Bioadhesive delivery system options
Several investigators have explored unique design concepts in an effort to enhance retention of bioadhesive dosage forms in
the GIT. These novel bioadhesive dosage forms include solutions, suspensions, gels, powders, microparticles or nanoparticles,
pellets, patches, and tablets (including minitablets and multilayer tablets). During the development of a bioadhesive delivery
system, the focus should be not only to achieve the desired therapeutic outcome but also to overcome the unfavorable environmental
condition and challenges found in various regions of the GI tract.
Solution, suspension, and gel-forming liquids.
Viscous bioadhesive liquids have been investigated primarily to coat the esophagus to act as a protectant or a vehicle for
drug delivery for the treatment of local disorders, including motility dysfunction, fungal infections, and esophageal cancer.
For the treatment of GERD and other esophageal disorders, a delivery system retained within the lower esophagus would be highly
desirable (46). Using sodium alginate suspension as a novel bioadhesive liquid, researchers showed that the esophageal surface
can be coated to protect against refluxate and can deliver therapeutic agents to the damaged mucosa (28, 47). The bioadhesive
gel of δ-5-aminolevulinic acid for local action within the esophagus has been investigated (48). The retention behavior of
various bioadhesive formulations was evaluated on the esophageal surface under conditions mimicking the saliva flow. Both
polycarbophil and xanthum gum demonstrated excellent bioadhesive potential, and carmellose sodium and theromosensitive poloxamer
(Lutrol 407) demonstrated poor retention. Recent work by Potts has examined the esophageal retention of liquid formulations
of Smart Hydrogel (GelMed, Lexington, MA), a thermosensitive hydrogel of poloxamer covalently linked to polyacrylic acid and
carbopol. This "esophageal bandage," upon oral administration, demonstrated significant retention within the esophagus (49).
Multiparticulates, microparticles, and nanoparticles.
Oral delivery systems based on multiparticulates, microparticles, and nanoparticles often exhibit improved performance in
comparison with monolithic matrix tablets. By diffusing into the mucous gel layer by virtue of their relatively small size,
these small immobilized carriers show a prolonged gastrointestinal residence time (50, 51). Figure 9 shows Spheromer-coated
beads adhering to the mucosal layer of everted rat jejunum. Studies have shown that these beads make a rapid interaction with
the mucosal surface and form a strong and long-lasting adhesive interaction (52). Rapid degradation of these polymers on the
surface generates new carboxylic acid groups that further aid in bioadhesion. Recent work has shown that, in addition to size
and chemistry, shape is also a critical feature of bioadhesive drug delivery particles and can dictate particle velocity,
diffusion and adhesion to the mucus surface in a complex manner (53).
Figure 9: An everted sac of rat jejunum incubated with Spheromer-coated microspheres, adhering to the mucosal surface, after
washing three times (52). (ALL FIGURES AND TABLES ARE COURTESY OF THE AUTHOR.)
Fine particles of ion-exchange resins display bioadhesive properties as a result of interactions between the highly charged
surface of polymers and the mucus (54). The residence time of cholestyramine, an anionic-exchange resin, was explored in fasting
and fed human subjects by gamma-scintigraphy. This study showed that materials with adherent properties can resist the housekeeper
sequences in the fasted subjects and will not be dislodged by food in the fed state. Contrary to conventional wisdom, this
study revealed that charge-based interactions associated with ion-exchange resins play a minor role and only a small percentage
of resin particles (approximately 20%) that made contact with the stomach lining were retained over an extended duration (55).
Figure 10: AUC and Cmax values following oral gavage administration of micronized (stock) paclitaxel, non-bioadhesive paclitaxel formulation, and
bioadhesive paclitaxel formulation in rats (57). (ALL FIGURES AND TABLES ARE COURTESY OF THE AUTHOR.)