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
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2095—Tabletting processes
• • 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
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
• • 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
  • A61K9/1682—Processes
  • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• • 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
  • C08J9/00—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof
  • C08J9/04—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof using blowing gases generated by a previously added blowing agent
  • C08J9/12—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof using blowing gases generated by a previously added blowing agent by a physical blowing agent
  • C08J9/122—Hydrogen, oxygen, CO2, nitrogen or noble gases
• • 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
  • C08J2201/00—Foams characterised by the foaming process
  • C08J2201/02—Foams characterised by the foaming process characterised by mechanical pre- or post-treatments
  • C08J2201/03—Extrusion of the foamable blend
• • 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
  • C08J2203/00—Foams characterized by the expanding agent
  • C08J2203/08—Supercritical fluid
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids

Definitions

• the present invention relates to a method for manufacturing a composite material comprising solid dispersions of a substance, in particular a pharmaceutical active ingredient, in a polymer matrix.
• the invention also makes it possible to control the porosity of the solid dispersions thus obtained.
• the present invention solves the difficulties explained above by allowing the manufacture of a material comprising solid dispersions of a substance, in particular a pharmaceutical active ingredient, in a polymer matrix, with a control of the porosity of the final material.
• the method which is the subject of the present invention is based on an extrusion process completed by the use of a supercritical fluid (FSC).
• FSC supercritical fluid
• the invention relates to a method for producing a composite material comprising solid dispersions of an active substance in a polymer matrix, the process comprising the following steps:
• the step of introducing the polymer matrix into an extruder the step of operating the extruder so as to modify the rheological properties of the polymer matrix
• the order of realization of these steps does not necessarily correspond to the order of the enumeration above.
• the supercritical fluid used is CO 2 carbon dioxide.
• the active substance used is a pharmaceutical active ingredient.
• the active substance and the polymer matrix are introduced together into the extruder, in particular via a hopper.
• the step of operating the extruder to modify rheological properties of the polymer matrix comprises the step of dispersing the active substance in the polymer matrix.
• the active substance and the supercritical fluid are introduced together into the extruder, in particular via the injection nozzle.
• the active substance is dissolved or dispersed in the supercritical fluid, the resulting mixture being then injected into the extruder.
• the supercritical fluid is dissolved in the active substance, the resulting mixture being then injected into the extruder.
• the dissolution of the supercritical fluid in the active substance is carried out in an autoclave container prior to injection of the mixture into the extruder.
• an emulsion of two liquid phases is produced, these two phases being obtained by mutual dissolution of the active substance and the supercritical fluid one in the other.
• obtaining the two liquid phases comprises the step of continuously supplying an autoclave container simultaneously with supercritical fluid and with active substance.
• the porosity of the solid dispersions obtained, in particular their size and their density is controlled according to the operating conditions.
• the operating conditions for controlling the porosity of the solid dispersions comprise at least one of the following parameters: temperature in the extruder; o pressure in the extruder; o injection rate of the supercritical fluid in the extruder.
• the invention also relates to a material, in particular a composite material, obtained by implementing the method defined above.
• Extrusion is a process of converting a raw material into a product of uniform shape and density by passing it through a restriction under controlled conditions.
• the transport is obtained by at least one rotating screw inside a fixed sleeve and the pressure generated by the screw pushes the material through the restriction, called die.
• a supercritical fluid is a fluid brought to a pressure and temperature beyond that of its critical point.
• Such a fluid has properties intermediate between those of gases and liquids, with in particular a density close to that of a liquid and a viscosity close to that of a gas.
• the most commonly used is carbon dioxide CO2. It has the advantages of being nontoxic, natural, gaseous under atmospheric conditions and having low critical coordinates of 7.4 MPa and 304 K, making it an ideal fluid for food and pharmaceutical applications.
• Supercritical carbon dioxide (CO2 SC) has already been widely used in the implementation of polymers. Its specific properties allow it to solubilize strongly and quickly in polymers. These high solubilities in particular cause the plasticization and swelling of the materials, with a modification of the mechanical and physical properties. Thus, CO2 lowers the temperature of glass transition, Tg, and the viscosity of many polymers without changing its viscoelastic behavior. For example, in the case of polystyrene, a Tg at 105 ° C. is lowered to 98 ° C. with a mass fraction of CO2 equal to 1% and at 46.4 ° C. with 5.9%.
• the surface tension ⁇ of polymers also decreases with the presence of FSC. For polystyrene at 200 ° C., this surface tension decreases linearly from 28 to 17 mJ.m-2 over a CO 2 pressure range of 1 to 10 MPa.
• CO 2 SC will modify the rheological properties of the material within the extruder and will act as expansion agent during the expansion during the passage in the die.
• solubilization in large amounts in the polymer will result in large expansions.
• the decrease in viscosity will lead to the limitation of mechanical stresses and the lowering of operating temperatures within the extruder. This will allow the manipulation of molecules with limited stability.
• the homogeneous nucleation rate Nh is defined as the number of pores created per unit of time and volume. According to classical theory, it can be expressed as follows:
• fh is the frequency factor
• Ch the gas concentration
• kB the Boltzmann constant
• T the temperature
• ⁇ Gh * the free energy for the formation of a critical gas nucleus
• ⁇ is the surface tension between the polymer and the gas and AP 1 is the supersaturation pressure, i.e., the pressure difference from the pressure that causes saturation of the polymer. Decreasing the surface tension or increasing the supersaturation pressure amounts to increasing the nucleation rate and the number of bubbles produced. Since the surface tension decreases with the pressure, the CO2 SC will, during expansion, allow the formation of bubbles at minimal surface energies, which results in a very fast and homogeneous nucleation and, consequently, a very fine porous structure.
• FIG. 1 shows the following elements implemented by the method according to the invention:
• the next step is to introduce a model active ingredient to develop the step for the manufacture of solid dispersions.
• Extrusion coupled with the use of an FSC allows the manufacture of solid dispersions of pharmaceutical active ingredients in a polymer matrix, reducing the temperatures and mechanical stresses in the extruded material. This allows the manipulation of a wider range of thermolabile molecules, as can pharmaceutical active ingredients.
• the coupling between the two technologies also allows the creation of porosity within the solid dispersion, without addition of residual compounds which could require an additional step for its elimination.
• the properties of CO 2 in particular make it possible to obtain a fine porosity and regular, and above all that can be controlled by the operating conditions.
• the process according to the invention is subject to several variants in the injection mode of the active substance.
• Three of these variants, described below, have in common the injection of the active substance together with the CO 2 and not with the polymer matrix.
• the polymer matrix is therefore the only component introduced into the extruder via the funnel or hopper 5.
• the active substance is dissolved, or optionally dispersed, in supercritical CO 2. This mixture is thus injected in place of the pure CO 2 via the injection nozzle 11. The following steps of the process remain unchanged.
• a second variant especially adapted to poorly soluble substances, consists of producing a mixture in which the supercritical CO 2 is dissolved in the active substance.
• This active substance is thus made liquid by this operation.
• the supercritical CO 2 is dissolved in an autoclave.
• a compound with a mass percentage of CO 2 of between 1% and 50%, typically of the order of 30%, is generally obtained.
• the advantage of this variant is that it makes it possible to promote the dispersion of the active substance in the polymer matrix, to operate at a lower temperature, to take better advantage of the changes in the rheological and diffusive properties. This also makes it possible to introduce the active substance in liquid form.
• a third variant consists in continuously supplying an autoclave simultaneously with active substance and with supercritical CO 2. There is then a mutual dissolution of the active substance and supercritical CO2, resulting in two fluid phases, one rich in active substance, the other in supercritical CO2.
• the order of magnitude of the mass compositions of each of these two phases is from 1% to 50%, typically of the order of 30% CO 2, for the heaviest phase consisting of the dissolution of CO 2 in the active substance, and from 90% to 100% CO 2 for the lightest phase constituted by the dissolution of the active substance in CO 2.
• These two phases are then agitated, for example by means of a Rushton-type turbine, in order to emulsify this mixture before introduction into the extruder via the injection nozzle 11.
• This method has the advantage of the two previous variants, guaranteeing moreover the constancy of the composition of the injected mixture.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Medicinal Chemistry (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Animal Behavior & Ethology (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Materials Engineering (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• Polymers & Plastics (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Processes Of Treating Macromolecular Substances (AREA)

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• 2005
  • 2005-06-10 FR FR0551577A patent/FR2886938B1/fr not_active Expired - Fee Related
• 2006
  • 2006-06-12 EP EP06763648A patent/EP1888676A2/de not_active Withdrawn
  • 2006-06-12 WO PCT/EP2006/063110 patent/WO2006131570A2/fr not_active Ceased

Non-Patent Citations (1)

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