Ocular toxicity of some corneal penetration enhancers evaluated by electrophysiology measurements on isolated rabbit corneas.
The influence on electrical resistance and membrane potential of rabbit corneas in vitro of some chemicals used as adjuvants in ophthalmic formulations was investigated, in the attempt to correlate changes in electrophysiological properties of the corneal tissue (possibly indicative of toxic/damaging effects to the corneal epithelium), with the promoting effect of the substances on transcorneal permeation in vitro of timolol maleate (TM). The chemicals, tested at different concentrations, were benzalkonium chloride (BAC), sodium ethylenediaminetetraacetate (EDTA), polyoxyethylene-20-stearyl ether (PSE), polyethoxylated castor oil (PCO), deoxycholic acid sodium salt (DC) and cetylpyridinium chloride (CPC). For these substances, definite correlations were found between promoting activity for permeation of TM and modification of electrophysiological parameters. These parameters were in all cases significantly altered by all agents at all concentrations after a 5-h contact. However, after a 1-h contact, 0.001% PSE and CPC did not significantly modify the corneal resistance, while PCO and PSE did not significantly modify the transcorneal potential at the tested concentrations. Only 0.001% PSE, a nonionic surfactant used as solubilizer and emulsifier, active as promoter for TM, did not modify both electrophysiological parameters to a significant extent after 1 h. The results of this study indicate correlations between ocular toxicity, promoting activity for transcorneal permeation of timolol and modification of the electrophysiological parameters.
Chetoni
P
P
Department of Bioorganic Chemistry and Biopharmaceutics, University of Pisa, 33 I-56126, Italy. chetonip@farm.unipi.it
Burgalassi
S
S
Monti
D
D
Saettone
M F
MF
D000277:Adjuvants, Pharmaceutic / Q000633:toxicity*; D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics; D000818:Animals; D001647:Bile Acids and Salts / Q000493:pharmacokinetics; D002614:Chelating Agents / Q000493:pharmacokinetics; D003315:Cornea / Q000187:drug effects / Q000378:metabolism*; D004492:Edetic Acid / Q000493:pharmacokinetics; D017097:Electric Impedance; D004594:Electrophysiology; D005128:Eye Diseases / Q000139:chemically induced* / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D010539:Permeability / Q000187:drug effects; D000644:Quaternary Ammonium Compounds / Q000493:pharmacokinetics; D011817:Rabbits; D013501:Surface-Active Agents / Q000493:pharmacokinetics; D013999:Timolol / Q000493:pharmacokinetics
D000277:Adjuvants, Pharmaceutic; D000319:Adrenergic beta-Antagonists; D001647:Bile Acids and Salts; D002614:Chelating Agents; D000644:Quaternary Ammonium Compounds; D013501:Surface-Active Agents; D013999:Timolol; D004492:Edetic Acid