MODIFICATION OF OCULAR AND SYSTEMIC ABSORPTION OF TIMOLOL FROM OCULAR INSERTS BY A BUFFERING AGENT AND A VASOCONSTRICTOR

Alkyl monoesters of poly(vinyl methyl ether-maleic anhydride) (PVM-MA) are promising bioerodible polymers for controlling drug release. The dissolution of these polymers and drug release from them are highly dependent on the pH on the polymer surface. In this study, we examined the effects of disodium phosphate buffer on in vivo release, and on ocular and systemic absorption of timolol given in matrices of monoisopropyi ester of PVM-MA ocularly in rabbits. The vasoconstrictor methaoxedrine was added to some matrices to reduce the systemic absorption of timolol. Timolol concentrations in tear fluid and plasma were measured using a radioreceptor assay. [3H]Timolol-labeled matrices were used to study ocular absorption of timolol. The unbuffered matrix yielded a lower peak concentration of timolol in tear fluid (64 ± 9 (S.E.) μg/ml) and a lower steady-state concentration (1.0 ± 0.1 ng/ml) in plasma 3 h later than the buffered one (Cmax, tear fluid = 104 ± 8 μg/ml: Cmax, plasma = 7.3 ± 1.1 ng/ml). Thus, disodium phosphate increases the rate of timolol release from the inserts several fold in tear fluid. Co-administration of methaoxedrine in buffered matrices decreased the peak timolol concentration in plasma about 3-times and increased that in tear fluid about 2-fold. In iris-ciliary body, administration of buffered matrices resulted in timolol concentrations that were comparable with the levels after eye drop instillation. Compared to the unbuffered matrices, disodium phosphate without or with methaoxedrine at least doubled the concentration ratio of iris-ciliary body to plasma. The best iris-ciliary body/plasma concentration ratios were achieved with the buffered matrices containing methaoxedrine. Conjunctival and nasal vasoconstriction by methaoxedrine improves the ocular to systemic concentration ratio of timolol several fold. Compared to eye drops timolol administration in the inserts reduced the systemic β-blocking activity significantly. © 1990.