Abstract
Purpose: :
Ketorolac ophthalmic solutions containing the preservative benzalkonium chloride are available for 4-times-daily administration (QID) as 0.4% and 0.5% aqueous solutions, pH = 7.4. This study evaluated the pharmacokinetics of a newly formulated, preservative-free 0.45% ketorolac solution, pH = 6.8, containing carboxymethylcellulose (CMC), developed to treat pain and inflammation following cataract surgery.
Methods: :
Bilateral ocular instillations of ketorolac ophthalmic solutions were administered to rabbits. Aqueous humor and iris ciliary body tissues were extracted, and concentrations of ketorolac were determined using liquid chromatography-tandem mass spectrometry.
Results: :
A novel CMC-based 0.45% ketorolac formulation increased ocular bioavailability by approximately 200% in aqueous humor and 300% in the iris-ciliary body relative to the 0.4% ketorolac formulation. In aqueous humor, the CMC-based 0.45% ketorolac formulation increased the maximum concentration (Cmax) from 211 to 389 ng/mL and area under the concentration time curve (AUC0-t) from 465 to 939 ng•hr/mL compared to the 0.4% ketorolac formulation. In iris-ciliary body, the CMC-containing 0.45% ketorolac solution increased Cmax from 216 to 450 ng/g and AUC0-t from 699 to 2040 ng•hr/g compared to the 0.4% ketorolac formulation. In pharmacokinetic simulations, twice daily (BID) administration of the CMC-based 0.45% ketorolac solution demonstrated higher ketorolac concentrations compared to QID administration with 0.4% ketorolac solution.
Conclusions: :
A novel CMC-containing formulation of 0.45% ketorolac improved ocular delivery of active drug. This ketorolac formulation permits dosing of BID vs QID.
Keywords: wound healing • inflammation