Oral controlled release. The most traditional manufacturing technique for sustained-release dosage forms is compression such as roller compaction
or tableting, which creates a matrix as the result of the formation of solid bridges. When subjected to a compression force,
drug and excipient particles undergo transitional packing. With an increase in the compression force and densification of
the formulation composition, deformation occurs at the points of contact of drug and excipient particles. Ductile materials
such as microcrystalline cellulose undergo plastic deformation while brittle materials such as lactose undergo brittle fracture.
Solid bridges are formed between particles when adjacent surfaces come into contact at the atomic level.
Figure 2: Dissolution of itraconazole solid-dispersion formulations: Sporanox (Janssen Pharmaceuticals) (▲), Hypromellose
extrudate (■), Eudragit (Evonik) E100 extrudate (▼), and Eudragit (Evonik) E100-PVPVA64 extrudate (•).The dissolution (paddle
method) was carried out in 500 mL SGFsp, at 37 °C, 100 rpm. Error bars indicate the standard deviation. (FIGURE 2 IS REPRODUCED
WITH PERMISSION FROM SIX ET AL (REF. 14) BY ELSEVIER)
A TSE process has been successfully applied to a prepared sustained-release drug-delivery system (18). Commonly used polymeric
drug-release retardants such as Eudragit RS, ethyl cellulose, and hydroxypropyl cellulose are thermal plastic materials that
can be readily processed in a TSE. During the extrusion process, polymeric drug-release retardants are fed and transferred
inside the heated barrel by corotating (or counter-rotating) twin screws. The polymeric materials soften as a result of the
shearing effect of the rotating screws. The molten mass is then pumped through the die attached to the end of barrel by the
screws and transformed into different physical shapes. The extrudate can either be directly shaped into a dosage form (19)
or milled down to granules which can be further processed into final dosage forms with a traditional compression process (20).
The mechanism for matrix formation during the melt-extrusion process is different from that during the compression process.
When processed above their glass-transition temperature and subjected to high pressure, thermoplastic components of the formulation
function as adhesive binders inside the extruder and are intimately mixed with other components. Thermoadhesive characteristics
of polymeric drug-release retardants are the mechanism for the formation of the matrix prepared using melt extrusion. Therefore,
good compaction properties required for the matrix formation in a compression process are not necesssary. Finished products
are expected to have lower porosity, higher tortuosity, and higher density in comparison with the dosage forms prepared by
conventional compression processes. For a diffusion-controlled drug-delivery system, slower drug release is typically observed
from materials processed using a melt extrusion process.
Strong interaction between individual components in the formulation can also occur during the extrusion process because certain
materials are mixed at the molecular level. Zhang and McGinity have observed the formation of insoluble chlorphenamine maleate
and Eudragit 4135F complexes due to hydrogen bond formation during the extrusion process (18). Exploitation of such interactions
in combination with greater control of diffusive properties of the matrix can be exploited to provide unique sustained release
properties. Additionally, abuse-deterrent and dose-dumping characteristics can be built into system using melt-extruded matrix
technologies. In a recent study by Roth and colleagues, researchers used Soliqs' Meltrex technology to prepare ethanol resistant
tablets of verapamil (21). Their research showed improved performance in vitro and in vivo.
Melt extrusion also has been used as an oral controlled platform for the production of minitablets and as a means to facilitate
the compression of multiparticulates. In a study conducted by De Brabander et al., researchers manufactured minitablets using
melt extrusion to prepare zero-order sustained-release tablets of ibuprofen that showed stability for a 12-month storage period
(22). Schilling et al. also reported on the application of melt extrusion to prepare matrices containing film-coated multiparticulates
(23). Under this design, the pellets were extruded with an external matrix agent and milled into a compressible granular powder
which could be combined with extragranular materials to provide improved compression cushioning while allowing for controlled
release. This technology could potentially allow for successful manufacture of tablets containing multiparticulates.
The literature shows overall that a melt-extrusion platform can provide many benefits for the production of controlled-release
systems. The ability to manufacture conventional controlled-release systems while maintaining the potential for single-step
dosage form manufacture presents unique opportunities for continued growth of this technology.