Duration 5min, Q&A 3min
Long-Term, Sustained Delivery of Rapamycin (Sirolimus) from an Implantable Device for the Treatment of Uveitis
The current clinical research on the intravitreal delivery of rapamycin (sirolimus) to treat posterior uveitis suggests that intravitreal injections are a direct way of delivering rapamycin while minimizing systemic side effects. However, results also suggest the need for a repeating bimonthly injection to maintain a therapeutic vitreal concentration of rapamycin. Long-term, sustained release of rapamycin from an intravitreal device is needed to provide a continuous therapeutic concentration of rapamycin in the vitreous without systemic side effects. This work proposes an implantable intravitreous device, composed of polycaprolactone thin films, which provides sustained delivery of rapamycin to the vitreous.
Polycaprolactone (PCL) solutions were spun-cast into thin films, which were cut into 6 mm diameter discs. Rapamycin was pelleted in a hand press and then placed between two PCL thin films. The PCL films were heat-sealed together around the rapamycin pellet to create a PCL thin film device enclosing the rapamycin payload.
To study in vitro rapamycin release, devices were loaded with 0.5-2.0 mg of rapamycin and incubated in phosphate-buffered saline at 37℃ on a continuous orbital shaker. Samples were collected at regular intervals and assayed for rapamycin concentration by UV absorbance. Varying thicknesses of PCL thin films were used in device fabrication to control the release rate of rapamycin. In vivo device performance was examined by device implantation into the vitreous of New Zealand White rabbits. Vitreous was removed for analysis either by partial sampling via vitrectomy or total vitreous removal after sacrifice. Histology, inflammation, and intraocular pressure were monitored for adverse effects. Liquid chromatography-tandem mass spectrometry was used to quantify rapamycin concentration in vitreous samples.
Results and Conclusion
Continuous rapamycin release was achieved in vitro through ten weeks with linear, zero-order kinetics, with sufficient rapamycin payload remaining to last approximately 2-3 years. Further in vitro experiments demonstrated that varying the thicknesses of the PCL thin films of the device allowed for tunable release, between 0.6 and 0.9 micrograms per day for the configurations tested. In vivo experiments have detected rapamycin release as long as the terminal timepoint of a 12 week experiment. No adverse effects attributable to the rapamycin device were observed. Together, these results demonstrate a step towards a device capable of delivering long-term, continuous therapeutic concentrations of rapamycin for the treatment of uveitis.
[ Keyword ]
rapamycin (sirolimus) / drug delivery device / uveitis / zero-order kinetics
[ Conflict of Interest ]