Formulation development of an ethylene vinyl acetate ring for sustained release of the experimental entry inhibitor DS003

Formulation development of an ethylene vinyl acetate ring for sustained release of the experimental entry inhibitor DS003

Authors
Diarmaid J. Murphy, Clare F. McCoy, Yahya H. Dallal Bashi, Brid Devlin, Jeremy Nuttall, Wendy Blanda, R. Karl Malcolm, Peter Boyd

Keywords
ethylene vinyl acetate, vaginal ring, DS003

Background
DS003 is an entry inhibitor being developed as a vaginal microbicide for HIV prevention. We report the development and in vitro testing of ethylene vinyl acetate (EVA) vaginal rings containing DS003 in support of pharmacokinetic/efficacy testing in macaques.

Methods
Matrix-type EVA rings containing 40%w/w DS003 were manufactured on a Babyplast injection molding machine. Initial drug content was measured by dissolving ring segments in dichloromethane (72hr, 37˚C) and determining the DS003 concentrations using UV spectroscopy at 350nm. In vitro release testing was performed into 100mL sodium acetate buffer (pH 4.2) containing 2% w/w Kolliphor® HS15, with daily sampling (except weekends) and complete media replacement. Drug release was quantified by reverse-phase HPLC. Residual DS003 content was measured following efficacy testing in macaques.

Results
Two ring batches were prepared with initial content values of 629±18 and 617±10 mg DS003 per ring, respectively. In vitro release testing showed linear cumulative release vs. time profiles indicating solubility-limiting release kinetics. The daily release rate (95% confidence interval) was 39.3 (37.8, 40.9) µg/day for rings tested immediately after manufacture, and 21.5 (20.7, 22.3) µg/day for rings tested after one month on storage at 4˚C, a release rate decline of ~45%. The mean total amount of DS003 released over 28 days in vitro was 1.1 mg for rings tested immediately and 0.66 mg for rings tested after one month storage. Mean residual content of rings returned from the macaque study was 628±16 and 629±32 mg DS003 per ring. Based on these values, it was not possible to determine definitively that DS003 was released from the rings in the macaque study.

Conclusion
In vitro release of DS003 was solubility constrained, reflecting the poor water solubility of DS003. A substantial reduction in release rate was observed following ring storage, likely due to time-dependent crystallisation of DS003 and/or the EVA polymer. Initial and residual DS003 content measurements of rings following testing in macaques suggested that no or only very small quantities of DS003 are released in vivo.