Kenzo Yamamura

Ophthalmic Preservatives as Absorption Promoters for Ocular Drug Delivery

The effects of ophthalmic preservatives on the drug permeability through isolated ocular membranes of albino rabbits were investigated using a two‐chamber glass diffusion cell. Tilisolol and fluorescein isothiocyanate (FITC)‐dextrans (average molecular weights 4400 and 9400 Da; FD‐4 and FD‐10, respectively) were used as model penetrants of ophthalmic β‐blockers and peptide drugs. Preservatives significantly enhanced the corneal penetration of not only tilisolol but also FITC‐dextrans. Especially, benzalkonium chloride increased the corneal permeability of FD‐4 and FD‐10 by 28·8 and 37·1 times, respectively. These results indicate the usefulness of ophthalmic preservatives as absorption promoters for the ocular delivery of β‐blockers and hydrophilic macromolecules. Preservatives also enhanced the conjunctival permeability of tilisolol, FD‐4 and FD‐10. The promoting effect of preservatives on the conjunctival drug penetration was smaller than that on the corneal one. Preservative increased the ratio of corneal to conjunctival permeability of tilisolol, FD‐4 and FD‐10.

Effect of Preservatives on Systemic Delivery of Insulin by Ocular Instillation in Rabbits

Abstract— The effects of absorption promoters and ophthalmic preservatives on the systemic absorption of insulin through the ocular route were investigated in albino rabbits. Insulin absorption was evaluated by its hypoglycaemic response. Although ocular instillation of insulin alone did not decrease the serum glucose concentration, instillation of insulin with absorption promoters such as EDTA and saponin decreased it. The promoting effect depended on the concentration of the absorption promoters. Of ophthalmic preservatives investigated (benzalkonium chloride, paraben, 2‐phenylethanol, benzyl alcohol and sorbic acid), benzal‐konium, chloride and paraben showed promoting effects. The promoting effect for benzalkonium chloride was reversible and dependent on concentration of both benzalkonium chloride and insulin in the formulation.

Controlled release and ocular absorption of tilisolol utilizing ophthalmic insert-incorporated lipophilic prodrugs

To control ocular drug delivery, the O-butyryl ester prodrug of tilisolol (BUTL) and the O-palmitoyl ester prodrug of tilisolol (PalTL) were incorporated into an ophthalmic insert. The released TL from BUTL inserts and PalTL inserts in pH 7.4 phosphate-buffered saline until 5 h were approximately 25% and 3% of that from TL inserts, respectively. In addition, BUTL was also released from BUTL inserts. However, PalTL was not released from the PalTL insert. The release of drugs from TL inserts and BUTL inserts was little affected by the addition of bovine serum albumin (BSA) in pH 7.4 phosphate-buffered saline. In contrast, the release of drugs from PalTL inserts were enhanced by the addition of BSA. After application of TL, BUTL, and PalTL inserts to the rabbit eye, the aqueous humor concentration of TL was prolonged compared with TL instillation, and the plasma concentration of TL was much lower than that of TL instillation. The ratios of the area under the TL concentration-time curve (AUC) in the aqueous humor to AUC in the plasma (AUC(aqueous)/AUC(plasma)) after application of BUTL until 8 h were 3.1-fold and 3.8-fold higher than those of the TL insert and PalTL insert, respectively.

Penetration of β-Blockers through Ocular Membranes in A1bino Rabbits

The purpose of this study was to investigate the barrier properties of ocular membranes for controlling the extent and pathway of ocular absorption of instilled β‐blockers.

Ocular Permeability of FITC-Dextran with Absorption Promoter for Ocular Delivery of Peptide Drug

The purpose of this study is to characterize an ocular permeability of FITC-dextran, as a model of peptide drug, and to evaluate the effects of absorption promoters on the ocular permeability of FITC-dextran. The in vitro penetrations of FITC-dextrans (average molecular weight 4400 and 9400: FD-4 and FD-10) were measured across the isolated corneal and conjunctival membranes of albino rabbits using a two-chamber glass diffusion cell. The corneal permeabilities of FD-4 and FD-10 were much lower than the conjunctival permeabilities. Scraping of corneal epithelium extremely increased the corneal permeabilities. The penetration parameters were estimated according to Ficks equation. Absorption promoters such as EDTA, taurocholic acid, benzalkonium chloride and saponin significantly increased corneal permeabilities of FD-4 and FD-10. Saponin showed the highest promoting activity. Conjunctival permeabilities of FD-4 and FD-10 were also enhanced by absorption promoters although the improvements of conjunctival permeabilities by absorption promoters were smaller than those of corneal permeabilities. Ratios of corneal to conjunctival permeabilities were enhanced by absorption promoters. These results indicate that an ocular delivery of instilled hydrophilic macromolecule is markedly low and a selective use of absorption promoter can improve the extent and pathway of its ocular absorption.

Sustained ocular delivery of tilisolol to rabbits after topical administration or intravitreal injection of lipophilic prodrug incorporated in liposomes

To improve the retention time of tilisolol in the precorneal area or vitreous body, we prepared liposomes incorporating the O‐palmitoyl prodrug of tilisolol. O‐Palmitoyl tilisolol was completely incorporated in the liposomes. After topical administration of O‐palmitoyl tilisolol liposomes to the rabbit eye, O‐palmitoyl tilisolol rapidly disappeared from the tear fluid. The inclusion of 2% carmellose sodium slightly prolonged the retention of O‐palmitoyl tilisolol in the tear fluid. After intravitreal injection of O‐palmitoyl tilisolol liposomes, there was a relatively prolonged retention of O‐palmitoyl tilisolol in the vitreous body. At 24 and 48 h after intravitreal injection of O‐palmitoyl tilisolol liposomes, the tilisolol concentration in the vitreous body was significantly higher compared with the concentration after intravitreal injection of tilisolol liposomes.

Characterization of ocular pharmacokinetics of beta-blockers using a diffusion model after instillation.

AbstractPurpose. To characterize the ocular pharmacokinetics of beta-blockers (timolol and tilisolol) after instillation in the albino rabbit using a mathematical model that includes a diffusion process. Methods. The disposition of fluorescein isothiocyanate-dextran (FITC-dextran, molecular weight 4400), timolol, and tilisolol was determined in tear fluid and aqueous humor after instillation or ocular injection in rabbits. The in vivo penetration parameters were estimated by fitting the concentration-time profiles to the Laplace equations based on a diffusion model using MULTI(FILT) program. Thein vivo permeability of drugs was measured across cornea using a two-chamber diffusion cell. Results. Concentration-time profiles of drugs in the tear fluid after instillation showed a monoexponential curve. Although a monoexponential curve was observed in the aqueous humor concentration of FITC-dextran after injection into the aqueous chamber, timolol and tilisolol showed a biexponential curve. On the basis of these results, anin vivo pharmacokinetic model was developed for estimation of penetration parameters. The in vitro partition parameters were higher than those of the in vivo parameters. Conclusions. The ocular absorption of timolol and tilisolol was characterized using an in vivo pharmacokinetic model and in vivo penetration parameters.

Ocular Membrane Permeability of Hydrophilic Drugs for Ocular Peptide Delivery

The purpose of this study is to investigate the ocular membrane permeability and the permeation mechanism of hydrophilic drugs such as thyrotropin‐releasing hormone (TRH), p‐nitrophenyl β‐cellopentaoside (PNP) and luteinizing hormone‐releasing hormone (LHRH).

In-situ Ocular Absorption of Ophthalmic β-Blockers through Ocular Membranes in Albino Rabbits

Ocular membranes have been characterized by in‐situ absorption of the ophthalmic β‐blockers carteolol (hydrophilic) and timolol and befunolol (lipophilic) using a cylindrical cell.