Pharmacokinetics of dinalbuphine sebacate and nalbuphine in human after intramuscular injection of dinalbuphine sebacate in an extended‐release formulation

Abstract

Nalbuphine is a semi-synthetic opioid indicated for the relief of moderate to severe pain. Its short half-life requires frequent injections in clinical practice, resulting in a greater incidence of adverse events. A prodrug of nalbuphine has been developed, dinalbuphine sebacate (DNS), dissolved in a simple oil-based injectable formulation, which could deliver and maintain an effective blood level of nalbuphine. 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 an 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, the effect of four esterase inhibitors was evaluated 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 h. It took approximately 6 days for the complete release of DNS into the blood stream where DNS was rapidly hydrolysed to nalbuphine; suggesting a single injection of 150 mg DNS in our extended-release formulation could provide long-lasting pain relief.

Comparison of the Efficacy and Safety of Dinalbuphine Sebacate, Patient-Controlled Analgesia, and Conventional Analgesia After Laparotomy for Gynecologic Cancers: A Retrospective Study

“… 28 Tien et al previously demonstrated DNS as an extended-release nalbuphine that takes approximately 6 days to completely release into the bloodstream. 29 When released, DNS can be rapidly hydrolyzed to nalbuphine by esterase to exert its analgesic effect. Therefore, with a lower maximum blood concentration, DNS has a better safety profile than nalbuphine itself.…”

<p>Preoperative Administration of Extended-Release Dinalbuphine Sebacate Compares with Morphine for Post-Laparoscopic Cholecystectomy Pain Management: A Randomized Study</p>

“… 29 Our results showed that the two treatments had a similar safety profile; none of the patients treated with DS reported postoperative pruritus, even among those who received rescue morphine. Based on pharmacokinetics of DS, the relatively low concentration of nalbuphine provided a background analgesic effect 30 which might explain why patients in DS group required no supplemental analgesics after 24 hours, by contrast those in the postoperative morphine group.…”

Extended-Release Dinalbuphine Sebacate Versus Intravenous Patient-Controlled Analgesia with Fentanyl for Postoperative Moderate-to-Severe Pain: A Randomized Controlled Trial

“…Extended-release dinalbuphine sebacate (ERDS, Naldebain ® , Lumosa Therapeutics, Taipei, Taiwan) is a pro-drug of nalbuphine, which acts as a mixed kappa opioid agonist/mu opioid antagonist providing sufficient analgesia for moderate to severe pain after a single intramuscular administration. ERDS can rapidly hydrolyze to nalbuphine by esterases in the human bloodstream [ 10 ]. A randomized study has reported that pre-operative intramuscular administration of ERDS exhibits a well-tolerated safety profile and weekly analgesic effect, less post-operative analgesics use, and prolonged time to the first use of analgesics in patients undergoing hemorrhoidectomy [ 11 ].…”