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WO2000056439A1 - Procede de preparation de particles - Google Patents

Procede de preparation de particles Download PDF

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Publication number
WO2000056439A1
WO2000056439A1 PCT/SE2000/000566 SE0000566W WO0056439A1 WO 2000056439 A1 WO2000056439 A1 WO 2000056439A1 SE 0000566 W SE0000566 W SE 0000566W WO 0056439 A1 WO0056439 A1 WO 0056439A1
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WO
WIPO (PCT)
Prior art keywords
scf
particles
substance
liquid
supercritical fluid
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PCT/SE2000/000566
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English (en)
Inventor
Johan Carlfors
Raouf Ghaderi
Original Assignee
Johan Carlfors
Raouf Ghaderi
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 Johan Carlfors, Raouf Ghaderi filed Critical Johan Carlfors
Priority to AU41578/00A priority Critical patent/AU4157800A/en
Publication of WO2000056439A1 publication Critical patent/WO2000056439A1/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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)

Definitions

  • This invention relates to the preparation of particles and, more specifically, to a new method for the preparation and an apparatus therefor.
  • the invention also relates to particles prepared by the method and their use in different areas.
  • particles have been prepared by milling of solids or by crystallisation from solutions.
  • the solution properties of supercritical fluids to a great extent are dependent on pressure and temperature, these properties can easily be controlled and varied. This means possibilities to precipitate/crystallise a substance with different properties as to size, form, and morphology. Furthermore, the supercritical fluid may specifically extract impurities in the substance.
  • the method is a continuous process with possibilities to recover solvents and to recycle the supercritical medium. Consequently, the process is well suited for industrial production.
  • environmentally acceptable gases can be used e g carbon dioxide.
  • Other suitable gases are nitric oxide, sulphur hexafluoride, ethylene, ethane etc. ⁇ im , until n PCT/SE00 0
  • a solution or dispersion is introduced with the actual substance(s), denoted “substance liquid” below, into the superc ⁇ tical medium, wherein the substance(s) is/are precipitated, on one hand, as a consequence of decreased solubility properties and, on the other hand, in consequence of extraction of the solvent of the substance liquid by the supercritical fluid, a so called “gas anti-solvent technique".
  • the method exists in different technical designs.
  • One example is the introduction of the substance liquid into the supercritical fluid via dispersion, atomisation of the solution in a spray nozzle, whereupon the dissolved substance(s) is/are precipitated in the form of particles upon contact with the supercritical fluid.
  • the dispersion via the spray nozzle is achieved in different ways.
  • One way is to apply a pressure gradient over the nozzle, the opening diameter of which is small (J. Bleich et al, International Journal of Pharmaceutics, 97 (1993) 111-117; Yeo et al, Biotechnology and Bioengineering, Vol. 41, 341-346 (1993).
  • Another way is to atomise the drops with ultrasound.
  • the substance liquid is either sprayed into a container already filled with SCF or in a continuous process, wherein SCF is continuously introduced into the container via a separate channel.
  • the continuous process has a higher production yield.
  • Another continuous process is to use a coaxial nozzle, wherein the substance liquid is introduced into a channel, whereas the supercritical fluid is introduced into the other channel and, thereby, facilitates the dispersion of the substance liquid.
  • SEDS method the particles are directly formed during the dispersion, because the supercritical fluid is introduced simultaneously with the substance liquid.
  • the supercritical fluid US-5.851,453, Mazen et al
  • This method means better possibilities to control particle properties such as particle size and form, as the dispersion is dependent on the flow rate of the two liquids, and the design of the spray nozzle itself.
  • a problem with this technical design of the spray nozzle is that the particle formation process is already initiated in the nozzle itself, as the substance liquid is brought in contact with the supercritical fluid. This means, for some substances, that the precipitation thereof begins before the dispersion of the liquid. In some cases, no particles at all are thereby obtained and, in other cases, particles are obtained but with relatively large diameters.
  • Another problem with this process is that the premature precipitation of substance sometimes is localised to the inner walls of the spray nozzle. This leads to a time dependent change of the inner diameter of the nozzle during the process. As a result, the particle size distribution of the final product thereby will be broadened leading to a less well-defined product. In some cases, the precipitation in the spray nozzle can lead to a total blockage thereof.
  • WO 9836825 Al (Bradford Particle Design Ltd.) relates to a method and apparatus for the formation of particles using a solution or suspension of a substance in a liquid and a first and a second supercritical fluid, respectively.
  • both supercritical fluids are introduced simultaneously in the same fluid inlet assembly.
  • many types of particles e.g. amorphous particles are difficult to prepare by such a process.
  • a solution to this problem is to add the first supercritical fluid in order to disperse a substance liquid and then, in a separate step, to add the second supercritical fluid order to extract the liquid carrier medium.
  • the invention constitutes an improvement in preparing many kinds of particles, especially particles of amorphous substances such as the particles composed of amorphous polymers prepared by the invention.
  • the substance liquid is sprayed through a suitably designed nozzle e g a coaxial spray nozzle together with a supercritical fluid, SCF-D (D stands for dispersion) characterised in that it has a veiy low extraction capacity with regard to the solvent for the substance solution.
  • SCF-D should lack interactions with the solution.
  • This SCF-D should be chosen in order to have minimal interactions with the substance liquid. SCF-D is only added in the potpose of increasing the dispersion of the substance liquid that later on, via the spray nozzle is sprayed into the reaction container in the form of drops.
  • the particle formation process starts through extraction of the solvent and a reduced solubility of the particle forming substance.
  • the particle fo ⁇ ning process takes place through the addition of another supercritical fluid, SCF-E (E stands for extraction) via a separate addition channel to the reaction container.
  • SCF-E is characterised in that it has a high extraction capacity with regard to the solvent or dispersing agent of the substance liquid.
  • One object of the invention is a method for the preparation of particles comprising the following steps:
  • the dispersion takes place in a nozzle spraying the dispersed mixture into a reaction vessel, the pressure and temperature of which is controlled leading to a supercritical state in the reaction vessel.
  • the extraction takes place inside the reaction vessel.
  • the supercritical medium with extracted solvent is removed continuously from the reaction vessel via an outlet system being particularly designed according to the invention in order to promote and support the extraction capacity in the process.
  • the process is continuous and, accordingly, well suited for production of large batches.
  • the two supercritical fluids have to been chosen starting from the criterion that the mixture of the liquids formed in the reaction vessel must exist in a supercritical state in order to ensure the extraction capacity of the supercritical fluids.
  • This can be achieved with a SCF-D having lower critical parameters than those of SCF-E.
  • One example is to use N 2 as SCF-D and C0 2 as SCF-E.
  • the use of a supercritical fluid, SCF-D, according to the invention mstead of compressed gases in order to disperse the liquid is advantageous, since it results in a well preserved extraction capacity of the supercritical medium, together with the prevention of a too early piecipitation of substance m the nozzle
  • Those substances that can be used m order to prepaie particles according to the invention can be of veiy diffeient kinds
  • One example is polymeis, amoiphous, semi-crystallme or crystalline, oiganic substances, and morgamc substances such as metals, oxides, ceramics, salts, or mixtures of these
  • solvents and dispersion media are suitable, or mixtures of two or more solvents and dispeising agents, suitably with a low toxicity
  • Some non-limiting examples are water, lowei ketones such as acetone, lower hydrocarbons such as hexane, lower alcohols such as methanol, ethanol, isopropanol, ethyl acetate, oi mixtures theieof Even chloimated hydiocaibons can be used but they are not prefe ⁇ ed because of then toxicity
  • the substance(s) is/are synthetical or natural polymers, solid organic substances, solid inorganic substances, salts, biomolecules such as piotems e g enzymes
  • the substance(s) ls/aie piefeiabfy bioactive foi thei Collaborationic use
  • Anothei object of the invention is an apparatus for the preparation of particles, comprising
  • a means 18, 2 in order to delivei to the apparatus a substance liquid comprising a) at least one substance of which the particles aie to be piepaied, and b) a liquid earner medium for the substance, a dispersing means 17 for the dispersion of the substance liquid and for the feeding of the dispersed substance liquid to the particle formation reactor 2,
  • a first feeding means 22, 17 for the feeding of a first supercritical fluid (SCF-D), with a minimal extraction capacity for the liquid carrier medium, to the dispersing means, and
  • SCF-D supercritical fluid
  • the dispersing means comprises a nozzle with separate channels foi the substance liquid and the fiist supercritical fluid (SCF-D), respectively It is prefe ⁇ ed that the delivery channels are designed as a coaxial spray nozzle It is also piefe ⁇ ed that the appaiatus comprises a fust outlet channel placed m the upper part of the reaction vessel and a second outlet channel placed in the lower part of the reaction vessel, in particulai wheiem the outlet channels are provided with filters
  • reaction vessel is a high piessure chamber and is provided with a thermostat and a piessme legulatoi
  • Another object of the invention is particles prepared by the method as described above, comprising one or more pure or mixed substances.
  • the particles comprise one or more substances incoiporated in one or several other substances.
  • the particles comprise substances having activity as pharmaceuticals.
  • Fig. 1 is a survey view of an apparatus according to the invention
  • Fig. 2 is a SEM photograph of DL-PLG particles prepared by the method according to the invention.
  • Fig. 3 is a SEM photograph of DL-PLA particles prepared by the method according to the invention.
  • Fig. 4 is a SEM photograph of L-PLA particles prepared by the method according to the invention.
  • Fig. 5 is a SEM photograph of DL-PLG particles with incoiporated hydrocortisone, prepared by the method according to the invention
  • Fig 6 is a SEM photograph of lysozyme particles prepared by the method according to the invention
  • Fig 7 is a SEM photograph of hydrocortisone particles prepared by the method accoidmg to the invention.
  • Fig 8 is a SEM photograph of DL-PLG particles with incoiporated uiease, prepaied by the method according to the invention
  • the mam pimciple for the piepaiation of particles fiom chemical substances comprises the dispersion of a substance liquid m a reaction vessel in thedepositednce of a supeicntical fluid
  • the mechanism foi the formation of particles is that the substance liquid is dispersed m the form of dioplets being induced by the simultaneous introduction of SCF-D into the vessel e g through a coaxial spray nozzle
  • the nozzle design accoidmg to the invention can vaiy but includes all nozzles designed in a mannei that SCF-D is introduced into the leaction vessel togethei with the substance liquid which lesults in the SCF-D flow lmpiovmg the substance liquid dispersion
  • the mnei diameteis of the openings foi the channels, through which SCF-D and the substance liquid
  • SCF-E is introduced into the reaction vessel through a separate introduction channel.
  • the SCF-E flow should be adapted with regard to the volume of the reaction chamber and with regard to the substance liquid flow with the intention to achieve an adequate high capacity for the extraction process.
  • the particles formed are accumulated in the reaction vessel during the continuous process, whereas the supercritical medium containing extracted solvent or dispersing agent is removed through outlet channels provided with filters. These are designed in order to ensure that enough SCF-E is being maintained in the reaction vessel compared to SCF-D which makes the extraction capacity during the process as efficient as possible. Thereby, the process becomes continuous. After a finished process, the reaction vessel is opened and the product is collected.
  • the invention comprises a method according to a new principle for the preparation of particles and an apparatus for the preparation of particles.
  • One embodiment of an apparatus is shown in Fig. 1. In this context it should be noted that this is only one of several possible designs of the principle comprised by the invention.
  • an apparatus comprises a reactor or a reaction vessel 2, wherein the particle formation takes place.
  • the reactor is accommodated in an oven 4 with a temperature control unit in order to make temperature control and regulation possible inside the reactor.
  • the supercritical fluid is obtained from a suitable gas being stored in a gas bottle 8 placed outside the surrounding oven.
  • the gas from the bottle is cooled in a cooler 10 and is fed to the reactor by means of a high-pressure pump 12 via a heat exchanger 14 and a pulse damper 16.
  • the pump 12 and the heat exchanger 14 are mn in order to transfer the gas to a supercritical state.
  • the oven 4 is then run and regulated in order to maintain this supercritical state during the operation of the apparatus.
  • the apparatus is also provided with a coaxial dispersing nozzle 17.
  • nozzles are well known per se and mainly comprise an inner and an outer channel surrounding the inner channel.
  • a substance liquid is fed through the inner channel from a storage bunker 18 situated outside the apparatus.
  • a supercritical fluid (SCF-D) is fed.
  • This supercritical fluid is kept in a gas bottle 20 placed outside the apparatus. It is possible to feed the substance liquid in the outer channel and to deliver the supercritical fluid through the inner channel but this is not as advantageous, because the dispersion becomes better the smaller diameter of the channel for the substance liquid.
  • There could also be more than one channel for the substance liquid if one desires to deliver different liquids containing different substances.
  • the apparatus is run in the following manner:
  • SCF-E C0 2
  • SCF-E is fed from the gas bottle 8 to the refrigerating machine 10 in order to be cooled to a liquid state. After that, it is fed to the high-pressure pump 12. It is pumped further with a constant flow from the high-pressure pump to the reaction vessel 2 via the heat exchanger 14 and the pulse damper 16.
  • SCF-D is fed from the vessel 20 via a thin needle valve that gives a constant SCF-D flow to the heat exchanger 24 and is, after that, fed to the coaxial nozzle 17, optionally via a pulse damper 19.
  • the substance liquid is fed from the vessel 18 via the high-pressure pump 21 through the inner channel of the coaxial nozzle 17.
  • SCF-D disperses the substance liquid by pressing it through the nozzle opening inside the high-pressure vessel 2.
  • the supercritical medium leaves the high-pressure vessel via two openings 26, 28 provided with filters placed in the upper and the lower part of the high- pressure vessel 2, respectively.
  • the orifices then converge to the outlet channel 30 and the medium is fed to the back pressure regulator 32.
  • the coaxial nozzle opening may vary from 0.02 to 2 mm.
  • the pressure difference between the SCF-D vessel 20 and the pressure vessel 2 is at least 5 bars and preferably higher.
  • the SCF-D flow is sufficiently high in order to achieve a sufficient dispersion of the substance liquid in the chosen nozzle, preferably at least 2 standard litres per minute (in a supercritical state).
  • the SCF-E (C0 2 ) flow in a liquid state should be high enough in order to achieve a sufficient extraction capacity in the chosen pressure vessel, preferably at least 10 ml per minute.
  • the liquid flow rate of the substance liquid should be sufficiently low in order to ensure a sufficient high solvent extraction to produce well-defined particles. This flow rate is dependent on the properties of the dissolved substance, the solvent, the extraction properties of the supercritical medium and the volume of the reaction vessel.
  • the mutual relationships between the three liquid flows, the volume of the reaction vessel, and the opening diameters of the inlet orifices are optimised to give particles with desired properties.
  • the reaction chamber is a thermostat-controllable high-pressure vessel, the volume of which is sufficiently big to give a sufficient extraction capacity.
  • the temperature is controlled in order to give a suitable temperature above or below the critical point.
  • the reaction vessel pressure may be kept constant and may be controlled with a back pressure regulator.
  • the term "supercritical fluid” refers to the phase state (supercritical state) that exists when a liquid is subjected to pressures and temperatures above the critical point; b) the term “critical point” regarding the temperature i e critical temperature refers to that temperature above which a gas cannot be liquefied by pressure alone.
  • the pressure under which a substance may exist as a gas in equilibrium with the liquid at the critical temperature is the critical pressure.
  • the critical temperatures and pressures of many compounds can e.g.
  • the term “extraction capacity” refers to the ability of an extraction medium to dissolve another substance or liquid; d) the term “lower critical parameters” refers to lower critical temperature and lower critical pressure; e) the term “substance liquid” referes to a liquid comprising a solution or a dispersion containing one or more substances of which one desires to prepare particles dissolved or dispersed in a solvent or a dispersing agent, or in a mixture of two or more solvents or dispersing agents; f) the term “compressed gas” refers to a gas brought to a lower volume and higher pressure than it otherwise would have at the same temperature; g) the term “SEM photograph” refers to a scanning electron microscope photograph; h) the term “s.d.” refers to standard deviation; i) the prefix "L” of a compound (such as L-PLA) refers to a stereoisomer i
  • DL-PLG is poly-DL-lactic glycolic acid
  • DL-PLA is poly-DL-lactic acid
  • L- PLA is poly-L-lactic acid.
  • They are all biodegradable polyesters, DL-PLG and DL- PLA being copolymers and L-PLA being a homopolymer.
  • DL-PLG, DL-PLN and L-PLA were purchased from Birmingham Polymers Inc., USA. Lysozyme from chicken egg white, hydrocortisone, and urease were purchased from Sigma, USA.
  • Particles were prepared from the polymer DL-PLG (50:50) that is amorphous.
  • a 2.3% (w/v) solution of the polymer in a mixture of organic solvents acetone: ethyl acetate: isopropanol, volume fraction 4:5.6:0.4
  • C0 2 was used as SCF-E.
  • the polymer solution flow was 0.13 ml per minute and the SCF-D flow was 12 litres per minute (in a supercritical state).
  • the SCL-E flow was 21 ml per minute (in a liquid state).
  • the chosen nozzle opening was 0.2 mm.
  • the pressure was 130 and 160 bars, respectively, and the temperature was 38°C and was kept constant during the process.
  • the particles were discrete and had an almost spherical form (Figure 2).
  • the particle size distributions were relatively narrow (Table I).
  • Particles were prepared from the polymer DL-PLA that is semi-crystalline.
  • a 2.3% (w/v) solution of the polymer in a mixture of organic solvents (acetone: ethyl acetate: hexane, volume fraction 1 :7.8: 1.2) has been dispersed by means of N 2 as SCF-D.
  • C0 2 was used as SCF-E.
  • the polymer solution flow was 0.15 ml per minute and the SCF-D flow was 12 litres per minute (in a supercritical state).
  • the SCF-E flow was 21 ml per minute (in a liquid state).
  • the chosen nozzle opening was 0.2 mm.
  • the pressure was 130 and 160 bars, respectively, and the temperature was 35°C and was kept constant during the process.
  • the particles were discrete and had an almost spherical form (Figure 3).
  • the mean particle size was approximately 10 ⁇ m that was independent of the pressure (Table
  • Particles were prepared from the crystalline polymer L-PLA.
  • a 2.3% (w/v) solution of the polymer in a mixture of organic solvents (methylene chloride: acetone: isopropanol, volume fraction 3.3:6.5:0.2) has been dispersed by means of N 2 as SCF-D.
  • C0 2 was used as SCF-E.
  • the polymer solution flow was 0.15 ml per minute and the SCF-D flow was 12 litres per minute (in a supercritical state).
  • the SCF-E flow was 21 ml per minute (in a liquid state).
  • the chosen nozzle opening was 0.2 mm.
  • the pressure was 130 and 160 bars, respectively, and the temperature was 40°C and was kept constant during the process.
  • the particles were discrete and had an almost spherical form (Figure 4).
  • the mean particle size was approximately 7 ⁇ m that was independent of the pressure (Table
  • Table I The particle size distribution from particles prepared by the method according to the invention
  • the invention has also been shown to be useful in incorporation of active substances (medical or chemical ones) in another substance.
  • particles prepared from DL-PLG (50:50) with incoiporated hydrocortisone are particles prepared from DL-PLG (50:50) with incoiporated hydrocortisone.
  • a 2.3% (w/v) polymer and 0.12 % (w/v) hydrocortisone solution in a mixture of organic solvents (acetone: ethyl acetate: isopropanol, volume fraction 4.15: 4.85: 1.0) has been dispersed by means of ⁇ 2 as SCF-D.
  • C0 2 was used as SCF-E.
  • the polymer solution flow was 0.15 ml per minute and the SCF-D flow was 12 litres per minute (in a supercritical state).
  • the SCF-E flow was 21 ml per minute (in a liquid state).
  • the chosen nozzle opening was 0.2 mm.
  • the pressure was
  • the particles were discrete and the mean particle size was approximately 9 ⁇ m (Figure 5). 51 % of the added amount of hydrocortisone was incoiporated in the polymer particles (Table II). Table II: volumetric particle size distribution and the relative amount of incorporated hydrocortisone (he) and urease (u) in regard of the added amount of the two substances for DL-PLG particles.
  • the standard error within parentheses is based on measurements from three batches.
  • the entrapment efficiency, EE is the fraction of the substance which was incorporated of the added amount of substance to the process.
  • Lysozyme microparticles were prepared by dispersion of lysozyme in a mixture of 0.001 M HC1 and ethanol (volume fraction 9.1 :0.9) in supercritical C0 2 as SCF-E by using N 2 as SCL-D.
  • the lysozyme concentration was 14.6% (w/w).
  • the protein solution flow rate was 0.02 ml per minute, with a N 2 and C0 2 flow rate of 8 standard litres per minute (in a supercritical state) and 21 ml per minute (in a liquid state), respectively.
  • the process pressure was 155 bars and the process temperature was 40°C.
  • the nozzle orifice was 0.2 mm.
  • the lysozyme particles obtained were discrete and had a volumetric particle size from 1 to 5 ⁇ m (see Fig. 6).
  • Hydrocortisone was dissolved in a mixture of acetone and ethanol (7.5:2.5). The hydrocortisone concentration was 12.8% (w/w). The solution was dispersed in supercritical C0 2 as SCF-E by using N 2 as SCF-D. The flow rate of the hydrocortisone solution, N 2 , and C0 2 was 0.152 ml per minute, 12 standard litres per minute (in a supercritical state), and 21 ml per minute (in a liquid state), respectively. The process pressure was 130 bars and the process temperature was 40°C. The nozzle orifice was 0.2 mm.
  • the hydrocortisone particles obtained were a mixture of discrete irregular and needle-shaped particles with a particle size from 1 to 5 ⁇ m (see Fig. 7).
  • the invention has also been shown to be useful in incorporation of active substances (medical or chemical ones) in another substance.
  • particles prepared from DL-PLG (50:50) with incoiporated urease A 2.3% (w/v) polymer and a 0.12% (w/v) urease solution in a mixture of organic solvents (acetone: ethyl acetate: isopropanol, volume fraction 4.15: 4.85: 1.0) and water respectively were codispersed by means of N 2 as SCF-D.
  • C0 2 was used as SCF-E.
  • the polymer solution flow was 0.15 ml per minute and the SCF-D flow was 12 litres per minute (in a supercritical state).
  • the SCF-E flow was 21 ml per minute (in a liquid state).
  • the chosen nozzle opening was 0.2 mm.
  • the pressure was 160 bars and the temperature was 38°C and was kept constant during the process.
  • the particles were discrete and spherical.
  • the mean particle size was 6 ⁇ m ( Figure 8). 46% of the added amount of urease was incoiporated in the polymer particles (Table II). Furthermore, 60% of the urease was released, in vitro, from the microparticles during one month. The enzymatic activity of the released urease from the microparticles was 82 ⁇ 4 (s.d.) %.

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Abstract

L'invention concerne un procédé de préparation de particles. Ce procédé comporte les étapes suivantes: - dispersion, par un premier fluide supercritique (SCF-D), d'une substance liquide contenant au moins un mélange composé d'une substance, de laquelle on prépare des particules, et d'un agent support liquide ; - extraction consécutive à la dispersion de la substance liquide, de l'agent support liquide par un autre fluide supercritique (SCF-E). Un appareil selon l'invention comprend un réacteur à formation de particules (2) dont la pression et la temperature peuvent être commandées, un moyen (18, 21) permettant la délivrance d'une substance liquide; un moyen d'alimentation (22, 17; 12, 6) destiné à deux fluides supercritiques (SCF-D, SCF-E) différents; une buse (17) destinée à la dispersion de la substance liquide et à l'alimentation du réacteur à formation de particules (2) en substance liquide dispersée.
PCT/SE2000/000566 1999-03-22 2000-03-22 Procede de preparation de particles WO2000056439A1 (fr)

Priority Applications (1)

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AU41578/00A AU4157800A (en) 1999-03-22 2000-03-22 Method for the preparation of particles

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SE9901059A SE9901059L (sv) 1999-03-22 1999-03-22 Metod för framställning av partiklar
SE9901059-7 1999-03-22

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003008082A1 (fr) * 2001-07-20 2003-01-30 Nektar Therapeutics Uk Limited Procede et appareil de preparation de particules
WO2005049192A1 (fr) * 2003-10-30 2005-06-02 Laboratoires Serono S.A. Procede et dispositif destines a refroidir et pulveriser des substances liquides ou pateuses
RU2296002C2 (ru) * 2001-02-26 2007-03-27 ДОМПЕ ФА.Р.МА С.п.А. Способ получения микронных и субмикронных частиц и предназначенное для этого устройство

Citations (4)

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Publication number Priority date Publication date Assignee Title
EP0125690A2 (fr) * 1983-05-16 1984-11-21 Union Camp Corporation Fractionnement d'acides gras polymérisés
JPH078202A (ja) * 1993-06-29 1995-01-13 Lion Corp 香辛料抽出物の製造方法
WO1996000610A1 (fr) * 1994-06-30 1996-01-11 University Of Bradford Procede et dispositif de formation de particules
WO1998036825A1 (fr) * 1997-02-21 1998-08-27 Bradford Particle Design Ltd. Procede et appareil pour la formation de particules

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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