Topical Protein Administration To The

There are several reasons why proteins are not administered as eyedrops: administered liquid is rapidly cleared from the ocular surface, resulting in a contact time that is limited to a few minutes or even less. Still, ocular drop instillation is widely used in the treatment of glaucoma and other diseases with low-molecular-weight drugs (e.g., prostaglandins, b-blockers, a-2 agonists). These small, hydrophobic drugs are able to partition into the cornea epithelium at adequate rates to allow pharmacologically relevant levels of ocular drug absorption. However, larger molecules like proteins and larger peptides are (>10 kDa) are typically quite hydrophilic and do not readily partition into the corneal epithelium (14). Paracellular permeation of therapeutic proteins and peptides across the corneal epithelium is very slow because of the tight junctions. Hamalainen et al. estimated the paracellular space of the corneal epithelium with polyethylene glycol permeation studies and subsequent effusion-based analysis of the pores (15). They concluded that the limiting paracellular pore size is about 2 nm in diameter, with a surface porosity of only 10~7. Thus, these narrow paracellular pores and the lipoidal cell membranes can dramatically block the permeation of proteins with diameters greater than 2 nm.

A metabolic barrier at the surface further limits the possibilities for significant protein drug absorption from tear fluid into the anterior segment of the eye. There are both endopeptidases and aminopeptidases in the corneal epithelium that limit the absorption of peptides and proteins (16). Overall, it is clear that transcorneal delivery of proteins does not work and other approaches are needed.

More than 20 years ago, Ahmed and Patton demonstrated that large molecules can permeate from the tear fluid into the eye via conjunctiva and sclera rather than through the cornea (11). The conjunctiva is more permeable than the cornea, particularly for hydrophilic and large molecules. Also, the sclera allows permeation of large molecules, and permeability across this membrane is not dependent on lipophilicity of the drug. Why is the cornea then considered to be the main absorption route for lipophilic drugs? Permeation of lipophilic drugs is similar in these two routes, and some drug is lost to the blood stream via the circulation in the conjunctiva. For large, protein-sized compounds, the relative permeability of the cornea is much less than that in the conjunctiva and sclera (16-18). Therefore, the noncorneal route of permeation may be advantageous for proteins (18). Accordingly, also the metabolic barrier (peptidases and proteases) is less prevalent in the conjunctiva than in the cornea (16).

Still today, the potential of the noncorneal route of protein absorption from the ocular surface to the inner eye has not been fully explored. Utilization of this route would require improved formulations that prolong the retention and improve permeation into the conjunctiva. Currently, cyclosporin is the only peptide or protein drug that is administered by topical ocular route. This hydrophobic peptide is given as an eyedrop emulsion to treat the condition known as dry eyes (19).

0 0

Post a comment