INFLUENCE OF DRUG-RELEASE RATE ON SYSTEMIC TIMOLOL ABSORPTION FROM POLYMERIC OCULAR INSERTS IN THE PIGMENTED RABBIT

There is an expectation that ocular inserts, regardless of the nature of the polymer, will faithfully reduce systemic drug absorption. This may not necessarily be so, however, since not all polymers would relea se drug at the same rate and to the same extent. The objective of the present study was to determine how drug release rate from various poly meric ocular inserts may influence systemic timolol absorption in the pigmented rabbit. The inserts tested were made of polyvinyl alcohol (P VA), hydroxypropylcellulose (HPC), or partial ethyl ester of poly(viny l methyl ether/maleic anhydride) (PVMMA), approximately 89.4% w/w in a ll cases. Some polyvinyl alcohol inserts contained timolol in salt for m with Carbopol 940 (PVA-C940), 8.6% w/w. The time course of timolol i n plasma over 6 hr was monitored using reversed phase HPLC. While all inserts reduced the peak timolol concentration in plasma (C(max)), onl y the PVA and HPC inserts, which released timolol rapidly in vitro, re duced the extent of systemic timolol absorption (AUC). On the other ha nd, both PVA-C940 and PVMMA inserts, which released timolol relatively slowly in vitro, increased the extent of systemic timolol absorption. Moreover, the time at which peak timolol concentration was achieved i n the plasma was much delayed, raising the possibility of delayed timo lol absorption until discharge of the presumably viscous and/or mucoad hesive solutions of PVA-C940 and PVMMA inserts into the nasal cavity. It may be concluded that not all polymeric ocular inserts reduce syste mic timolol absorption. Whether an insert would do so depends on the i nterplay of residence time in the conjunctival sac and rate of drug re lease from the insert.