Extended release of timolol from nanoparticle-loaded fornix insert for glaucoma therapy

摘要

We have developed a cylindrical insert that can be inserted in the fornix for extended release of glaucoma drug timolol. The insert is prepared by incorporating timolol-loaded nanoparticles into a poly hydroxyl ethyl methacrylate (p-HEMA) matrix. A 1-mm diameter, 7.5-mm long insert with 25% (w/w) particles can release timolol for about 10 days at an average rate of about 15 μg/day, which may be therapeutically effective. The increase in particle fraction increases drug loading, but also increases the release duration. The net effect of increasing the particle fraction is a significant increase in release duration, but a decrease in daily drug release rates, in the first few weeks. The release duration increases to about 1 and 3 months on increasing the particle fraction to 50% and 75%, respectively. The average daily release rates in the first 3 weeks are 15, 9, and 3 μg/day for the inserts with 50%, 75%, and 100% (w/w) particles, respectively. The mechanism of release is hydrolysis of the ester bond that links timolol to the propoxylated glyceryl triacrylate matrix, and thus the release profiles fit a first order reaction model. The water content of the inserts decreases from 31% to almost zero on increasing the particle loading from 25% to 100%. The rate constant for the hydrolysis decreases with an increase in particle loading in the insert most likely due to the reduction in the water content. The inserts can be packaged in wet conditions and stored in a refrigerator, but the inserts will exhibit a burst release caused by release of the drug from the particles into the p-HEMA matrix during the shelf life. Also, the magnitude of drug release after the initial burst is reduced due to the storage. The burst effect could potentially be avoided by packaging the inserts in a dry state, with hydration before insertion.