Local controlled release of 1-hydroxyethylidene diphosphonate using silicone-rubber matrices. Effects of sterilization on in vitro release and in vivo efficacy

Calcification (CALC) is the most frequent cause of the clinical failure of bioprosthetic heart valves (BHVs). Controlled release of disodium ethanehydroxydiphosphonate (EHDP) has been demonstrated to inhibit subdermal BHV calcification at effective low local doses, avoiding adverse effects. However, the eventual circulatory use of controlled release EHDP necessitates addressing several critical issues that may affect efficacy. These include the effects of sterilization on EHDP release and the efficacy of sustained release matrices containing CaEHDP, which is less soluble than NaEHDP. The effects of CaEHDP-NaEHDP incorporation and steam sterilization on controlled release of EHDP from silicone-rubber matrices was studied both in vitro and in vivo using a rat subdermal model and sheep tricuspid valve replacements. Autoclaved EHDP matrices (20% wt/wt) released 88.9% ± 7.84 of contained drug after 140 days in vitro, compared with control (87.6% ± 10.3 cumulative release). Autoclaved EHDP matrices completely inhibited BHV CALC in 60 day rat subdermal implants (8.84 ± 3.68 μg Ca⁺⁺/mg tissue), comparable to nonsterilized EHDP-loaded matrices (7.06 ± 2.00 μg Ca⁺⁺/mg tissue). Nontreated CALC levels were 183 ± 7.60 μg Ca⁺⁺/mg tissue. Na-CaEHDP co-incorporation into silicone rubber matrices markedly prolonged controlled release with the 1:1 Na-CaEHDP mixture demonstrating an extrapolated release duration of approximately 20 years, assuming the total amount of dispersed drug was released. Data from tricuspid valve replacements in sheep demonstrate erratic control calcification (41.3 ± 14.9 μg Ca⁺⁺/mg tissue), but complete suppression of BHV calcification with Na₂EHDP controlled release (5.74 ± 1.35 μg Ca⁺⁺/mg tissue) after 150 days.