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MUCOADHESION THEORIES, Although the chemical and physical basis of mucoadhesion are not yet well understood, there are six classical theories adapted from studies on the performance of several materials and polymer-polymer adhesion which explain the phenomenon (Hägerström, 2003; Huang et al., 2000; Smart, 2005). Electronic theory, Electronic theory is based on the premise that both mucoadhesive and biological materials possess opposing electrical charges. Thus, when both materials come into contact, they transfer electrons leading to the building of a double electronic layer at the interface, where the attractive forces within this electronic double layer determines the mucoadhesive strength (Mathiowitz, Chickering, Lehr, 1999)., Adsorption theory, According to the adsorption theory, the mucoadhesive device adheres to the mucus by secondary chemical interactions, such as in van der Waals and hydrogen bonds, electrostatic attraction or hydrophobic interactions. For example, hydrogen bonds are the prevalent interfacial forces in polymers containing carboxyl groups (Hägerström, 2003; Huang et al., 2000; Lee, Park, Robinson, 2000; Smart, 2005). Such forces have been considered the most important in the adhesive interaction phenomenon (Smart, 2005) because, although they are individually weak, a great number of interactions can result in an intense global adhesion (Mathiowitz, Chickering, Lehr, 1999). Wetting theory, The wetting theory applies to liquid systems which present affinity to the surface in order to spread over it. This affinity can be found by using measuring techniques such as the contact angle. The general rule states that the lower the contact angle then the greater the affinity (Figure 3). The contact angle should be equal or close to zero to provide adequate spreadability (Mathiowitz, Chickering, Lehr, 1999)., FIGURE 3 – Schematic diagram showing influence of contact angle between device and mucous membrane on bioadhesion., The spreadability coefficient, SAB, can be calculated from the difference between the surface energies γB and γA and the interfacial energy γAB, as indicated in equation (1) (Smart, 2005)., (1), The greater the individual surface energy of mucus and device in relation to the interfacial energy, the greater the adhesion work, WA, i.e. the greater the energy needed to separate the two phases (Smart, 2005)., (2), Diffusion theory, Diffusion theory describes the interpenetration of, both polymer and mucin chains to a sufficient depth to create a semi-permanent adhesive bond (Figure 4). It is believed that the adhesion force increases with the degree of penetration of the polymer chains (Mathiowitz, Chickering, Lehr, 1999). This penetration rate depends on the diffusion coefficient, flexibility and nature of the mucoadhesive chains, mobility and contact time (Hägerström, 2003; Huang et al., 2000; Lee, Park, Robinson, 2000; Smart, 2005). According to the literature, the depth of interpenetration required to produce an efficient bioadhesive bond lies in the range 0.2-0.5 µm. This interpenetration depth of polymer and mucin chains can be estimated by equation 3:, (3), where t is the contact time, and Db is the diffusion coefficient of the mucoadhesive material in the mucus. The adhesion strength for a polymer is reached when the depth of penetration is approximately equivalent to the polymer chain size (Mathiowitz Chickering, Lehr, 1999)., In order for diffusion to occur, it is important that the components involved have good mutual solubility, that is, both the bioadhesive and the mucus have similar chemical structures. The greater the structural similarity, the better the mucoadhesive bond (Mathiowitz Chickering, Lehr, 1999)., FIGURE 4 – Secondary interactions resulting from interdiffusion of polymer chains of bioadhesive device and of mucus., Fracture theory, This is perhaps the most-used theory in studies on the mechanical measurement of mucoadhesion (Mathiowitz Chickering, Lehr, 1999). It analyses the force required to separate two surfaces after adhesion is established (Hägerström, 2003; Smart, 2005). This force, sm, is frequently calculated in tests of resistance to rupture by the ratio of the maximal detachment force, Fm, and the total surface area, A0, involved in the adhesive interaction (equation 4):, (4), In a single component uniform system, the fracture force, sj, which is equivalent to the maximal rupture tensile strength, sm, is proportional to the fracture energy (gc), for Young’s module (E) and to the critical breaking length (c) for the fracture site, as described in equation 5:, (5), Fracture energy (gc) can be obtained from the reversible adhesion work, Wr (energy required to produce new fractured surfaces), and the irreversible adhesion work, Wi (work of plastic deformation provoked by the removal of a proof tip until the disruption of the adhesive bond), and both values are expressed as units of fracture surface (Af)., (6), The elastic module of the system (E) is related to the stress (s) and to the shear (e) by Hooke’s law:, (7), In equation 7, the stress is the ratio between force (F) and area (A0), and shear is given by the ratio between the variation of system thickness (Dl) and the original thickness (l0)., A criticism of this analysis is that the system under investigation must have known physical dimensions and should be constituted by a single and uniform material. In virtue of this, the relationship obtained cannot be applied to analyze the fracture site of a multiple component bioadhesive. In this case, the equation should be expanded to accommodate elastic dimensions and modules for each component. Besides, it must be considered that a failure of adhesion will occur at the bioadhesive interface. However, it has been demonstrated that the rupture rarely occurs at the surface, but near it (Mathiowitz Chickering; Lehr, 1999) or at the weakest point, which can be the interface itself, the mucus layer or the hydrated region of the mucus, as illustrated in Figure 5 (Smart, 2005)., Since the fracture theory is concerned only with the force required to separate the parts, it does not take into ac-, FIGURE 5 – Regions where the mucoadhesive bond rupture can occur., count the interpenetration or diffusion of polymer chains. Consequently, it is appropriate for use in the calculations for rigid or semi-rigid bioadhesive materials, in which the polymer chains do not penetrate into the mucus layer (Mathiowitz Chickering, Lehr, 1999). Mechanical theory, Mechanical theory considers adhesion to be due to the filling of the irregularities on a rough surface by a mucoadhesive liquid. Moreover, such roughness increases the interfacial area available to interactions thereby aiding dissipating energy and can be considered the most important phenomenon of the process (Peppas, Sahlin, 1996; Smart, 2005)., It is unlikely that the mucoadhesion process is the same for all cases and therefore it cannot be described by a single theory. In fact, all theories are relevant to identify the important process variables (Lee, Park, Robinson, 2000)., The mechanisms governing mucoadhesion are also determined by the intrinsic properties of the formulation and by the environment in which it is applied (Lee, Park, Robinson, 2000). Intrinsic factors of the polymer are related to its molecular weight, concentration and chain flexibility. For linear polymers, mucoadhesion increases with molecular weight, but the same relationship does not hold for nonlinear polymers. It has been shown that more concentrated mucoadhesive dispersions are retained on the mucous membrane for longer periods, as in the case of systems formed by in situ gelification. After application, such systems spread easily, since they present rheological properties of a liquid, but gelify as they come into contact the absorption site, thus preventing their rapid removal. Chain flexibility is critical to consolidate the interpenetration between formulation and mucus (Lee, Park, Robinson, 2000)., Environment-related factors include pH, initial contact time, swelling and physiological variations. The pH can influence the formation of ionizable groups in polymers as well as the formation of charges on the mucus surface. Contact time between mucoadhesive and mucus layer determines the extent of chain interpenetration. Super-hydration of the system can lead to build up of mucilage without adhesion. The thickness of the mucus layer can vary from 50 to 450 µm in the stomach (Smart, 2005) to less than 1µm in the oral cavity. Other physiological variations can also occur with diseases (Lee, Park, Robinson, 2000)., None of these mechanisms or theories alone can explain the mucoadhesion which occurs in an array of different situations. However, the understanding of these mechanisms in each instance can help toward the development of new mucoadhesive products (Smart, 2005).