External-stimuli biodegradable hydrogels for combination-drug therapy with concomitant release rates – design considerations

A variety of diseases could benefit from a combination therapy. Typical examples include tuberculosis, leprosy, malaria, HIV and numerous anti-cancer modalities. For this purpose, an assortment of drug carriers has been developed in which two or more drug entities are packed in a single vehicle, most commonly micro- or nano particulate systems or polymer drug conjugates designed for systemic delivery. To achieve a locoregional delivery of combination therapy, implantable devices are required. Typical examples for current technologies include, drug loaded stents, brachytherapy and brain wafers such as Gliadel^®. Using a breast cancer mouse model, we have already shown that a biodegradable implant made of crosslinked chitosan can be used in brachytherapy for the prevention of post-surgery metastases recurrence in the tumor bed.

A major obstacle associated with locoregional combination therapy is the conceivable difference in the water solubilities of the drugs, affecting the desired concomitant release rate at the site of embedding. This problem could be overcome by formulating a degradable platform in which the release rates are governed by erosion rather than diffusion over a predetermined period of time. We have exploited this notion in the past for increasing the bioavailability of poorly absorbed drugs in the gastrointestinal tract by their concomitant release, together with absorption enhancers, at similar rates. In the context of locoregional cancer therapy we developed second generation multidrug vehicles in which the erosion was triggered, externally, by de-crosslinking buffers of varying concentrations. We tested these vehicles (e.g. calcium alginate beads, controlled eroded by oxalate solution), pre-clinically, for the prevention of post-surgery metastasis spread, using Nutlin-3 and liposomal doxorubicin and showed that the concomitant release increased the drugs’ efficacy in a synergistic manner.

The complexity associated with the design of erodible, synchronized platforms can be largely assisted by using statistically based factorial design analysis. Such analysis enables the identification of possible interactions among the formulation variables. We are currently employing a design of experiment (DOE) methodology including Definitive Screening Design and Fractional Factorial Design to construct remote erodible matrices in order to synchronize the release rates of highly- and poorly-water soluble drug models by external triggering.