ENHANCED SYSTEMIC ABSORPTION WITH PERMEATION ENHANCERS

VI. ENHANCED SYSTEMIC ABSORPTION WITH PERMEATION ENHANCERS

One of the major problems associated with the ocular delivery of peptide drugs is their poor systemic bioavailability. This may be overcome by using penetration enhancers. Most permeation enhancers need to be evaluated with caution, since most of these agents cause local irritation to the eye. Among them the most effective are Brij-78 and BL-9, because these com- pounds have been shown to enhance insulin absorption to a significant extent without causing any noticeable irritation (78). Table 6 lists the pene-

Peptides and Proteins as Therapeutic Agents 507 Table 6 Effects of Various Permeation Enhancers on Systemic

Absorption of Insulin Following Ocular Administration

Concentration

Insulin absorption

enhanced Permeation enhancer

of enhancer

Saponin 0.5 4.0 1.0 7.0

Fusidic acid 0.25 2.3 0.5 2.7 1.0 3.9 2.0 7.5

Polyethylene-9-laurylether (BL-9) 0.25 2.6 0.5 4.5 1.0 6.0 2.0 7.6

Polyethylene-20-stearylether (Brij 78) 0.5 6.8 1.0 6.3

Polyethylene-20-oleorylether (Brij 99) 0.5 4.0

tration enhancers that have been examined for enhancing insulin absorption by the ocular route and their relative performance (93). Saponin, fusidic acid, and Brij-99 possess high irritation potential and therefore cannot be used. As indicated earlier, the same surfactants are also capable of enhan- cing the absorption of calcitonin (101).

The permeability barrier of the corner to hydrophilic molecules is presumed to reside in the epithelial layer. The presence of tight junctions render the epithelium almost impermeable to all but the smallest molecules. Grass and Robinson have shown that the aqueous channel of the cornea has

a cut-off of around 90 D (102). Other studies have suggested a close relation- ship between epithelial permeability (or tight junction integrity) and the cell cytoskeleton (103,104). Treatment with cytochalasins or removal of extra- cellular calcium ions cause opening of tight junctions and increase tight junction permeability (105,106). Cytoskeletal modulators have been explored as corneal penetration enhancers (107,108). The efficacy of EDTA, bile salts, and cytochalasin B (109) in enhancing the ocular perme- ability of hydrophilic compounds has been examined. Cytochalasin B has the ability to increase corneal permeability with minimum membrane damage, indicating its potential as an ocular penetration enhancer. Further development of novel penetration enhancers with highly specific foci of action, good reversibility, and minimal toxicity is needed for any realistic delivery of peptides and proteins by the ocular route.

508 Dey et al.

VII. CONCLUSIONS With breakthroughs in biotechnology, newer and more potent peptide and

protein drugs are emerging in the market. The majority of these polypep- tides require special delivery systems. However, since most of these com- pounds are very potent, require low doses, and are well absorbed from the mucous membrane, their delivery via the ocular route may be viable. However, one of the principal problems in the ocular delivery of peptide and protein drugs is that of relatively low bioavailability to the ocular tissues. This problem may be circumvented by the use of penetration enhan- cers. The conjunctival administration of this class of compounds to achieve therapeutic levels in the systemic circulation may well be possible in the near future. We hope that novel drug delivery systems will be developed to deliver potent polypeptide drugs through the ocular route.

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