Geomatrix® system* for controlled release of drugs

Ubaldo Conte, Lauretta Maggi

Department of Pharmaceutical Chemistry, University of Pavia, Via Taramelli 12, 27100 Pavia Italy.

A new delivery device, in the form of a multi-layer tablet, has recently been proposed for constant drug release: Geomatrix® Technology. It consists of a hydrophilic matrix core, containing the active ingredient, and one or two impermeable or semi-permeable polymeric coatings (films or compressed barriers) applied on one or both bases of the core (Fig. 1).

Fig. 1: Geomatrix Technology: two- and three-layer systems

The presence of the coatings modifies the hydration/swelling rate of the core and reduces the surface area available for drug release. These partial coatings provide a modulation of the drug dissolution profile: they reduce the release rate from the device and shift the typical time-dependent release rate towards constant drug release (1-5).

The film coatings act as an inert and impermeable obstacle to water penetration and to drug diffusion through the underlying protected surfaces, but, during dissolution, the shape and extension of the film cannot change while the core swells. For this reason the core exposes in time an increasing extension of its surface to the interaction with the dissolution medium and, as a consequence, the protection effect of the film is progressively minimized during the release process.

To solve this problem a new type of polymeric coating or barrier was developed. The barriers are made up of a hydrophilic swellable polymer and can be applied by compression (5); they swell simultaneously with the core so maintaining covered the whole extension of the base surface of the tablet until the end of the dissolution process. In this case, the ratio of coated-uncoated surface is better balanced compared to the film coated systems, and this ratio remains quite constant during the swelling-release process (2). Moreover, the multi-layer systems swell and gel completely and finally dissolve, leaving no residues in the gastro-intestinal tract.

* GEOMATRIX® is a trade mark of Jago Pharma, Muttenz, CH.

These compressed barriers prove to be much more effective and versatile compared to the films in the modulation of the release profile (3-4) and, above all, they are feasible from an industrial standpoint.

A number of barrier compositions were formulated and tested to reach the most suitable control of the dissolution process. In particular a barrier made up of high viscosity hydroxypropylmethylcellulose (HPMC), which is characterized by very slow hydration and gelling rates, provides an excellent protection of the coated surfaces of the active core for extended times. This type of barrier, being quite impermeable to drug diffusion for long periods of time, is particularly useful to control the release of soluble drugs for once a day administration. On the other hand, if the device contains drugs of low solubility, the release rates obtained are generally too slow. In this case, to maintain the linearization of the dissolution profile, while increasing the release rate, a different approach is proposed: a new barrier is designed whose protective effect towards hydration, swelling, erosion (and consequently towards the release process) is time-dependent, being at the maximum at the beginning and progressively reduced during the dissolution process (Fig. 2).

Such a time-dependent barrier is obtained using HPMC of low viscosity. The behaviour and efficiency of this type of coating were tested on active cores coated by compression on the whole surface (press-coated devices): during the dissolution test, the shell is progressively eroded and removed from the system in a well-defined period of time and, only when the active core is cleared of its coating, does the drug release start (6).

Fig. 2: Swelling behaviour of the Geomatrix three-layer systems with the different types of barrier coatings: erodible or gellable.

The ability of the erodible barrier to control drug release from the Geomatrix systems is investigated on different core compositions, using drugs characterized by a different water solubility and their release profiles are compared. Moreover, to investigate which is the prevailing action mechanism of the different types of coatings in the modulation of drug release, tablets coated by compression on the whole surface were prepared and their dissolution profiles were analysed.

Also the morphological modification of the devices during dissolution and particularly of the barrier layers is examined and the extension of the gelled and glassy phases was measured using a penetrometer and a video-microscope equipped with an image-analyser.

Both types of polymeric barrier are able to modulate drug release from the multi-layer devices. Their time-dependent coating effect modulates water penetration and drug release from the protected surfaces for a programmable period of time, until the coating is eroded or swollen. When the erodible barrier is completely dissolved, the release process depends only on the formulation characteristics of the active core. The swellable coating, instead, shows a double effect: as long as a portion of the coating remains in a solid state, it protects the underlying surfaces from hydration and drug diffusion, but even when completely gelled, still acts as a modulating device: prevents the core erosion process, provides a further diffusion path-length to drug release and acts as a diffusion barrier.

The swellable barrier that shows a stronger protective effect is more suitable to control the release of soluble drugs while the erodible barrier provides a more accurate modulation of the dissolution profile of sparingly soluble drugs.

References

1) Colombo P., Conte U., Gazzaniga A., Maggi L., Sangalli M. E., Peppas N. A., La Manna A. Drug release modulation by physical restrictions of matrix swelling, Int. J. Pharm. 1990, 63, 43-48.

2) Conte U., Maggi L., Colombo P., La Manna A., Multi-layered hydrophilic matrices as constant release devices (Geomatrix® systems), J. Contr. Rel. 1993, 26, 39-47.

3) Conte U., Colombo P., Maggi L., La Manna A., Compressed barrier layers for constant drug release in swellable matrix tablets, STP Pharma Sci. 1994, 4, 107-113.

4) Conte U., Maggi L. Modulation of the dissolution profiles from Geomatrix® multi-layer matrix tablets, containing drugs of different solubility. Biomaterials, 1996, 17, 889-896.

5) Conte U., La Manna A., Colombo P., Tablets with controlled-rate release of active substances, US Patent Application 07/926,380, 1992.

6) Conte U., Maggi L., Torre M. L., Giunchedi P., La Manna A. Press-coated tablets for time-programmed release of drugs, Biomaterials 1993, 14, 1017-1023.