Ocular absorption

Hyaluronic acid is a linear polysaccharide found in the highest concentrations in soft connective tissues where it fills an important structural role in the organization of the extracellular matrix (23,24). It has been used in ophthalmic preparations to enhance ocular absorption of timolol, a beta blocker used for the treatment of glaucoma (25), and in a viscoelastic tear formulation for conjunctivitis (26). The covalent binding of adriamycin and daunomycin to sodium hy-aluronate to produce water-soluble conjugates was recently reported (27). 

Fig. 9 Pharmacokinetic scheme for ocular absorption, distribution, and elimination.

Wilson, C. G. Tomlinson, E. Davis, S. S. Olejnik, O., Altered ocular absorption and disposition of sodium cromoglycate upon ion-pair and complex coacervate formation with dodecylbenzyldimethyl-ammonium chloride, J. Pharm. Pharmacol. 31, 749-753 (1981). 

Although the ocular absorption of peptide as well as nonpeptide drugs is poor [96,196-198], the ocular route is by far the least studied for the usefulness of penetration enhancers. This is in part due to the perceived sensitivity of ocular tissues to irritation and the fear of corneal and conjunctival damage caused by the enhancers. Whereas the rat nasal epithelium may tolerate up to 5% sodium glycocholate [199], ocular administration of sodium glycocholate at a concentration of 2% and beyond induces reddening of the eye and tear production in rabbits (Kompella and Lee, unpublished observation). 

Nevertheless, there are reports on enhancement of ocular drug absorption by bile salts [33], surfactants [200], and chelators [149], Newton et al. [35] demonstrated that Azone, an enhancer widely tested in transdermal drug delivery [201], increased the ocular absorption of cyclosporine, an immunosuppressant, by a factor of 3, thereby prolonging the survival of a corneal allograft. In 1986, Lee et al. [34] reported that 10 pg/mL cytochalasin B, an agent capable of condensing the actin microfilaments, increased the aqueous humor and iris-ciliary body concentrations of topically applied inulin (5 kDa) by about 70% and 700%, respectively, in the albino rabbit. 

Morimoto et al. [33] demonstrated that the ocular absorption of hydrophilic compounds over a wide range of molecular weights could be increased by 2 and 10 mM sodium taurocholate and sodium taurodeoxycholate in a dose-dependent manner. The compounds were glutathione (307 Da), 6-carboxyfluorescein (376 Da), FTTC-dextran (4 kDa), and insulin (5.7 kDa). Of the two bile salts, sodium taurodeoxycholate was more effective. At 10 mM, this bile salt increased the permeability of 6-carboxyfluorescein from 0.02% to 11%, glutathione from 0.08% to 6%, FITC-dextran from 0% to 0.07%, and insulin from 0.06% to 3.8%. Sodium taurocholate, on the other hand, increased the permeability to 0.13%, 0.38%, 0.0011%, and 0.14%, respectively. Taurodeoxycholate was more effective than taurocholate in the nasal epithelium as well [202], This difference in activities can possibly be attributed to their micelle-forming capability, which is higher for taurodeoxycholate, a dihydroxy bile salt [190],... 

VHL Lee, S Li, MF Saettone, P Chetoni, H Bundgaard. (1991). Systemic and ocular absorption of timolol prodrugs from erodible inserts. Proc Int Symp Controlled Release Bioact Mater 18 291-292. 

U Pleyer, B Elkins, D Ruckert, S Lutz, J Grammer, J Chou, KH Schmidt, BJ Mon-dino. (1994). Ocular absorption of cyclosporine A from liposomes incorporated into collagen shields. Curr Eye Res 13 177-181. 

VHL Lee, LW Carson, S Dodda Kashi, RE Stratford Jr. (1986). Metabolic and permeation barriers to the ocular absorption of topically applied enkephalins in albino rabbits. J Ocular Pharmacol 2 345-352. 

DS Chien, RD Schoenwald. (1986). Improving the ocular absorption of phenylephrine. Biopharm Drug Disp 7 453-462. 

AK Mitra, TJ Mikkelson. (1982). Ophthalmic solution buffer systems. I. The effect of buffer concentration on the ocular absorption of pilocarpine. Int J Pharm 10 219-229. 

Jarvinen K, Jarvinen T, Urtti A. Ocular absorption following topical delivery. Adv Drug Deliv Rev 16 3-19 (1995). 

Toropainen E, Ranta VP, Talvitie A, Suhonen P, Urtti A. Culture model of human corneal epithelium for prediction of ocular absorption. Invest Ophthalmol Vis Sci 42 2942-2948 (2001). 

The relative contributions of dermal/ocular absorption, ingestion, and inhalation of silver compounds to the development of these ocular deposits and skin color changes are not known. However,... 

Individual members of the AG and SEFA family have been studied for their ability to promote the nasal and ocular absorption of peptide drugs in rats, mice, cats, dogs, and monkeys [1,6,10,53,54,84—90]. Dose-escalation studies were conducted in rats to determine the potencies of each of the AGs and SEFAs as enhancers for the ocular and nasal absorption of insulin and to determine the contribution of the alkyl chain and the sugar moiety. Insulin... 

Pillion, D.J., S. Hosmer, and E. Meezan. 1998. Dodecylmaltoside-mediated nasal and ocular absorption of lyspro-insulin Independence of surfactant action from peptide multimer dissociation. Pharm Res 15 1641. 

Drug Delivery Systems for Enhanced Ocular Absorption... 

Drug binding to tear proteins resulting in a lower free drug concentration for ocular absorption... 

Using a new approach that involves the utilization of the mucoadhesive property of polymers to improve the ocular absorption of poorly absorbed drugs. 

Even though we are currently far from having penetration enhancers that fulfill all or most of the above requirements, several classes of ocular absorption enhancers, however, are being evaluated for their suitability under the conditions of use by various groups. This chapter aims to discuss various classes of ocular absorption enhancers, along with the basic modes of drug transport and the mechanism by which these penetration enhancers act. Further, new categories of penetration enhancers, which have been reported more recently, are also included. 

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