Background & Aims

There is an urgent demand for non-addictive analgesics with enhanced safety in clinical post-surgical pain management, to prevent the side effects, addiction and abuse of opioids. Although a few long-acting sustained-release formulations containing Bupivacaine (Bu) have been approved (Exparel® and its generic drug Aihengping(AHP, CHN brand ???®)) or in research (Probudur), their analgesic duration is notably behind the time of 30 days expected by FDA. Additionally, safety concerns remain regarding cardiovascular (CV) and central nervous system (CNS) toxicity caused by high content of Bu in these formulations. It has been reported that Exparel has a significant correlation with systemic toxicity (LAST, including CV and CNS toxicity), specifically a mortality as high as 8.5% among 130 reported toxic cases. To obtain new ultra-long-acting safe analgesic, we modified the structure of amide local anesthetics and developed a new serial of tert-amine analgesic molecules, among which is EL012.

Methods

EL012 hydrochloride and positive controls (Bu, Levobupivacaine(LBu)) were dissolved in normal saline to prepare different concentrations of solutions, and their analgesic effects were evaluated in Hartley guinea pigs and SD rats, by defining the inhibition of the cutaneous trunci muscle reflex in pin-prick (PP) tests after subcutaneous (SC) injections of 0.6 ml solutions. Similar PP test in rats by 26g von Frey filament was also carried out for EL012 and AHP. At various time after injection in rats, the concentration at the injection site (SC), the systemic residue and elimination (SC), as well as the drug distribution in the brain after intravenous injection (IV) were measured for EL012 and Bu. In vitro, the efficacy and the cardiotoxity of EL012 were compared with Bu through the IC50 values of human Nav1.7 and Nav1.5. The safety of EL012 was further investigated using LD50 in mice, local histopathology at injection site and wound healing test in rats.

Results

1) 50% efficient analgesic duration (PP test, SC): a) Guinea pigs (10.0mM): 96h (n=9) for EL012 and 2h (n=10) for Bu; b) Rats (10.0 mM): 192h (n=8) for EL012 and 4h (n=3) for LBu; c) Rats (by 26g von Frey filament): 96h (n=10) for EL012 (2.8mM) and 3h (n=10) for AHP (46.1mM), and the efficiency-time AUC of EL012 is about 280% of AHP (0.083-264h). 2) IC50 of Nav1.5 and Nav1.7: 21.08 and 16.70 ?M for EL012; 6.84 and 20.73 ?M for Bu. 3) Max-concentration in brain (10min, rats, IV): 0.089 nmol/g for EL012 and 4.417 nmol/g for Bu. 4) Local concentration (rats, SC, 10mM): 1220.8-462.3µg/g for EL012 (0.42-5h) and 717.3-4.8µg/g for Bu (0.33-5h), respectively. 5) Elimination (240h, rats, SC, 3.5mM): 3.2nmol/g at injection site, and below the limit of detection in blood or organ tissue. 6) Histological examination (312h, rats, SC, 2.8mM): minimal to no irritant response observed. 7) LD50 (mice, IV): 17.5 mg/kg for EL012 and 6.78 mg/kg for Bu. 8) Wound healing (rats): no significant difference among EL012 (7.7mM), Bu (7.7mM), and saline groups.

Conclusions

Our studies show that the newly designed EL012 has a much longer local retention time, and long-acting analgesic duration to be 48 times longer than Bu and LBu after SC administration in guinea pigs and rats. The same locally administered EL012 has a 32 times longer analgesic duration than AHP, a long-acting sustained-release formulation of Bu liposomes, even though the dosage of EL012 is less than 1/16 of the Bu contained in AHP. In addition, EL012 has a potentially lower CV and CNS toxicity than Bu, as well as potentially higher general safety, based on lower concentration in brain (2% of Bu), higher IC50 value of Nav1.5 (3 times higher than Bu), rare irritation by pathological examination, and greater mice LD50 value of EL-012 in vivo assays. Therefore, EL012, a tert-amine analgesic molecule, is very promising to be developed into a novel non-opioid analgesic drug that can be administered locally, characterized by ultra-long-acting analgesic effects and enhanced safety.

References

Opioid crisis and side effects:
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Exparel information:
[3]FDA Exparel Label.
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Aihengping information:
[5]Aihengping information on website of National Healthcare Security Administration https://www.nhsa.gov.cn/attach/Ypsn2023/YPSW202300088/YPSW202300088-W1(ppt).pdf
Probudur information:
[6]https://virpaxpharma.com/products/#Product-Pipeline
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FDA guidance for non-opiod anagesics development:
[8]GUIDANCE DOCUMENT. Development of Non-Opioid Analgesics for Acute Pain; Draft Guidance for Industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/development-non-opioid-analgesics-acute-pain-draft-guidance-industry
Controversial views on Exparel’s efficacy:
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Pin-prick test method:
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Presenting Author

Qingeng Li

Poster Authors

Qingeng Li

Professor

Jiangsu Nhwa-Luokang Pharmaceutical R&D Co., Ltd.

Lead Author

Jie Chen

Lead Author

Changwen Li

Lead Author

Kai Wang

Lead Author

Yi Shen

Lead Author

Xiaohu Dong

Lead Author

Shuai Jiang

Lead Author

Qianling Yang

Lead Author

Yan Liu

Lead Author

Jingyuan Wan

Lead Author

Qingsong Jiang

Lead Author

Wengao Jiang

Lead Author

Topics

  • Specific Pain Conditions/Pain in Specific Populations: Post-surgical/Post-traumatic Chronic Pain