Vaginal Ring for Sustained Release of DL-lactide as a Lactic Acid Pro-drug

Background: There is interest in developing vaginal ring (VR) products for long-acting administration of lactic acid (LA). However, LA is generally not compatible with silicone elastomers, the most common material for fabrication of VRs. Here, we investigate the potential for controlled release of the LA-prodrug DL-lactide (LT) from a silicone elastomer VR. LT is a cyclic dimer of lactic acid which hydrolyses to form LA.

Methods: The kinetics of LT hydrolysis were studied. Matrix-type silicone elastomer (DDU-4320) rods containing LT (11% w/w) were prepared by reaction injection molding (80°C, 3 min). In vitro release testing of individual rods (n=8) placed in a 0.2% v/v solution of Tween 80 was performed over 10 days, with half the replicates having their release medium changed daily and the other replicates having drug release accumulated. The amounts of LT and LA released were quantified by HPLC. pH of the release medium was also monitored over the release period.

Results: Unlike LA, LT was compatible with silicone elastomer and did not inhibit cure. The rate constant for hydrolysis of LT at 37° C was 0.05658 days-1. LT was released the matrix-type silicone elastomer rods continuously over the 10-day period. Day 1 daily release was between 15-25 mg, while Day 10 values ranged from 0.2-0.5 mg. Hydrolysis of LT also occurred in the release medium, as evidenced by the detection of LA by HPLC. pH of the medium was significantly lowered due to release of LT, with values dropping as low as 2.75 on Day 1. On Day 10, a mean pH of 3.5 was achieved with daily release medium change. When medium was not replaced daily, a mean pH of 2.5 was recorded.

Conclusions: Matrix-type silicone elastomer rods containing 11% w/w LT provided in vitro release of LT and rapid conversion via hydrolysis to the monomeric LA. The LA thus produced led to reduced pH in the release medium.