5-Flurouracil microencapsulation and impregnation in hyaluronic acid hydrogel as composite drug delivery system for ocular fibrosis

Effective and sustained release formulations of antimetabolite 5-Flurouracil (5Fu) for ocular fibrosis are highly desirable for success of glaucoma filtration surgery (GFS). However, burst release and rapid clearance of carriers and/or drug still exist as major limitations. Here, we report the feasibility of encapsulating 5Fu in sustained release carrier of poly (d,l-lactide-co-glycolide) (PLGA) microspheres (MPs) and impregnating in a hyaluronic acid (HA) hydrogel as unit dose formulation. In order to optimize the encapsulation process by solid-in-oil-in-water emulsion technique, the effects of PLGA end groups, PLGA concentration, and 5Fu loading were studied systematically. The MPs were extensively characterized for surface morphology, particle size distribution, thermal properties, crystallinity, residual solvent, syringeability, and in vitro release. The optimized formulation of MPs was ~94 μm in size and released 5Fu in a sustained manner for up to two weeks. In our concept, MPs are dispersed first in HA solution and then cross-linked in situ after injection into the conjunctival space. Thus, syringeability experiments were also carried out with 5Fu-loaded MPs and 0.5% HA solution. To further prolong 5Fu release, a derivatized HA with methacrylic anhydride was photocross-linked along with 5Fu-loaded PLGA MPs to develop the composite hydrogel formulation. Our experimental results show that 5Fu release can be effectively controlled by PLGA MPs-loaded HA composite hydrogel for longer therapeutic benefits. These composite hydrogel systems improve the ocular residence time of the carrier and the drug, and hence could be potentially explored as injectable unit dose formulation for GFS.