Pharmacokinetics of dinalbuphine sebacate and nalbuphine in Human after Intramuscular Injection of dinalbuphine sebacate in an Extended-Release Formulation

Nalbuphine is a semi-synthetic opioid indicated for the relief of moderate to severe pain. Its short half-life requires frequent injections in clinical practices, resulting in greater incidences of adverse events. We have developed a prodrug of nalbuphine, dinalbuphine sebacate (DNS), dissolved in a simple oil-based injectable formulation, which could deliver and maintain effective blood nalbuphine level. An open-label, prospective, two-period study was performed in healthy volunteers to verify the extended blood concentration profile of nalbuphine. Twelve healthy Taiwanese were randomized to receive intramuscular injection of 20 mg nalbuphine HCl and 150 mg DNS sequentially with a washout period of 5 days. To prevent DNS hydrolysis during sample analysis, we evaluated the effect of four esterase inhibitors in the quantitation of DNS in human whole blood and thenoyltrifluoroacetone was chosen. The bioavailability of nalbuphine from intramuscularly injected DNS relative to that from nalbuphine HCl was 85.4%. The mean absorption time of nalbuphine from DNS was 145.2 hr. It took approximately 6 days for complete release of DNS into blood stream where DNS was rapidly hydrolyzed to nalbuphine; suggesting a single injection of 150 mg DNS in our extended-release formulation could provide a long-lasting pain relief.