FR2886938A1 - EXTRUSION PROCESS FOR MAKING SOLID DISPERSIONS OF PHARMACEUTICAL ACTIVE INGREDIENTS IN A POLYMERIC MATRIX - Google Patents

Abstract

The invention relates to an extrusion process for producing solid dispersions of pharmaceutical active ingredients in a polymer matrix and controlling the porosity of the solid dispersions thus obtained. The method comprises: - the step of introducing the polymer matrix into an extruder (1), - the step of operating the extruder (1) so as to develop rheological properties of the polymer matrix, - the step to place CO2 under supercritical conditions and to inject it into the extruder (1), - the step of introducing an active substance into the extruder (1), - the step of mixing the CO2 and the substance active with polymer matrix to ensure a monophasic state to the mixture thus obtained, the step of relaxing the mixture thus obtained to give it a microporous structure.

Description

EXTRUSION METHOD FOR MANUFACTURING DISPERSIONS

  SOLIDS OF ACTIVE PHARMACEUTICAL PRINCIPLES IN A MATRIX

POLYMER

  The present invention relates to an extrusion process for producing solid dispersions of pharmaceutical active ingredients in a polymer matrix and controlling the porosity of the solid dispersions thus obtained.

  DESCRIPTION OF THE TECHNICAL PROBLEM Conventional extrusion processes involve high temperatures and mechanical stresses, which do not allow the manipulation of fragile molecules.

  In addition, porosity is not a controllable parameter without the addition of nucleating agents. This may involve the presence of residues in the material and the need for an additional step to remove them.

  Processes using supercritical technology often allow moderate operating temperatures, but their discontinuous nature often limits their potentiality in the context of industrialization. In addition, they frequently involve the use of other solvents than CO2, such as ethanol or DMSO (dimethyl sulfoxide).

  State of the art With a growing number of new molecules with low aqueous solubility, the bio-availability of active ingredients remains one of the major challenges in the development of the formulation. In this context, the preparation of a solid dispersion has a high potential.

  Extrusion, a process widely used in the plastics industry, is currently being studied for the manufacture of solid dispersions of pharmaceutical active ingredients. It is indeed a stable process whose scaling is possible, and which is free of problems related to the use of solvent. However, the operating temperature remains one of the critical variables of the process since it must allow the plasticization of the polymer without degrading the active molecule.

  Processes using supercritical technology also allow the manufacture of solid dispersions, while maintaining the moderate operating temperature and the reduced amounts of solvents. However, this technology comes up against difficulties when scaling up.

  Early work on the use of supercritical fluid extrusion coupling was conducted by an American team from Cornell University. They were interested in creating porosity within agri-food compounds. Two patents have been filed, with subsequent scientific publications: Rizvi SSH, Mulvaney SJ, Extrusion Processing with Supercritical Fluids, US Patent 5120559 (1992), Rizvi SSH, Mulvaney SJ, Supercritical Fluid Extrusion Process and Apparatus, US Patent 5417992 ( 1995), Subsequently, a similar process was patented for the manufacture of microcellular polymers, with, in particular, a more precise description of the resulting porosity: Park CB, Suh NP, Baldwin DF For these documents, only the physical structuring of the matrix is commented on. US Pat. No. 5,861,053 (1999) & US Patent No. 6051174 (2000). The chemical nature of the material is not discussed, particularly in the case of a mixture between two compounds such as a solid dispersion.

  The present invention solves the difficulties explained above by allowing the manufacture of solid dispersions of pharmaceutical active ingredients 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).

  The invention relates to an extrusion process for producing solid dispersions of pharmaceutical active ingredients in a polymer matrix and controlling the porosity of the solid dispersions thus obtained. The method is characterized in that it comprises the following steps: - the step of introducing the polymer matrix into an extruder, - the step of operating the extruder so as to develop rheological properties of the polymer matrix, the step of placing CO2 under supercritical conditions and of injecting it into the extruder, the step of introducing an active substance into the extruder, the step of mixing the CO2 and the active substance with the polymer matrix to ensure a monophasic state to the mixture thus obtained, the step of relaxing the mixture thus obtained to give it a microporous structure.

  According to a first embodiment of the invention, the extrusion process is characterized in that the step of introducing the active substance into the extruder (1) comprises the step of solubilizing or dispersing the active substance in the CO2, prior to the injection of CO2 into the extruder (1).

  According to a second embodiment of the invention, the process is characterized in that: the step of introducing the active substance into the extruder (1) comprises the step of introducing the active substance into the extruder (1 with the polymer matrix, in particular via a hopper (5) of the extruder (1), the step of actuating the extruder (1) so as to develop the rheological properties of the polymer matrix comprises the step of dispersing the active substance in the polymer matrix.

  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.

  An FSC (supercritical fluid) is a fluid brought to a pressure and a temperature beyond those 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 (7.4 MPa and 304 K), making it an ideal fluid for food and pharmaceutical applications.

  CO2 SC (supercritical CO2) has already been widely used in the implementation of polymers. Its specific properties allow it to solubilize strongly and rapidly in the 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 glass transition temperature, 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 6 of the 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 range of CO2 pressure of 1 to 10 MPa.

  As part of the extrusion process, the CO2 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. Thus, 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 in the following way: Nh = fhCh exp (-AGh * / kBT) (1) fh is the frequency factor, Ch the gas concentration, kB the Boltzmann constant, T the temperature and AGh * the free energy for the formation of a critical gas nucleus, expressed by: OGh * = 167163 / 34P2 (2) 6 is the surface tension between the polymer and the gas and OP1 the supersaturation pressure that is, the pressure difference from the pressure that causes the polymer to saturate. 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 pressure, the CO2 SC will allow, during the expansion, the formation of bubbles at minimal surface energies, which results in a very fast and uniform nucleation and, consequently, a very fine porous structure.

  A particularity of the coupling of the extrusion and the CO2 SC resides in the fact that the amount of dissolved CO2 SC and the relaxation can be controlled by the adjustment of the operating conditions and, consequently, the expansion, the size and the Pore density can be fixed to obtain new materials, with a wide range of properties.

  FIG. 1 shows the following elements used by the process according to the invention: 1: extruder 2: CO2 tank 3: pump 4: motor 5: feeding funnel of the extruder (hopper) 6: worm 7: mixer 8: die 9: temperature sensor 10: pressure sensor The following steps appear: -supply the component (s) (conveying and dosing unplasticized granules or powder); development of the rheological properties of the mixture (preparation, dispersion and plasticization) during a conventional phase for an extrusion process; injection of CO2, pure or containing the active substance, previously placed under supercritical conditions; - mixing to ensure a monophasic state of the material; nucleation / pore growth caused and controlled by thermodynamic instability created by sudden relaxation during passage through the die.

  Initially, an extruder was modified so that CO2 SC could be injected into the extruded material.

  Then, preliminary experiments were carried out on polystyrene (PS). This step helped to take control of the technology. Today, the injection of CO2 is controlled and the effect on the porosity of operating parameters such as pressures, flow rates or temperatures has been observed.

  The next step is to introduce a model active ingredient to develop the step for the manufacture of solid dispersions.

  Advantages of the Invention Extrusion coupled with the use of an FSC enables the manufacture of solid dispersions of pharmaceutical active principles in a polymer matrix, by reducing the temperatures and the mechanical mechanical stresses within 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 CO2 in particular make it possible to obtain a fine and regular porosity, and above all that can be controlled by the operating conditions.

  The experimental results clearly confirm the advantages of such a reduction coupling of T (temperature) and P (pressure) in the extruder barrel, control of the nucleation and the porosity of the polymer, which demonstrates the viability of the polymer. application to the field of pharmaceutical molecules.

Claims (3)

  1. Extrusion process for manufacturing solid dispersions of pharmaceutical active ingredients in a polymer matrix and controlling the porosity of the solid dispersions thus obtained; the method being characterized in that it comprises the following steps: the step of introducing the polymer matrix into an extruder (1), the step of actuating the extruder (1) so as to develop properties rheology of the polymer matrix, - the step of placing CO2 under supercritical conditions and injecting it into the extruder (1), the step of introducing an active substance into the extruder (1), -l step of mixing the CO2 and the active substance with the polymer matrix to ensure a monophasic state to the mixture thus obtained, the step of relaxing the mixture thus obtained to give it a microporous structure.   2. Extrusion process according to claim 1 characterized in that the step of introducing the active substance into the extruder (1) comprises the step of solubilizing or dispersing the active substance in the CO2, prior to the injection of CO2 into the extruder (1).   3. Extrusion process according to claim 1, characterized in that: the step of introducing the active substance into the extruder (1) comprises the step of introducing the active substance into the extruder (1) with the polymer matrix, in particular via a hopper (5) of the extruder (1), the step of operating the extruder (1) so as to develop the rheological properties of the polymer matrix comprises the step of dispersing the active substance in the polymer matrix.