Drug Compatibility and Distribution Assessments of a Bupivacaine-Polymer Formulation Measured Following Site-Directed Injection in Mice

Background: A long-acting local anaesthetic agent would enable superior post-operative analgesia. Our slow-release bupivacaine-polymer formulation comprising 15% bupivacaine loaded into a poly (DL-lactic acid co castor oil 3:7), DL-LA:CO was effective for up to 96 hours. In this study we determined in vivo drug levels of the formulation from plasma and tissue assay and we tested the feasibility of drug level assessments from an exudate sample collected in a novel device near the injection-site.

Methods: Prior to formulation injection, a titanium cylinder dual-open-ended chamber was implanted in the dorso-lumber region of female ICR mice, to be used as a biological compartment. Following a healing period, the bupivacaine-polymer formulation was injected close to the sciatic nerve. Formulation assay samples were collected over one-week post-injection; exudate was drawn from the chamber in the anaesthetised animal; and blood and tissue samples from the sacrificed animal. Bupivacaine distribution in the exudate and plasma samples was determined by liquid chromatography–mass spectrometry developed for these experiments, and in tissue samples by high -performance liquid chromatography.

Results: Bupivacaine was detected during the first 24h following formulation injection in all three samples (exudate, plasma and tissue), and decreased to almost undetectable levels by day 7 post-injection.

Conclusion: Bupivacaine drug assay measured from an exudate sample may be applicable in addition or as a replacement for standard plasma and tissue assay in studies of drug pharmacokinetic distribution. The high sensitivity and simplicity of the metallic chamber implant to detect drug concentration and exudate analysis was confirmed in sever hepatic impairment.

Author(s):   Ickowicz DE, Houri-Haddad Y, Domb AJ, Golovanevski L, Weiniger CF

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