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Dinalbuphine sebacate

(Redirected from Sebacoyldinalbuphine)

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]

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• IMTooltip Intramuscular injection: 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
  • Bis[(4R,4aS,7S,7aR,12bS)-3-(cyclobutylmethyl)-4a,7-dihydroxy-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-9-yl] decanedioate
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC52H68N2O10
Molar mass881.120 g·mol−1
3D model (JSmol)
  • C1CC(C1)CN2CC[C@]34[C@@H]5[C@H](CC[C@]3([C@H]2CC6=C4C(=C(C=C6)OC(=O)CCCCCCCCC(=O)OC7=C8C9=C(C[C@@H]1[C@]2([C@]9(CCN1CC1CCC1)[C@@H](O8)[C@H](CC2)O)O)C=C7)O5)O)O
  • InChI=1S/C52H68N2O10/c55-35-19-21-51(59)39-27-33-15-17-37(45-43(33)49(51,47(35)63-45)23-25-53(39)29-31-9-7-10-31)61-41(57)13-5-3-1-2-4-6-14-42(58)62-38-18-16-34-28-40-52(60)22-20-36(56)48-50(52,44(34)46(38)64-48)24-26-54(40)30-32-11-8-12-32/h15-18,31-32,35-36,39-40,47-48,55-56,59-60H,1-14,19-30H2/t35-,36-,39+,40+,47-,48-,49-,50-,51+,52+/m0/s1
  • Key:ALOIOAGKUOQNID-ITCIXCFHSA-N

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][6] It was developed to extend the duration of action of nalbuphine, which has a short duration and requires frequent injections.[7][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]

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, Health Sciences Authority of Singapore in December 2020, the Ministry of Public Health of Thailand in December 2021, the Drug Control Authority of Malaysia in 2022, State Service of Ukraine on Medicines and Drugs Control and Brunei Darussalam Medicines Control Authority (BDMCA) in 2023.[3][4] Development is ongoing in the United States, China, Korea, and the Philippines.[8]

Medical uses

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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.[8]

 
Pack shot of Naldebain

Pharmacology

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Pharmacodynamics

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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][9][10][11][12]

Pharmacokinetics

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The release mechanism of dinalbuphine sebacate (DNS) upon IM injection is as follows:[13]

  1. Upon intramuscular injection, Naldebain first forms an oil depot in the muscle
  2. The oil depot gradually disperses as small droplets in the surrounding tissues
  3. The prodrug dinalbuphine sebacate gradually diffuses out from the droplets, after which it gets hydrolyzed to the active ingredient nalbuphine via two different mechanisms:
    • a small portion of the prodrug gets hydrolyzed by esterases to release the active ingredient, nalbuphine, in the surrounding tissue cells
    • the majority of the prodrug enters the bloodstream through local tissue lymph drainage and gets hydrolyzed to nalbuphine in the blood

References

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  1. ^ a b c d 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". Biopharmaceutics & Drug Disposition. 38 (8): 494–497. doi:10.1002/bdd.2088. PMID 28741675. S2CID 10814898.
  2. ^ a b c 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 Metabolism and Disposition. 33 (3): 395–402. doi:10.1124/dmd.104.002451. PMID 15608131. S2CID 13206545.
  3. ^ a b "Dinalbuphine sebacate - Lumosa Therapeutics". AdisInsight. Springer Nature Switzerland AG.
  4. ^ a b "Lumosa Therapeutics Partners with Camargo Pharmaceutical Services in the Development of Naldebain(R) in the US". www.prnewswire.com (Press release).
  5. ^ a b c d e Yeh CY, Jao SW, Chen JS, Fan CW, Chen HH, Hsieh PS, et al. (May 2017). "Sebacoyl Dinalbuphine Ester Extended-release Injection for Long-acting Analgesia: A Multicenter, Randomized, Double-Blind, And Placebo-controlled Study in Hemorrhoidectomy Patients". The Clinical Journal of Pain. 33 (5): 429–434. doi:10.1097/AJP.0000000000000417. PMID 27518486. S2CID 21247898.
  6. ^ 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". Journal of Chromatography. B, Biomedical Sciences and Applications. 746 (2): 241–247. doi:10.1016/S0378-4347(00)00326-1. PMID 11076077.
  7. ^ Huang PW, Liu HT, Hsiong CH, Pao LH, Lu CC, Ho ST, Hu OY (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". Biomedical Chromatography. 27 (7): 831–837. doi:10.1002/bmc.2867. PMID 23460034.
  8. ^ a b "Lumosa Therapeutics". www.lumosa.com.tw. Retrieved 2023-11-23.
  9. ^ Narver HL (March 2015). "Nalbuphine, a non-controlled opioid analgesic, and its potential use in research mice". Lab Animal. 44 (3): 106–110. doi:10.1038/laban.701. PMID 25693108. S2CID 25378355.
  10. ^ Schmidt WK, Tam SW, Shotzberger GS, Smith DH, Clark R, Vernier VG (February 1985). "Nalbuphine". Drug and Alcohol Dependence. 14 (3–4): 339–362. doi:10.1016/0376-8716(85)90066-3. PMID 2986929.
  11. ^ Barash PG (2009). Clinical Anesthesia. Lippincott Williams & Wilkins. pp. 489–. ISBN 978-0-7817-8763-5.
  12. ^ 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". Journal of Medicinal Chemistry. 50 (9): 2254–2258. doi:10.1021/jm061327z. PMC 3357624. PMID 17407276.
  13. ^ "BarashLumosa Therapeutics". www.lumosa.com.tw. Retrieved 2020-12-18.
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