Various theories have been worked out in the last decades that explain the mechanisms with which mucoadhesives adhere to the mucous layer. The theories of mucoadhesion are primarily based on the classical theories of metallic and polymer adhesion. Four main theories exist that describe the possible mechanisms of mucoadhesion: the electronic, the adsorption, the wetting, and the diffusion theory.
• The electronic theory assumes that transfer of electrons occurs between the mucus and the mucoadhesive due to differences in their electronic structures (Derjaguin et al., 1977, 1994). The electron transfer between the mucus and the mucoadhesive polymer leads to the formation of a double layer of electrical charges at the interface of the mucus and the mucoadhesive with the result of attraction forces inside the double layer.
• The adsorption theory is based on the attraction forces between the mucus and the mucoadhesive. The attraction is achieved via molecular bonding caused by secondary forces such as hydrogen and van der Waals bonds (Kinloch, 1979, 1980; Gu et al., 1988; Mikos and Peppas, 1989; Chickering and Mathiowitz, 1999). The resulting attractive forces are considerably larger than the forces described by the electronic theory.
• The wetting theory correlates the surface tension of the mucus and the mucoad-hesive with the ability of the mucoadhesive to swell and spread on the mucus layer and indicates that interfacial energy plays an important role in mucoad-hesion (Good and Girrfalco, 1960; Helfland and Tagami, 1972; Kaelble and Moacanin, 1977; Peppas and Buri, 1985). By calculating the interfacial energy from the individual spreading coefficients of the mucus and mucoadhesive or by calculating a combined spreading coefficient, good predictions about the mucoadhesive performance can be obtained (Lehr et al., 1992a, 1993). The wetting theory has the most impact on the mechanism of mucoadhesion since spreading of the mucoadhesive over the mucus (and vice versa) is a prerequisite for the validity of all other theories.
• The diffusion theory was proposed first by Voyutskii (1963) and assumes that both the mucoadhesive surface and the mucoadhesive polymer come in the first step in contact to each other. In a second step it is postulated that both the mucin polymers and the mucoadhesive polymer chains interpenetrate each other with subsequent physical entanglement and hydrogen bonds. The interpenetration has to be sufficiently deep in order to become substantial and is dependent on the molecular weight, degree of crosslinking, chain length, flexibility, and spatial conformation of the polymers (Kinloch, 1980; Park and Robinson, 1985; Mikos and Peppas, 1986; Ponchel et al., 1987; Duchene et al., 1988; Peppas and Stahlin, 1996). Jabbari et al. (1993) and Peppas and Huang (2004) were the first to introduce the interdiffusion theory in mucoadhesion. It was proposed that in an aqueous environment the free polymers have enough mobility to diffuse. After intimate contact of the mucus and the mucoadhesive carrier, the free polymer chains, which are initially in the mucus or mucoadhesive parts, may diffuse across the interface due to a chemical potential gradient. After a period of time, the diffused chains form effective interaction sites in the interfacial region. Desai et al. (1992) experimentally estimated the diffusion coefficients of certain proteins in the porcine mucus on the order of 10-7cm2/s. The diffusion coefficients of free mucins were about 10-8cm2/s in mucus while aggregated mucins have diffusion coefficients of 10-11 to 10-12 cm2/s (Bansil et al., 1995). In addition to their low diffusion coefficients, the dynamics of polymer chain diffusion across the interface is rather complex (Wool, 1995). First visualization studies (plastic sections of freeze substituted samples) showed the mucoadhesive interface as an irregular borderline with many coves and invaginations, but were sharp rather than hazy. While with light microscopy mucus glycoproteins could be identified unambiguously by specific histochemical reactions, there was no evidence for intermixing using plastic sections of freeze substituted samples. Hence, the interpenetration depth at the mucus/polymer interface may not be in the micron scale but in the nanorange. (Lehr et al., 1992c). Though direct observations of free chain interpenetration in the interface between mucus and mucoadhesives are not possible, recent experimental observations support the interdiffusion contribution to adhesion. Jabbari and coworkers (1993) proved mucin interpenetration at the poly(acrylic acid)/mucin interface using ATR-FTIR spectroscopy. Their results showed clearly that the concentration of mucin inside the PAA gel increases with time. Sahlin and Peppas (1996) used near-field FTIR microscopy to study the free PEG chains diffusion across PAA hydrogel. The diffusion process was confirmed and the diffusion coefficients were on the order of 10-8 to 10-9 cm2/s.
None of these theories give a complete description of the mechanisms involved in mucoadhesion. The total phenomenon of mucoadhesion most probably is a combination of all these theories. Some investigators divide the mucoadhesion process into sequential phases, each of which is associated with a different mucoadhesion mechanism (Lee et al., 2000; Solomonidou et al., 2001; Dodou et al., 2005): First, the polymer gets wet and swells (wetting theory). Then, noncovalent (physical) bonds are created within the mucus-polymer interface (electronic and absorption theory). Finally, the polymer and protein chains interpenetrate (diffusion theory) and entangle together to form subsequently noncovalent (physical) and covalent (chemical) bonds (electronic and adsorption theory).
It may become clear that the mechanisms of mucoadhesion are of utmost importance for the effectiveness of mucoadhesive polymers, which are intended to act as absorption enhancers for improved drug absorption. There are two important aspects to consider: first the residence time of a mucoadhesive (particulate) drug delivery system after attachment to the mucus according to the mechanisms discussed above for prolonged drug delivery, and second the interpenetration of the mucoadhesive polymers into the mucus layers covering the absorptive mucosal tissues, and their interactions with the sugar residues of the glycocalix in order to elicit a response reaction which results in the transient opening of the tight junctions and allows a paracellular transport of the hydrophilic drug molecules along this route. These aspects will be discussed in the following sections.
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