-01), pages 14 - 18, XP000482886, ISSN: 0939-6411 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2109443A1 (fr) * 2007-02-09 2009-10-21 AstraZeneca AB Procédé de préparation d'une dispersion stable de particules submicroniques amorphes solides dans un milieu aqueux
EP2109443A4 (fr) * 2007-02-09 2012-08-22 Astrazeneca Ab Procédé de préparation d'une dispersion stable de particules submicroniques amorphes solides dans un milieu aqueux
EP2407150A1 (fr) * 2010-07-16 2012-01-18 Justus-Liebig-Universität Gießen Nano- et microparticules polymèriques pour maintenir la tension de surface dans les poumons et pour la protection de les tensioactifs pulmonaire
WO2012010159A1 (fr) * 2010-07-16 2012-01-26 Justus-Liebig-Universität Giessen Nano-, méso- et microparticules polymères biodégradables pour le maintien d'une tension superficielle réduite dans le poumon et pour la protection de l'agent tensio-actif pulmonaire
US20130149535A1 (en) * 2010-07-16 2013-06-13 Justus-Liebig-Universitat Giessen Biodegradable nano-, meso-, and micro-polymer particles for maintaining a low surface tension in the lung and for protecting the pulmonary surfactant
JP2013545717A (ja) * 2010-07-16 2013-12-26 ユストゥス−リービッヒ−ウニヴェルジテート・ギーセン 肺の表面張力を低く維持し、肺サーファクタントを保護するための生分解性ナノ、メソ及びマイクロポリマー粒子
WO2012059936A1 (fr) 2010-11-03 2012-05-10 Padma Venkitachalam Devarajan Compositions pharmaceutiques destinées à l'administration de médicaments colloïdaux
WO2012107694A1 (fr) * 2011-02-10 2012-08-16 Alpol Cosmetique Microparticules cationiques et utilisation dans le domaine des cosmeto - textiles
FR2971437A1 (fr) * 2011-02-10 2012-08-17 Alpol Cosmetique Nouvelles microparticules cationiques et utilisation dans le domaine des cosmetotextiles
WO2021083989A1 (fr) 2019-10-31 2021-05-06 Evonik Operations Gmbh Procédé de préparation de nano ou microparticules comprenant un polymère porteur et un ou plusieurs principes biologiquement actifs
US11819576B2 (en) 2019-10-31 2023-11-21 Evonik Operations Gmbh Process for preparing nano-or microparticles comprising a carrier-polymer and one or more biologically active ingredients

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