The production of polymer particles with specific physicochemical and size properties is an increasing challenge for drug delivery in the pharmaceutical area. These particles, whose size typically lies within the micrometer range, consist of synthetic biocompatible polymers that contain active materials and can be applied to living systems (in vivo) without inducing undesirable effects. For this purpose, biodegradable polymers are commonly used as materials for sustained-release delivery systems because the control of their physicochemical features makes it possible to design a specific release profile for the drug . Particulate drug delivery systems are useful for several routes of administration. They can be administered as dry powders for inhalation applications or as aqueous suspensions by parenteral, topical, or oral routes. Parenterally, polymer particles containing a drug whose size is within the 1- to 100-pm range can be administered either subcutaneously or intramuscularly to obtain sustained-release depots , thus minimizing the frequency of drug administration. Intravenously, suspensions of polymer nanoparticles containing a drug, whose diameter is less than 1 pm, can be administered to increase the systemic circulating time of the drug, reduce toxicity, and target solid tumors . Thus, polymer micro- and nanoparticles are of great importance for drug delivery and targeting.
Current methods for preparation of drug-containing polymer microparticles are mainly based on emulsion-solvent extraction or phase separation techniques. The former technique requires dissolution of the polymer in an organic solvent, dispersion or dissolution of the drug in this solution, emulsification of this organic phase in an aqueous solution, and subsequent extraction of the solvent by evaporation or dilution in a large excess of water . The latter technique involves dispersion of drug in an organic solution of a polymer and addition of a nonsolvent, either a polymer or an organic solvent, to induce the phase separation of a polymer-rich phase containing the drug; an additional organic solvent is then used in a large excess to harden the microspheres .
A serious drawback of these techniques is the extensive use of organic solvents to either dissolve the polymer or induce phase separation and hardening. Most of these organic solvents are toxic; moreover, they are suspected to be responsible for biological inactivation of large molecules such as proteins . Due to the large amounts of solvents used in these processes, it is not possible to completely remove them from the particles, which is required prior to their in vivo use. The removal of residual solvents currently involves heating, which is not appropriate for heat-labile drugs. In addition, these methods display other major drawbacks. For instance, in the emulsification phase, the emulsionsolvent extraction method requires the use of surfactants that have then to be removed from the end product. This process also leads to a wide particle size distribution, and to a low drug loading in the case of water-soluble drugs due to drug partitioning between the organic and aqueous phase.
Other methods reported in the literature for the preparation of particulate polymer drug delivery systems do not use any organic solvent. They are based on hot-melt procedures, which involve shear and heat that can have a detrimental effect on fragile molecules .
Accordingly, there is a strong interest in new methods for production of polymer particles, which can be carried out without any organic solvent and under conditions that have minimal detrimental effect on the drug encapsulated, especially in the case of fragile molecules such as peptides and proteins.
The use of supercritical fluids (SCFs) as vehicles for the production of polymer particles with therapeutic applications is a recent development. SCFs appear to be one of the most promising factors in the development of new production techniques that completely eliminate organic solvents or minimize their use, and are carried out under mild temperature conditions. An SCF is a fluid whose pressure and temperature are simultaneously higher than those at the critical point, i.e., the end point of the liquid-gas phase transition line (Fig. 1). Several features of SCFs make them versatile and appropriate for production of polymer particles. They display some liquidlike properties, such as a high density, and other gaslike ones such as low viscosity and high diffusivity. The most important property of an SCF is its large compressibility near the critical point. The combination of liquidlike density and large compressibility is of major interest, since it leads to a fluid whose solvent power can be continuously tuned from that of a liquid to that of a gas, with small variations of pressure. Because of its low critical temperature (Tc = 31.1 °C) and environmentally acceptable nature, CO2 is the most widely used SCF in pharmaceutical development and process-
-80 -70 -60 -SO -40 -30 -20 -10 0 10 20 30 40 50 60
-80 -70 -60 -SO -40 -30 -20 -10 0 10 20 30 40 50 60
FIG. 1 Schematic projection of the pressure-temperature phase diagram for a substance. CO2 has been chosen as an illustrative compound (critical temperature, Tc = 31.1°C, critical pressure, Pc = 73.8 bar; TP, triple point; CP, critical point).
ing. It actually offers many advantages. CO2 is a readily available, nontoxic, and nonflammable agent that is generally recognized as safe and has a low cost. It allows one to work at moderate temperatures and leaves no toxic residues since it turns back to a gas phase at ambient conditions. Due to its unique properties, CO2 is used routinely in large-scale operations for decaffeination of coffee beans and extraction of hops .
Several SC CO2-based processes have been reported in the literature for the production of drug-loaded polymer micoparticles. These processes currently use CO2 either as:
A solvent of the polymer and the drug from which particles are precipitated; this is known as the rapid expansion from supercritical solutions (RESS) process .
A swelling and plasticizing agent that is dissolved in the polymer until a gas-saturated solution is obtained, which is later expanded to cause supersaturation and particle precipitation. This is known as the particles from gas-saturated solutions (PGSS) process .
An antisolvent that causes precipitation of the polymer initially dissolved in an organic solvent. This is known as the gas antisolvent (GAS)  or supercritical antisolvent (SAS) process, and has many related modifications, e.g., aerosol solvent extraction system (ASES) process and solution-enhanced dispersion by SCF (SEDS) process [12,13]. A solvent for polymerization in dispersed media of acrylic and vinyl monomers .
This chapter will first briefly describe the basic aspects of SCFs and will then present the various SCF-based techniques for the production of drug-loaded polymer particles. For each technique, the typical physicochemical features of the particles obtained will be given in terms of particle size, drug loading, and morphology, and the factors influencing the characteristics of the SCF products will be discussed. Examples of drug delivery systems prepared using these processes will also be presented. The advantages and limitations of the processes will be pointed out and discussed, especially as regards the production yield and the scale-up issues. Finally, the potential of the polymer particles produced using SCF-based processes for therapeutic applications will be envisaged.
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