Lee V H, Li S Y, Sasaki H, Saettone M F, Chetoni P
Department of Pharmaceutical Sciences and Drug Targeting Center, University of Southern California, School of Pharmacy, Los Angeles.
J Ocul Pharmacol. 1994 Summer;10(2):421-9. doi: 10.1089/jop.1994.10.421.
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 release 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 polymeric ocular inserts may influence systemic timolol absorption in the pigmented rabbit. The inserts tested were made of polyvinyl alcohol (PVA), hydroxypropylcellulose (HPC), or partial ethyl ester of poly(vinyl methyl ether/maleic anhydride) (PVMMA), approximately 89.4% w/w in all cases. Some polyvinyl alcohol inserts contained timolol in salt form with Carbopol 940 (PVA-C940), 8.6% w/w. The time course of timolol in plasma over 6 hr was monitored using reversed phase HPLC. While all inserts reduced the peak timolol concentration in plasma (Cmax), only the PVA and HPC inserts, which released timolol rapidly in vitro, reduced the extent of systemic timolol absorption (AUC). On the other hand, 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 in the plasma was much delayed, raising the possibility of delayed timolol absorption until discharge of the presumably viscous and/or mucoadhesive solutions of PVA-C940 and PVMMA inserts into the nasal cavity. It may be concluded that not all polymeric ocular inserts reduce systemic timolol absorption. Whether an insert would do so depends on the interplay of residence time in the conjunctival sac and rate of drug release from the insert.
人们期望眼部插入剂，无论其聚合物的性质如何，都能切实降低全身药物吸收。然而，情况未必如此，因为并非所有聚合物都会以相同的速率和程度释放药物。本研究的目的是确定各种聚合物眼部插入剂的药物释放速率如何影响有色家兔体内噻吗洛尔的全身吸收。所测试的插入剂由聚乙烯醇（PVA）、羟丙基纤维素（HPC）或聚（乙烯基甲基醚/马来酸酐）的部分乙酯（PVMMA）制成，所有情况下含量约为89.4% w/w。一些聚乙烯醇插入剂含有噻吗洛尔与卡波姆940（PVA-C940）的盐形式，含量为8.6% w/w。使用反相高效液相色谱法监测血浆中噻吗洛尔6小时的时间进程。虽然所有插入剂都降低了血浆中噻吗洛尔的峰值浓度（Cmax），但只有在体外快速释放噻吗洛尔的PVA和HPC插入剂降低了全身噻吗洛尔吸收的程度（AUC）。另一方面，在体外相对缓慢释放噻吗洛尔的PVA-C940和PVMMA插入剂都增加了全身噻吗洛尔吸收的程度。此外，血浆中达到噻吗洛尔峰值浓度的时间大大延迟，增加了噻吗洛尔吸收延迟的可能性，直到PVA-C940和PVMMA插入剂可能的粘性和/或粘膜粘附溶液排入鼻腔。可以得出结论，并非所有聚合物眼部插入剂都能降低全身噻吗洛尔吸收。一种插入剂是否能做到这一点取决于在结膜囊中停留时间与从插入剂中药物释放速率之间的相互作用。
