"Smart" co-drugs. Rapid intravitreal delivery of 5-FU and prolonged delivery of steroid from the same erodible device
Purpose: The aim of this work was to develop a small implantahle hioerodihle device giving sustained release of 5-FU for 1-2 weeks and sustained release of a steroid for over 2 months. Previous work had indicated that this may be optimal for the treatment of intraocular proliferative diseases such as PVR. Methods: Co-Drugs were prepared by conjugating 5-FU to fluocinolone acetonide (FA) or triamcinolone acetonide (TA) via extremely labile covalent bonds. The resulting Co-Drugs were dissolved in buffered aqueous solutions or cow vitreous and both their degradation half-life and the rate of regeneration of parent 5-FU steroid determined. Sustained release pellets of the Co-Drugs were prepared by direct compression of 3 mg of the powder in a 1.5 mm tablet die. The release rates of 5-FU, steroid or intact Co-Drug were then measured in vitreous or phosphate buffer over a period of 30 days. Results; Both CoDrugs were highly labile in buffer and vitreous with half-Hies of less than 3 minutes and each quantitatively regenerated 5-FU and their respective steroid. Pellets of 5FU/TA gave complete release of 5-FU over 4 days followed by slower release of TA. Co-drugs of 5FU/FA gave linear release of 5-FU over approximately 10 days. Release of FA was linear for 10 days but then declined to a much slower rate (also linear) once the 5-FU had been released. Conclusions: The 5FU/FA Co-Drug appears to provide an intial high release of 5-FU maintained for 10 days followed by lower sustained release of FA. Future work will evaluate the use of this codruc svstcm in a PVR model.