Prerequisites for successful bioadhesive oral dosage form
The promise of bioadhesive-based oral delivery systems has fostered numerous investigations with limited success. Different
types of transmucosal oral systems have been explored using various bioadhesive polymers. A majority of these systems are
based on hydrophilic hydrogel polymers and are designed primarily for buccal or sublingual applications. When these hydrophilic
polymers are used for oral bioadhesive systems for drug delivery in the GIT, they typically hydrate prematurely upon contact
with the stomach contents before developing interactions with the mucosal surface. In the event that some weak interactions
do occur, these systems cannot withstand the high turbulence of the stomach environment, and the result is premature emptying.
Therefore, although the range of hydrophilic bioadhesive polymers and their application in various low-turbulence conditions
is quite broad, their usefulness in oral dosage forms, especially in designing of systems for systemic delivery, is generally
limited.
Table I: Bioadhesive oral drug delivery systems used in various human trials. (ALL FIGURES AND TABLES ARE COURTESY OF THE
AUTHOR.)
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An ideal bioadhesive oral dosage form must meet several prerequisites to be successful. The first prerequisite to target a
gastrointestinal site is that the behavior of the dosage form must be reproducible. Although many bioadhesive polymers have
exhibited promising results in vitro and in vivo in animals, few benefits have been shown in human trials. The results of human clinical trials with bioadhesive oral dosage
forms are summarized in Table I. Recently, Säkkinen evaluated the passage and retention of chitosan granules in the small
intestine by gamma-scintigraphy in fasted human volunteers (14). Although chitosan showed marked bioadhesive capabilities
in vitro, retention of the chitosan formulation in the upper small intestine was not sufficiently reproducible, and the duration of
retention was similar to lactose granules used as a control. In developing a site-specific bioadhesive system for furosemide,
a model drug with a narrow absorption window in the upper GIT, administration of furosemide in chitosan granules resulted
in bioavailability lower than that from a conventional immediate-release formulation, thereby indicating that the bioadhesive
formulation could not be retained long enough in the upper GIT in humans (15).
The second prerequisite for a bioadhesive system is that it should rapidly attach to the mucosal surface and maintain a strong
interaction to prevent displacement. Spontaneous adhesion of the system at the target site is critical and can be achieved
through bioadhesion promoters that use tethered polymers (16). Contact time should also be sufficiently long at the target
site, normally longer than that needed for complete drug release. As hydrophilic bioadhesive polymers tend to lose adhesiveness
upon hydration, restricted hydration and formation of a rigid gel network would be desirable for prolonged adhesion (17).
A short retention time, in relation to the drug release rate, will compromise bioavailability.
The third prerequisite for a successful and effective bioadhesive system is that the bioadhesion performance should not be
impacted by surrounding environmental pH. Studies have shown that the bioadhesiveness of polymers with ionizable groups are
affected by surrounding pH. For example, polyacrylic acid is more bioadhesive when the majority of the carboxylic acid groups
are in the ionized state. Polyanhydride-based hydrophobic bioadhesive polymers (e.g., Spheromers, Spherics, Mansfield, MA)
undergo erosion that is mainly affected by the aqueous environment and not by pH of the surrounding medium. Studies have shown
that as anhydride-based polymers degrade at the mucus surface, carboxylic acid groups are formed at the transected polymer
chain ends, which generate a new polymer surface rich in carboxylic acid end groups (18). These hydrophilic functional groups
then form hydrogen bonds with surrounding mucin strands that in turn penetrate the newly created surfaces. The result is the
formation of both chemical and mechanical bonds. As the degradation process proceeds, a more porous surface rich with carboxyl
groups is created, allowing for even greater adhesion that is essential to the success of an oral bioadhesive system. In earlier
studies, one family of rapidly degradable polyanhydrides [poly (FA:SA)] produced bioadhesive interactions with rat small intestine
tissue that were substantially stronger than all other polymers in this class (18). The fact that these bioadhesive polymers
are stable in the acidic environment of the stomach and eventually degrade at pH ≥7.4, make them ideal for targeted delivery
to the stomach and small intestine (19).
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