Depot

An increasing number of drugs are being approved for delivery via depots, which are able to release drugs in situ over a desired time-course and thereby decrease dosing frequency and promote patient compliance. Several controlled-release studies of oligonucleotides are reported in the literature. In one such example the anti-VEGF aptamer Macugen was formulated with poly(lactic-co-glycolic) acid (PLGA) to yield a controlled-release matrix that was between 2 and 3.5% PE-Gylated aptamer by mass (0.4-0.6% oligonucleotide by mass) (Carrasquillo et al., 2003). This particulate solid released aptamer over a three-week period in in vitro studies. Additional evidence was presented for the release of the aptamer in vivo using a transcleral route into the eyes of Dutch-belted rabbits. Higher loading levels of PLGA are achievable for oligonucleotides that are not PEGylated. For example Putney et al. (1999) reported loading levels of up to 10% oligonucleotide by mass in the presence of cations such as polyamines or zinc. In this study con-trolled-release was sustained over 9 days in vitro when the oligonucleotide was formulated in the presence of a 10-fold excess of zinc acetate by mass. In vivo efficacy data in a murine melanoma xenograft model was also presented.

PLGA is generally regarded as safe, it is used as a controlled-release matrix in over ten FDA-approved products, and additionally has been used as suture silk for decades. Under physiological conditions, PLGA gradually degrades to non-toxic monomers.

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