Transport Across the Epithelial Barrier

The oral, buccal, nasal, vaginal, and rectal cavities are all internally lined with one or more layers of epithelial cells. Depending on the position and function in the body, epithelial cells can be of varied forms, ranging from simple columnar, to cuboidal, to squamous types. Irrespective of their morphological differences, these cells are extremely cohesive. The lateral membrane of these cells exhibits several specialized features that form intercellular junctions (tight junction, zonula adherens, and gap junction), which serve not only as sites for adhesion but also as seals to prevent flow of materials through the intercellular spaces (paracellular pathway) and to provide a mechanism for intercellular communication. Below the epithelial cells is a layer of connective tissue called the lamina propria, which is bound to epithelium by the basal lamina. The latter also connects epithelium to other neighboring structures. The luminal side of the epithelium is covered with a more or less coherent, sticky layer of mucus. This is the layer that first interacts with foreign materials (e.g., food, drugs, bacterial organisms, and chemicals).

Various transport processes used by low molar mass drugs to cross the epithelial barrier lining oral, buccal, nasal, vaginal, and rectal cavities include passive diffusion, carrier-mediated transfer systems, and selective and nonselective endocytosis. Additionally, polar materials can also diffuse through the tight junctions of epithelial cells (the paracellular route). Evidence also exists that suggests that macromolecules (particulate and soluble), including peptides and proteins, can reach the systemic circulation, albeit in small amounts, following administration by these routes. This offers potential in certain therapies, such as immune reactions and hormone replacement treatments. Both passive-and active-transport pathways may occur simultaneously. Passive transport is usually higher in damaged mucosa, whereas active transport depends on the structural integrity of epithelial cells.

Harris (27) reported that nasal administration of biopharmaceuticals (polypeptides) resulted in bioavailabilities of the order 1% to 20% of administered dose, depending on the molar mass and physiochemical properties of the drug. It is widely accepted that macromolecules with a molar mass of less than 10,000 can be absorbed from the nasal epithelium into the systemic circulation in sufficient amounts without the need for added materials, except for bioadhesives (28). Larger molecules, such as proteins [e.g., interferon, granulocyte colony-stimulating factor (G-CSF), and human growth hormone], however, require both a penetration enhancer (e.g., bile salts and surfactants) and a bioadhesive. Since the entire dose passes through one tissue, these flux enhancers may cause deleterious effects to the nasal mucosa and muciliary function. Cyclodextrins (29) and phospholipids (30) have been reported to significantly increase the absorption of macromolecules without causing any damage to the nasal mucosal membrane. The phospholipid approach is particularly attractive in that phospholipids are biocompatible and bioresorbable and thus pose no threat of toxicity. Lectin isolated from Bandeiraea simplicifolia has been shown to be almost exclusively specific to the M cells of nasalassociated lymphoid tissue and hence offers potential for targeting the upper respiratory tract (31,32).

The transport of macromolecules across intestinal epithelium may occur by cellular vesicular processes involving either fluid-phase pinocytosis or specialized (receptor-mediated) endocytic processes (33). Matsuno et al. (34) reported that spheres of 20 nm in diameter, when given orally to suckling mice, pass through the epithelial layer and become localized in the omentum, the Kupffer cells of the lumen, the mesenteric lymph nodes, and even the thymic cortex. Studies with poly(alkylcyanoacrylate) nanocapsules smaller than 300 nm in size suggest that particles can also pass intact through the intestinal barrier by the paracellular route (35). Harush-Fenkel et al. (36) reported a reduced permeation of positively and negatively charged poly(ethylene glycol)-D,L-polylactide (PEG-PLA) nanoparticles (size 89.6 ± 4 nm and 96.4 ± 3 nm, respectively) through the apical plasma membrane of the polarized epithelial cells of the GI tact. This was attributed, in part, to the mucosal barrier and low endocytosis rates at the apical side of the membrane. Both cationic and anionic nanoparticles were reported to enter the cells mainly by the clathrin-mediated endocytic pathway; the positively charged particles showed increased uptake than the negatively charged counterparts. A significant amount of nanoparticles transcytosed and accumulated in the basolateral membrane. Some anionic but not cationic nanoparticles routed through the lysosomal degradative pathway. These results suggested that positively charged particles show potential not only for delivering drugs to epithelia but also for transcytosing drugs in the blood circulation.

The M cells found in Peyer's patches have also been suggested to transport particles. These are specialized absorptive cells known to absorb and transport indigenous bacteria (i.e., Vibrio cholerae)\ macromolecules, such as ferritin and horseradish peroxidase; viruses; and carbon particles, from the lumen of the intestine to submucosal lymphoid tissue (33,37,38). It has been reported that hydrophobic, negatively charged or neutral particles of size smaller than 5 |im are better taken up by M cells; particles smaller than 1 |im in size accumulate in the basal medium, while larger particles remain entrapped in the Peyer's patches (39). Transport of absorbed materials to the systemic circulation through lymph fluid and by lymphocytes has also been suggested to be possible. An increase in the lymph flow or a decrease in the blood supply could make lymphatic uptake of particles important (37). Since Peyer's patches are more prevalent and larger in young individuals and drastically decrease with increasing age, the transport by this route is of significance in younger individuals (40). Lectins [e.g., Ulex europaeus agglutinin 1 (UEA-1)] show high specificity for sugar residues of glycoconjugates present on cell surfaces and are thus useful for drug and antigen targeting nasal, intestinal, cecal, and other epithelia M cells (41).

Various physicochemical, physiological, and biochemical factors that can influence the absorption of drugs, including peptides and proteins, from the GI tract have been reviewed (39,42-44). A variety of penetration enhancers have been found useful in improving intestinal absorption of peptides and other macromolecular drugs. These include chelators (e.g., ethylene diamine tetraacetic acid and citric acid); natural, semisynthetic, and synthetic surfactants (e.g., bile salts, derivatives of fusidic acid, sodium lauryl sulfate, polyoxyethylene-9-laurylether, and polyoxyethylene-20-cetylether); fatty acids and their derivatives (e.g., sodium caprate, sodium laurate, and oleic acid); and a variety of mixed micelle solutions (45,46). It must be noted that the sensitivity of penetration enhancers varies depending on the regions; a general rank order suggested for different regions is rectum > colon > small intestine > stomach. Although considerable progress has been made, the bioavailabilities of macromolecules (peptides/proteins) delivered via these routes are often suboptimal because of their poor absorptions and stabilities (45,47).

Absorption of drugs from the buccal cavity occurs via transcellular and paracellular pathways; the latter being the predominant route of absorption. Drugs administered in the oral cavity avoid the hepatic first-pass effect and reach the systemic circulation through the reticulated vein and jugular vein (48). A number of hydrophilic macromolecules, such as peptides, oligopeptides, and polysaccharides, have been investigated. However, there is little evidence to suggest that soluble or particulate macromolecules can be transported across the buccal mucosa (49). Recently, it has been suggested that lectins or lectin-like molecules, which can bind to cell surface glycoconjugates, or systems containing ligands specific to endogenous lectins located on epithelial surface, could be used to target and improve delivery by this route (41,48).

The absorption of drugs from the rectal cavity has been studied in some detail (50). Muranishi et al. (51) have shown that a significant increase in the absorption and lymphatic uptake of soluble and colloidal macromolecules can be achieved by pretreating the rectal mucosal membrane with lipid-nonionic surfactant mixed micelles. They found no evidence of serious damage of the mucosal membrane. Davis (47) suggested that the vaginal cavity could be an effective delivery site for certain pharmaceuticals, such as calcitonin, used for the treatment of postmenopausal osteoporosis. Working with a human ex vivo uterine perfusion model, Bulletti et al. (52) demonstrated that drugs, when delivered vaginally, first undergo uterine pass effect, suggesting that the vaginal route can be used to target drugs to the uterus.

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