Antibiotic/nonsteroidal anti-inflammatory codrugs for topical application

Purpose: This study investigated ion-paired codrug suspensions tobramycin with diclofenac as a means to achieve increased residence time and ocular absorption after topical application. Methods: Solutions of sodium diclofenac were prepared and added to solutions of tobramycin sulphate. When mixed together a low solubility precipitate of tobramycin diclofenate was formed which was in dynamic equilibrium with free diclofenac and tobramycin. 1.5 ml of the suspensions were placed in microcentrifuge tubes and, after brief centrifugation, 0.5 ml of the supernatant was removed for analysis. Buffer was replaced and the codrug was resuspended by vortex mixing. This process was repeated until no drug was detectable in the receptor. The corneal absorption of diclofenac as a free solution and as a suspension of tobramycin diclofenate was measured in vitro using excised rabbit corneas in modified Ussing diffusion chambers. Drainage from the precorneal tear film was also assessed in rabbits. Animals received either 25 ul of sodium diclofenac (0.5%) or 25 ul of an equimolar tobradiclofenate suspension. Samples of the tear film were periodically taken and assayed by HPLC. Results: The serial dilution experiment showed that the codrug maintained a diclofenac concentration of 0.5 +/- 0.1 mg/ml in the supernatant despite up to 20 serial dilutions while in vitro the apparent permeability coefficient of diclofenac was increased by codrug formation. In vivo the codrug appeared to be well tolerated and as a suspension, drainage from the tear film was decreased drainage from the eye with up to 100 ug/ml measured in the tears after 15 minutes compared to none detectable 5 minutes after instillation of a 0.5% diclofenac drop. Conclusion: This work suggests that increased ocular retention and corneal permeability coefficient of tobramycin and diclofenac is achievable by codrug formation.

Duke Scholars

Author Hongtao Michael Guo Orthopaedic Surgery