Barrier conjunctival

Basic hydrodynamic phenomena govern the duration of exposure of corneal and conjunctival membranes to the therapeutic agents. Rapid clearance provides a temporal barrier to drug delivery. 

Because mucin and/or cilia systems of AIC cultured epithelial cells may work as a barrier for drug transport, lower Papp values are expected in cell layers cultured in AIC than in LCC methods. However, it was interesting to note that no significant differences in Rapp values were observed between the cell layers cultured with the two methods (Table 9.1). This is in contrast to solute permeabilities reported previously for cell layers cultured with LCC versus AIC methods [76, 80], For example, Yang et al. reported that Rapp of lipophilic solutes (e.g., various /3-blockers) across the primary cultured conjunctival epithelial cell layer are about threefold lower when cultured under AIC than LCC conditions, suggesting that the permeability of AIC cultured cell layers generally better reflects that of the excised tissue than LCC counterparts. Mathias et al. [76] also reported that the permeability of hydrophilic solutes across the primary rabbit tracheal epithelial cell layer cultured under AIC conditions was only half of that observed for cell layers cultured under... 

Chapter 13 The Conjunctival Barrier in Ocular Drug Delivery 309... 

P. Saha, K. J. Kim, and V. H. Lee. A primary culture model of rabbit conjunctival epithelial cells exhibiting tight barrier properties. Curr Eye Res 15 1163-1169... 

Similarly, the 4-methoxy-2-naphthylamides of Leu, Ala, Arg, and Glu (6.1, R=side chain of amino acid, R =MeO) were used to assess the type and activity of aminopeptidase in homogenates of conjunctival, nasal, buccal, duodenal, ileal, rectal, and vaginal tissues from rabbits. This systematic comparison afforded a better understanding of the role of the aminopeptidase barrier in peptide absorption from oral vs. non-oral routes [18]. In a comparable manner, the y-glutamyltranspeptidase and dipeptidase activities were investigated in mammary tissue with the 4-nitroanilides of Leu, Met, Lys, Glu, and Asp (6.2, R=side chain of amino acid) [19]. 

The limbus is the anatomic junction between the transparent cornea and the conjunctiva, a tissue in which the vessels circulate. At this level, there would be the limbal stem cells, cells generating the differentiated epithelial cells of the cornea. The essential property of the cornea is transparency. The seriousness of the ocular bum consists in the loss of the comeal transparency. Actually the limbus is a real barrier to the conjunctiva. In the following months, a serious ocular bum will result in the development of a conjunctival cover leading to a loss of vision. 

The limbus autograft requires a good quality corneal reepithelialization for 75-100% patients and the constitution of a barrier preventing the neovascular cicatricial phenomena of conjunctival origin [18, 21, 22]. The date of intervention from the date of bum is a subject of argument. Most authors consider that it is better to wait several months for the inflammatory reaction to decrease. However, some authors recommend an earlier intervention, before the development of complications due to the LSC deficit [16, 23]. 

The superficial two to three cell layers of the corneal and conjunctival epithelium are the main barrier for the permeation of topically applied compounds. In this rate-limiting cell layer, the transcellular permeation is dictated by the lipophilicity of the cell membrane whereas the paracellular permeation is limited by the paracellular pore size and density. Vesicular penetration (e.g., receptor- or endocytosis-mediated) of macromolecules across surface epithelium is possible [33], However, the proposed mechanism is energy consuming (e.g., incorporation into pinocytotic vesicles and phagosomes) and thus more feasible in cell lines with abundant intracellular energy sources like corneal endothelium and RPE [34-37]. 

An absorption promoter can control the extent and pathway of the ocular and systemic absorption of instilled drug solution by altering not only the corneal but also the conjunctival drug penetration. Most of the agents discussed above show different effects on the corneal and conjunctival membranes. The different response of corneal and conjunctival barriers to absorption promoters can be exploited and used to control the extent and pathway of the ocular and systemic absorption of drugs instilled into the eye. The mechanism of action of absorption promoters and the barrier properties of membranes are the two factors that define drug permeability. 

In addition to the corneal route, topically applied ocular drugs may be absorbed via a noncorneal absorption route that involves drug transport across the bulbar conjunctiva and underlying sclera into the uveal tract and vitreous humor.65 The intercellular spaces of the conjunctival epithelium are wider than those of the corneal epithelium. As a result, the conjunctiva has higher permeability than the cornea to agents such as mannitol, inulin, and FITC-dextran.86 The penetration of peptides, however, is limited by enzymatic degradation.87 The limit of molecular size for conjunctival penetration is between 20,000 and 40,000 Da. Vitreous can act as an aqueous and unstirred diffusion barrier to drug permeation.64... 

Figure l6-3 Fluorescein photograph of conjunctival staining taken without barrier filter. (From Courtney RC, Lee JM. Predicting ocular intolerance of a contact lens solution by use of a filter system enhancing fluorescein staining detection. Int Contact Lens CUn 1982 9 302-310.)... 

Propionibacterium acnes, commonly isolated from the skin, is the most frequently found anaerobe. Factors and conditions such as blepharitis, dry eye syndrome, meibomian gland dysfunction, and contact lens use may influence the composition of the normal flora or cause disruption to normal epithelial microbial barriers, either of which can lead to disease in susceptible patients. Although immunocompromised individuals may harbor Candida albicans, fungi are considered opportunistic pathogens. Little evidence supports the existence of any indigenous fungi in the normal conjunctival flora. 

Other major physiological barrier mechanisms are due to tear production and the blink reflex. The conjunctival and corneal surfaces of the eye are continuously lubricated by a film of fluid secreted by the conjunctival and lachrymal glands. The lachrymal glands secrete a watery fluid called tears, and the sebaceous glands on the margins of the eyelids secrete an oily fluid which spreads over the tear film. The latter reduces the rate of evaporation of the tear film from the exposed surface of the eyes. Blinking assists to evenly spread the tear film over the surface of the eye and to drain the tears via the nasolachrymal duct into the nose, and ultimately down the back of the throat into the gastro-intestinal (GI) tract. 

---