Dinalbuphine sebacate

Dinalbuphine sebacate (DNS), also known as nalbuphine sebacate or as sebacoyl dinalbuphine ester (SDE) and sold under the brand name Naldebain, is a non-controlled opioid analgesic which is used as a 7-day long-acting injection in the treatment of moderate to severe postoperative pain.[3][4][5] It was invented by professor Oliver Yoa-Pu Hu (National Defense Medical Center) and codeveloped with Lumosa Therapeutics. Naldebain received market approvals from Taiwan FDA in March 2017 and Health Sciences Authority of Singapore in December 2020.[3][4][6] Development is ongoing in the United States, China, Switzerland, Thailand and Malaysia.[7] The compound is a diester of nalbuphine (Nubain) joined via a sebacic acid linker, and acts as a long-lasting prodrug of nalbuphine via slow hydrolysis.[5][2][8] It was developed to extend the duration of action of nalbuphine, which has a short duration and requires frequent injections.[9][5][2][1] Whereas nalbuphine must be injected every 4 to 6 hours, a single injection of DNS lasts for up to 7 to 10 days.[5] Nalbuphine, and hence DNS, acts as a mixed agonist/antagonist opioid modulator, or more specifically as a moderate-efficacy partial agonist or antagonist of the μ-opioid receptor and as a high-efficacy partial agonist of the κ-opioid receptor.[5][10][11][12][13]

Dinalbuphine sebacate
Clinical data
Other namesDNS; Nalbuphine sebacate; Sebacoyldinalbuphine; SDN; Sebacoyl dinalbuphine ester; SDE; LT-1001
Routes of
administration		Intramuscular injection
Drug classOpioid analgesic
Pharmacokinetic data
Bioavailability• IM: 85.4% (relative to nalbuphine)[1]
MetabolismHydrolysis[2]
MetabolitesNalbuphine[1]
Elimination half-life• DNS: 83.2 hours (mean absorption time: 145.2 hours)[1]
• Nalbuphine: 4.0 hours
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC52H68N2O10
Molar mass881.120 g·mol−1
3D model (JSmol)

Medical uses[14]

NALDEBAIN is indicated for the relief of moderate to severe acute postsurgical pain, administered intramuscularly. The product is available in single-use vials; 2 mL single use vial (75 mg/mL) for IM injection is packaged in a carton.

Pack shot of Naldebain sold in Taiwan

Mechanism[14]

The release mechanism of dinalbuphine sebacate (DNS) upon IM injection is as follows:

1. The injected Naldebain is first forming an oil depot in the muscle

2. The oil depot gradually dispersed to small droplets in the surrounding tissues

3. The prodrug DNS diffused out from the surface of oil droplets, and once released, a small portion of the prodrug get hydrolyzed by esterases to release the active ingredient, nalbuphine, in the surrounding tissue cells, while the majority of the prodrug would enter the blood stream through local tissue drainage (e.g., lymph flow) and get hydrolyzed to nalbuphine in the blood.

References
  1. Tien YE, Huang WC, Kuo HY, Tai L, Uang YS, Chern WH, Huang JD (November 2017). "Pharmacokinetics of dinalbuphine sebacate and nalbuphine in human after intramuscular injection of dinalbuphine sebacate in an extended-release formulation". Biopharm Drug Dispos. 38 (8): 494–497. doi:10.1002/bdd.2088. PMID 28741675. S2CID 10814898.
  2. Pao LH, Hsiong CH, Hu OY, Wang JJ, Ho ST (March 2005). "In vitro and in vivo evaluation of the metabolism and pharmacokinetics of sebacoyl dinalbuphine". Drug Metab. Dispos. 33 (3): 395–402. doi:10.1124/dmd.104.002451. PMID 15608131. S2CID 13206545.
  3. "Dinalbuphine sebacate - Lumosa Therapeutics - AdisInsight". adisinsight.springer.com.
  4. "Lumosa Therapeutics Partners with Camargo Pharmaceutical Services in the Development of Naldebain(R) in the US". www.prnewswire.com.
  5. Yeh CY, Jao SW, Chen JS, Fan CW, Chen HH, Hsieh PS, Wu CC, Lee CC, Kuo YH, Hsieh MC, Huang WS, Chung YC, Liou TY, Chiu HH, Tseng WK, Lee KC, Wang JY (May 2017). "Sebacoyl Dinalbuphine Ester Extended-release Injection for Long-acting Analgesia: A Multicenter, Randomized, Double-Blind, And Placebo-controlled Study in Hemorrhoidectomy Patients". Clin J Pain. 33 (5): 429–434. doi:10.1097/AJP.0000000000000417. PMID 27518486. S2CID 21247898.
  6. "Lumosa Therapeutics Co., Ltd. on LinkedIn: #analgesic #HSA #ASEAN". www.linkedin.com. Retrieved 2020-12-18.
  7. "Lumosa Therapeutics". www.lumosa.com.tw. Retrieved 2020-12-18.
  8. Pao LH, Hsiong CH, Hu OY, Ho ST (September 2000). "High-performance liquid chromatographic method for the simultaneous determination of nalbuphine and its prodrug, sebacoyl dinalbuphine ester, in dog plasma and application to pharmacokinetic studies in dogs". J. Chromatogr. B. 746 (2): 241–7. doi:10.1016/S0378-4347(00)00326-1. PMID 11076077.
  9. Huang, Pei-Wei; Liu, Hung-Ta; Hsiong, Cheng-Huei; Pao, Li-Heng; Lu, Chih-Cherng; Ho, Shung-Tai; Hu, Oliver Yoa-Pu (July 2013). "Simultaneous determination of nalbuphine and its prodrug sebacoly dinalbuphine ester in human plasma by ultra-performance liquid chromatography-tandem mass spectrometry and its application to pharmacokinetic study in humans: UPLC-MS/MS quantification nalbuphine and sebacoly dinalbuphine". Biomedical Chromatography. 27 (7): 831–837. doi:10.1002/bmc.2867.
  10. Narver HL (March 2015). "Nalbuphine, a non-controlled opioid analgesic, and its potential use in research mice". Lab Anim (NY). 44 (3): 106–10. doi:10.1038/laban.701. PMID 25693108. S2CID 25378355.
  11. Schmidt WK, Tam SW, Shotzberger GS, Smith DH, Clark R, Vernier VG (February 1985). "Nalbuphine". Drug Alcohol Depend. 14 (3–4): 339–62. doi:10.1016/0376-8716(85)90066-3. PMID 2986929.
  12. Paul G. Barash (2009). Clinical Anesthesia. Lippincott Williams & Wilkins. pp. 489–. ISBN 978-0-7817-8763-5.
  13. Peng X, Knapp BI, Bidlack JM, Neumeyer JL (May 2007). "Pharmacological properties of bivalent ligands containing butorphan linked to nalbuphine, naltrexone, and naloxone at mu, delta, and kappa opioid receptors". J. Med. Chem. 50 (9): 2254–8. doi:10.1021/jm061327z. PMC 3357624. PMID 17407276.
  14. "Lumosa Therapeutics". www.lumosa.com.tw. Retrieved 2020-12-18.


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