PROCEDIMIENTO CON USO DE GRÁFICAS

Most polymeric implants are prepared by extrusion [121]. Generally, extrusion describes a process during which the raw material is forced through an orifice or a die. For that purpose at least two main components are necessary: (1) a transport system that may impart a mixing function and (2) a die system, which forms the material. The pressure required for extrusion depends on the design of the die, on the extrusion rate, and in particular on the rheological characteristics of the formulation. With respect to the method used to adapt the viscosity, extrusion can be classified into molten systems (hot-melt extrusion) and semisolid systems. Semisolid systems are generated by dispersing a high portion of solid material in a liquid phase [219]. This technique is widely used to prepare granules or pellets, whereas for the preparation of parenteral controlled release devices mostly the hot melt extrusion technique is applied [121].

Since PLA and PLGA fulfil the basic prerequisite of thermoplasticity, various peptides have been embedded into these matrices by hot melt extrusion. In order to enable the flow through the extruder die, the drug and the polymer have to be heated above the glass transition temperature. The obtained rods are cooled and cut to a specified length. Finally, sterilization of the implants can be accomplished by gamma-irridation [121].

According to their design, various extruder types can be distinguished. Among them ram and screw extruders are particularly capable for the production of controlled release systems [219].

4.3.1. RAM EXTRUSION

The setup of a ram extruder is schematically illustrated in Figure 2. The extruder consists of a barrel that is pre-filled with the powder mixture. By means of a piston (or ram) the material is forced through the die at the bottom of the barrel [219].

piston barrel die piston barrel die

Figure 2: Schematic setup of a ram extruder.

The extrusion process can be divided into three phases: (1) compression, (2) steady state flow, and (3) forced flow. The first phase is characterised by a large displacement of the piston with little pressure increase leading to the compaction of the powder to a plug prior to extrusion. After the maximal density of the material is reached, the pressure increases until the material commences a continuous extrusion (steady state flow). Optimally, when the piston is very close to the die forced flow occurs (Figure 3) [219].

Figure 3: Typical force displacement plot for a ram extrusion [219].

The area under the steady state curve represents the work required for extrusion [219]. Pito et al., for instance, used this value to evaluate the extrudability of various saturated polyglycolysed glyceride formulations. It was shown that the melting temperature correlates well with the energy required to produce extrudates. Furthermore the applied force strongly depends on the die diameter, the length-to- radius-ratio, and the extrusion rate [171].

Compared to twin-screw extrusion, ram extrusion is a non-continuous procedure (unless more than one barrel is employed). Since only small amounts of substance are necessary, ram extrusion is mostly used in laboratory scale. In lab scale, also a very simple modification of the ram extrusion procedure is often applied – the extrusion through a needle.

Ram extrusion has been performed with semisolid systems as well as with molten materials. An example for the latter technique is the preparation of BSA-loaded rods based on poly(orthoester) [90, 187]. Zhu and Schwendeman developed an extrusion process without the employment of heat [262]. The semi-solid system of protein powder suspended in an acetone PLGA solution was extruded through a needle into a silicon tube. Afterwards, the solvent was evaporated first at room temperature and then by vacuum drying for 24 h. Semi-solid extrusion was further utilised for the preparation of collagen mini-rods. Fujioka et al., for instance, prepared co- lyophilisates of interferon and collagen, which were wetted with distilled water leading to a gel that could be forced through a nozzle [76].

Semisolid extrusion apparently offers the advantage that heat is generated only by friction. Consequently, the risk of temperature induced denaturation is reduced compared to hot-melt extrusion. However, the employment of an aqueous solution as wetting agent may result in a highly concentrated protein solution in which the carrier material is dispersed. Thus, the possibility of molecule collisions followed by aggregation may increase [250].

4.3.2. SCREW EXTRUDER

The screw type extruder consists of at least one rotating screw inside a stationary cylindrical barrel. At the end of the barrel a die is connected to shape the implant [219].

The extrusion channel can be divided into three distinct sections (Figure 4). Within the first zone, the feed zone, the extruder is loaded. After the feeding zone the transition zone follows. Within this zone the pressure increases due to the reduction of the thread pitch while maintaining a constant flight depth or due to the reduction flight depth while maintaining the thread pitch [25, 219]. Thus, a compression of the material takes place. Finally, the material arrives the metering zone as a homogeneous plastic melt suitable for extrusion. In this last section the pulsating flow is reduced and a uniform delivery rate through the die is achieved [219].

Figure 4: Component parts of a single screw extruder [25].

Because of the high extrusion rates that can be achieved with single- or twin-screw extruders, they are predominantly applied in the industrial manufacturing of implants [121].

Based on this technology two commercially available release systems, Implanon®

and NuvaRing®, were developed. Implanon® is administered subcutaneously to deliver a progestagen for a period of three years. The vaginal ring NuvaRing® is designed for the liberation of both a progestagen and an estrogen for a period of 21 days. Since the carrier material polyethylene vinyl-acetate (EVA) is non-erodable, the implants need to be removed after the release period. In both systems the drug is delivered from a coaxial fibre. The fibre consists of a drug loaded core, which is enveloped with a thin polymer membrane. The steroids within the core polymer are either dispersed as solid crystals or molecularly dissolved. The co-axial fibres are prepared with the help of two single screw extruders that are connected with a spinning block. Core and membrane polymer are melted separately within one of the single screw extruders and delivered to a spinneret, where the coaxial fibre is formed [235, 236].