Biol. Pharm. Bull. 30(9) 1768—1772 (2007)

monly used in pharmacotherapy in ophthalmology as far as convenience and safety are concerned. However, absorption of drugs after instillation is restricted because of the barrier properties of surface ocular tissues, such as the cornea and conjunctiva. Use of penetration enhancers is one means of improving such restrictions. From a safety point of view, it is important to maintain the viability of the living epithelial cells after application of the enhancers. Among the penetration enhancers studied previously, cationic polymers such as chitosan, aminated gelatin, and poly-L-arginine are reported to increase the transepithelial absorption of peptide drugs by dissociation of tight junction assemblies which restrict the paracellular permeation in intestinal and nasal epithelia without producing significant epithelial damage. Thus, polycationic polymers may be useful penetration enhancers for ocular drug delivery. In a previous in vitro study, we showed that poly-L-arginine (PLA), a cationic polymer, with a molecular weight range of 14.0—141.4 kDa, increased the epithelial transport of pyridoxamine (MW: 241.1) and FITC-labeled dextran (MW ca. 3.8 kDa, FD-4) through the excised cornea, conjunctiva, and conjunctiva/sclera composite by changing paracellular permeability. Because the PLA-induced recovered after removal of PLA, similar to that reported in the nasal epithelium and PLA did not affect the cellular viability as depicted by MTT assay, PLA can be used as an absorption enhancer for ocular drug delivery. However, until now, the in vivo enhancing ability and potential toxicity of PLA after instillation have not been examined. The purpose of the present study was to evaluate the effect of PLA on the intraocular absorption of pyridoxamine and FD-4 and the potential toxic effects after instillation of PLA solution in rabbits. PLA with a molecular weight of 35.5 kDa was chosen for the present study. Drug concentrations in aqueous humor and vitreous body was measured after single and multiple instillations of PLA solution to evaluate the in vivo enhancing ability. The potential toxicity was evaluated by microscopic observation of the cornea, production of TNF-a , and thickness of the corneal epithelia and stroma which is used as an index of corneal inflammation.