Tilisolol Hydrochloride

The purpose of this study is to characterize the transport of tilisolol and timolol through the corneal epithelium, which is believed to be a tight barrier of ocular drug absorption. Cultured normal rabbit corneal epithelial cells (RCEC) were used to investigate drug transport. Primary RCEC were seeded on a filter membrane of Transwell-COL insert coated with fibronectin and grown in Dulbecco's modified Eagle's medium/nutrient mixture F-12 with various supplements. Beta-blocker permeability through the RCEC layer was measured to assess the transcellular permeability coefficient (P(transcell)) in the absence or presence of inhibitors. The transcellular permeability of tilisolol was dependent on drug concentration although timolol showed no concentration dependency. Tilisolol flux from the apical to the basal side was larger than in the opposite direction although timolol showed no direction dependency. The transcellular permeability of tilisolol from the apical to the basal side was inhibited by sodium azide, tetraethylammonium, quinidine, taurocholic acid, guanidine and carnitine. Tilisolol had an active mechanism in uptake to the corneal epithelium, probably by the organic cation transporter family, although timolol predominantly permeated via passive diffusion. This RCEC system was useful to characterize the ocular permeation mechanism of drugs.

We newly prepared a unique one-side-coated insert that releases drug from only uncoated side. The purpose of this study is to determine whether ocular and systemic absorption of ophthalmic drug could be altered by an inserting direction of the insert in rabbit eyes. One-side-coated insert was prepared by attaching a polypropylene tape on the one side of the polymer disc of poly(2-hydroxypropyl methacrylate) (HPM) containing tilisolol as a model ophthalmic drug. The insert was applied in the lower conjunctival cul-de-sac of albino rabbits with the uncoated side facing bulbar conjunctiva/sclera (SC insert) or palpebral conjunctiva (CJ insert). At the adequate intervals, the tear fluid, plasma, aqueous humor, conjunctiva, and sclera were collected and the drug concentrations were determined by an HPLC. A release of tilisolol from the one-side-coated insert was twice slower than from the uncoated insert. Ocular application of the one-side-coated insert produced the constant concentrations of tilisolol in the tear fluid over 180 min. SC insert showed higher drug concentrations in the aqueous humor and sclera, and lower drug concentrations in the plasma and conjunctiva than CJ insert.The one-side-coated insert can alter the ocular and systemic absorption of drug by an inserting direction.