Mechanisms of Action of Absorption Enhancers

Absorption promoters (penetration enhancers) can influence the mucosa in different ways:

• By acting on the mucous layer

• By acting on the membrane components

• By acting on the tight junctions

Figure 6.2. Tight junctions are intercellular connections that hold epithelial cells together at their apical end (left). An enlargement of a tight junction is also presented (right). With permission from Junginger and Verhoef (1998)

6.2.3.1 Action on the Mucus Layer

The mucous layer covering the cell surface of the mucosa can be seen as an unstirred layer, acting as a barrier to the diffusion of drug molecules (Marriott and Gergory, 1990). The main components of the mucous layers include water (up to 95% by weight), mucin (generally no more than 5% by weight), inorganic salts (about 1% by weight), carbohydrates, and lipids (Marriott and Gregory, 1990). Mucin represents more than 80% of the organic components of mucus (Lichtenberger, 1992) and controls the gel-like structure (Marriott and Gregory, 1990). Mucins are O-linked glycoproteins (Strous and Dekker, 1992). From a polymer science viewpoint, mucins are block copolymers with branched and unbranched blocks. Both types of the blocks have protein backbone chains, but the branched blocks have highly branched oligosaccharide chains attached to them (Peppas and Huang, 2004). Ionic surfactants have been found to be able to reduce the mucus viscosity and elasticity (Martin et al., 1978). On the other side absorption of drugs across any mucosal tissue may involve interactions with the mucus gel overlying the tissue. Bhat et al. (1996) demonstrated that drug binding to the mucus glycoproteins is nonspecific in nature with similar types of binding forces and can reduce the amount of free drug available for absorption.

In addition, mucoadhesive polymers are thought to interfere with the mucous layer, first by covering the mucous surface and then by interpenetration of the mucous network (Lehr et al., 1992c; Lehr et al., 1993; Peppas and Huang, 2004). As a consequence of both mechanisms, absorption enhancers are thought to reduce the barrier function of the mucus layer and increase drug permeability. On the other side, Schipper et al. (1999) could show that the binding of the mucoadhesive polymer chitosan (cf. Sect. 6.3.3.3) to the epithelial cell surface and subsequent absorption enhancing effect of the hydrophilic drug atenolol were significantly reduced in mucus producing and covered cell cultures (HT29-H cultures). When the mucus layer was removed prior to the addition of chitosan, the cell surface binding and absorption-enhancing effects of the chitosans were increased. It is suggested that the only modest absorption-enhancing effect of chitosan with mucus can be overcome by increasing the local concentrations of both chitosan and drug, i.e., through formulation of the chitosan into a particulate dosage form.

6.2.3.2 Action on Membrane Components

As already mentioned, the membranes of epithelial cells contain phospholipids and proteins. The hydrophobic interaction between the acyl chains of lipid molecules results in the formation of a well-organized phospholipid bilayer. These ordered bilayers are poorly permeable to both macromolecules and highly polar low molecular weight compounds. Numerous studies have shown that absorption enhancers can increase the permeability of membranes by affecting biological membrane components such as proteins and lipids.

In an early but very important review Swenson and Curatolo (1992) reported on methods for the enhancement of the oral absorption of polar drugs, including polar peptides and proteins. The enhancers reviewed are bile salts, anionic detergents, nonionic detergents, medium chain glycerides, salicylates, acyl amino acids, acyl carnitines, lysolecithin, ethylene diamine tetraacetic acid (EDTA), and various particulate systems. Also Anderberg and Artursson (1992) studied a series of surfactants registered in solid oral drug products. The effects of anionic sodium dodecyl sulfate (SDS) and nonionic (polysorbate 80 and polyoxyl 40 hydrogenated castor oil) surfactants as well as the effects of bile salts (sodium taurocholate, sodium taurodeoxycholate, and sodium taurodihydro-fusidate (STDHF)) on epithelial permeability and integrity were studied using Caco-2 cell monolayers. It was observed that all surfactants demonstrated a concentration-dependent effect on the permeability of hydrophilic markers. However, the effects of anionic surfactants were more pronounced compared to those of nonionic absorption enhancers. Altered cell morphology and cell membrane damage were observed after exposure to SDS, STDHF, and polysorbate 80. It was also shown that the absorption enhancers increased the permeability of marker molecules via the paracellular and transcellular routes.

The most likely mechanism by which low molecular weight absorption enhancers promote drug absorption is by solubilizing the phospholipids and membrane proteins, and thus increasing membrane permeability (Lichtenberg et al., 1983). In addition, surfactants, bile salts, and fatty acids influence both the transcellular and paracellular routes of absorption (Table 6.1). As most of the examples of the absorption enhancers given also possess (to some extent) surfactant-like properties, they might mix with the phospholipid bilayer of the membrane and thus be partly absorbed. This absorption could result not only in strong membrane damage, but also in toxic side-effects due to penetration interfering with cell organelles (Junginger and Verhoef, 1998).

A special class of absorption enhancers for hydrophilic compounds are cyclo-dextrins, which are cyclic oligosaccharides of six, seven, or eight d-glycopyranose units, denoted as a-, (3-, and y- cyclodextrins, respectively. The three-dimensional ring structure of these compounds resembles a truncated cone, of which the internal cavity has slight hydrophobic properties and the outer surface is hydrophilic. Because of these structural features, cyclodextrins can form inclusion complexes with lipophilic drugs, thereby increasing their solubility in aqueous solutions (Uekama et al., 1982; Szejtli, 1988). Just recently Mannila and coworkers (2005) studied the effects of randomly methylated ( -cyclodextrin on the sublingual bioavailabililty of various cannabinoids in rabbits and found increased uptake in the systemic circulation. Furthermore, cyclodextrins (particularly methylated ( -cyclodextrins) can enhance the nasal absorption of peptide drugs such as insulin, although marked interspecies differences have been reported (Verhoef et al., 1994). The mechanism of action of methylated (-cyclodextrins as absorption enhancers for hydrophilic drugs is probably by transiently changing the mucosal permeability (by extraction and inclusion of membrane cholesterol) and opening of the tight junctions (Marttin et al., 1997; Junginger and Verhoef, 1998).

Table 6.1. Classes of absorption enhancers and their mechanisms of action

Class

Examples

Mechanism

Transport ways

Surfactants

Na-laurylsulfate

Phospholipid acyl

Transcellularf

Polyoxyethelyne-

chain petrubation

Paracellularf

g-laurylether

Bile salts:

Na-deoxycholate

Reduction mucus

Na-glycocholate

viscosity Peptidase inhibition

Na-taurocholate

Fatty acids

Oleic acid Short fatty

Phospholipid acyl

Transcellularf

acids

chain petrubation

Paracellular

Cyclodextrins

a-, |3- and

Inclusion of membrane

Transcellularf

Y-cyclodextrin

compounds

Paracellularf

Methylated

| -cyclodextrins

Chelators

EDTA

Complexation of Ca2+

Transcellularf Paracellularf

Polycrylates

Opening of tight junctions

Paracellularf

Positively charged

Chitosan salts

Ionic interactions with

Paracellularf

polymers

Trimethyl chitosan

negatively charged groups of glycocalix

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