A novel in situ-forming ophthalmic drug delivery system from alginates undergoing gelation in the eye

Poor bioavailability of ophthalmic solutions caused by dilution and drainage from the eye can be overcome by using in-situ-forming ophthalmic drug delivery systems prepared from polymers that exhibit reversible liquid-gel phase transition. In the present paper, we demonstrate that an aqueous solution of sodium alginate can gel in the eye, without the addition of external calcium ions or other bivalent/polyvalent cations. The extent of alginate gelation and consequently the release of pilocarpine, depended on the percent guluronic acid (G) residues in the polymer backbone. Alginates with G contents of more than 65%, such as Manugel DMB, instantaneously formed gels upon their addition to simulated lacrimal fluid, while those having low G contents, such as Kelton LV, formed weak gels at a relatively slow rate. In vitro studies indicated that pilocarpine is released slowly from alginate gels, over a period of 24 h, and the release occurs mostly via diffusion from the gels. Dissolution of the hydrogels in the releasing media was negligible for the first 12 h of incubation at 37°C. Intraocular pressure (IOP) measurements of rabbit eyes treated with 2% (w/v) pilocarpine nitrate in solution, or in the in-situ gel forming formulation composed of the high G content DMB alginate, indicated that DMB significantly extended the duration of the pressure reducing effect of pilocarpine, to 10 h, as compared to the 3 h when pilocarpine nitrate was delivered as a solution. In contrast, there was no apparent difference in the duration and extent of IOP decrease between rabbits treated with pilocarpine in solution or in the Kelton LV alginate eye drop formulations. The overall results of this study indicate that the in situ-gelling alginate system, based on polymers with high G contents, is an excellent drug carrier for the prolonged delivery of pilocarpine.