Administering a drug by the parenteral route has the advantages of bypassing the absorption process and the first-pass metabolism, thereby maximizing the bioavailability. For this reason, such a route is still the most used for administration of macromolecular drugs.
Parenteral administration, however, has the disadvantage of being invasive, and hence, hardly accepted by the patient. Also, with cancer drugs it generates serious toxicity problems. On the other hand, the oral route, which is the most accepted by the patients as noninvasive and practical, has the inconveniences of requiring a prompt absorption of the drug, and of exposing it to the harsh conditions of the stomach and to metabolic degradation processes, including hepatic firstpass metabolism, which limits the bioavailability of many drugs, such as cardiovascular drugs, analgesics, and peptides.
Drug administration via the nasal, buccal, vaginal, and ocular mucosae is noninvasive, is not subjected to hepatic first-pass metabolism and harsh environmental conditions, and further, mucosal surfaces are readily accessible. These benefits have prompted the numerous studies that have been carried out in recent years on transmucosal drug absorption. Generally, hydrophilic drugs that cross the epithelia via the paracellular route, such as, for example, peptides and proteins, have a poor permeability across the membrane, resulting in insufficient bioavailability. Therefore, reversible modifications of the drug molecule, for example, by making a permeable prodrug, or of the epithelial barrier structure, for example, by permeation enhancers, are required.
The approaches that have been, and are currently being investigated for transepithelial drug delivery have very recently been discussed by Majumdar and Mitra . Other recent reviews deal with the issues relevant to the optimization of absorption across specific mucosal surfaces, such as the intestinal , nasal [3,4], buccal [5-8] and ocular  ones, or to the paracellular penetration enhancement via modulation of the tight junctions connecting epithelial cells [10-12]. Low molecular weight enhancers have been studied and applied for the last two decades (fatty acids, glycerides, chelators) or for longer (bile salts, surfactants). More recent are the studies on high molecular weight enhancers, in fact, the first report on the transmucosal absorption-enhancing properties of a semisynthetic polymer, chitosan, dates back to 1994 . Since then, numerous studies have been carried out to evaluate the efficacy of polymeric absorption enhancers, their mechanisms of action, their structure-activity relationships and their safety. In regard to the last of these issues, it is observed that, unlike the low molecular weight enhancers, the physicochemical characteristics of which favor their own absorption, high molecular weight polymers are generally not absorbed, and this minimizes the risk of systemic toxicity. Another important advantage of macromolecular enhancers over small molecular weight compounds resides in the fact that most of the former have mucoadhesive properties, which often act in synergism with the permeability-enhancing ones by facilitating and prolonging contact of the polymer molecule with the epithelium surface.
The enormous potential of the enhancer approach to an effective, comfortable, and safe transmucosal administration of challenging drugs has stimulated an ever-increasing interest in putting to test new prospective polymeric enhancers.