TQ-1020 (Levorphanol Extended Release Tablets)
TQ-1020 (Levorphanol ER) is a proprietary once-a-day extended release dosage form of the opioid analgesic levorphanol in an abuse deterrent drug delivery system. The final tablet formulation has undergone GMP manufacture, stability testing, in vitro abuse deterrence testing and human bioavailability evaluation.
We have completed a randomized, single-dose, crossover study of the oral bioavailability of Levorphanol ER vs. immediate release levorphanol in 15 healthy volunteers under a U.S. IND. The results of our study indicate that Levorphanol ER provides a robust extended release profile suitable for once-a-day dosing, when compared with an immediate release reference drug, as demonstrated by a significantly reduced peak plasma concentration (Cmax) and a significantly longer time to peak plasma concentration (Tmax). The pharmacokinetic profile of Levorphanol ER compares very favorably with the profile of a recently approved once-a-day dosage form of another opioid.
Once-a-Day, Extended Release Pharmacokinetic Profile
Abuse Deterrent Levorphanol (n=15)
Rationale for Levorphanol ER
Levorphanol ER has a highly differentiated pharmacologic profile when compared with morphine, hydromorphone, oxycodone, fentanyl, hydrocodone and oxymorphone, including analgesic action at multiple opioid and non-opioid receptors.
Levorphanol ER is the only available opioid which exerts analgesia through a combination of μ-(morphine like) opioid effects, κ (kappa) opioid effects, NMDA antagonism, and potent serotonin and norepinephrine reuptake inhibition. It is therefore uniquely suited as initial opioid therapy and for use in morphine tolerant patients.
How does Levorphanol ER work?
Broad Spectrum, Multimodal Analgesia in a Single Molecule
Benefits of Activity at Multiple Opioid Receptors
Although earlier schools of thought recommended the development of highly selective opioid agonists acting at a single opioid receptor subtype, it is now appreciated that action at multiple opioid receptor subtypes can be therapeutically advantageous. Levorphanol is 5, 10 and 20 fold more potent than morphine at the μ (mu), δ (delta) and κ (kappa) receptor, respectively.
Contributions from Delta (δ ) Opioid Receptor Activity
Both δ-and µ-opioid receptors are known to mediate analgesia. However, in contrast to µ-opioid receptors, activity at the δ-opioid receptor is associated with reduced potential for opioid dependence and tolerance, and δ-opioid agonists can provide relief from inflammatory pain and bone cancer pain. Moreover, there is a synergistic interaction between the µ- and δ-opioid receptors to enhance analgesia without enhancing the undesirable µ-opioid receptor side effects such as respiratory depression and tolerance. Therefore, Levorphanol ER, with activity at both the mu-and δopioid receptors may be expected to demonstrate a high degree of analgesic efficacy and potency with a reduced side-effect profile when compared to morphine-like opioids..
Contributions from Kappa (κ) Opioid Receptor Activity
Both κ-and µ-opioid receptors are known to mediate analgesia. However, in contrast to µ-opioid receptors, activity at the κ-opioid receptor is associated with reduced abuse potential, and κ-opioid agonists can provide relief from inflammatory, visceral and neuropathic pain. Moreover, there is a synergistic interaction between the µ- and κ-opioid receptors to enhance analgesia without enhancing the undesirable µ-opioid receptor side effects. Therefore, Levorphanol ER, with activity at both the µ-and κ-opioid receptors may be expected to demonstrate a high degree of analgesic efficacy and potency with a reduced side-effect profile when compared to morphine-like opioids.
Levorphanol ER provides balanced opioid analgesia in a single molecule from its primary effects at the μ (mu) opioid receptor, supplemented by its effects at δ (delta) and κ (kappa) opioid receptors. When combined with its effects potent norepinephrine and serotonin reuptake inhibition, Levorphanol ER provides a broad spectrum multimodal analgesic.
TQ-1020 Combines Opioid & Nonopioid Analgesia
Multiple mechanism of pain relief in a single molecule
What others are saying about levorphanol …….
“New studies have identified unique properties of some of the μ-opioid drugs in the treatment of neuropathic pain. In the study by Rowbotham et al. levorphanol was used. It differs from morphine in its broader interactions with not only the μ1-receptor but also with both κ and δ receptors, and it has been shown to provide analgesia in animals that are tolerant to morphine. In fact, levorphanol has been suggested as an alternative for pain management in morphine-tolerant patients on the basis of these studies in animals.”
From: Opioids and Chronic Neuropathic Pain (Editorial), New England Journal of Medicine, 2003,348:1279-80; 27:13:1279-80. Kathleen M. Foley, MD, Professor of Neurology, Neuroscience and Clinical Pharmacology & Attending Neurologist, Memorial Sloan-Kettering Cancer Center, New York.
Abuse Deterrent Profile of Levorphanol ER Tablets
The abuse/tamper resistant properties of our GMP formulation of Levorphanol ER has been extensively evaluated and compared with the extended release oxycodone. Levorphanol ER demonstrates a robust abuse deterrent profile, when compared with extended release oxycodone. Abuse deterrent testing of Levorphanol ER has included:
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Levorphanol ER Tamper Resistant and Abuse Deterrent
Release Testing From Tampered Dosage Form
Intellectual Property and Market Exclusivity
TheraQuest has several method of use and pharmaceutical composition patent applications for levorphanol ER. Furthermore, it will have postmarketing exclusivity in the U.S. (Hatch Waxman and pediatric) and be difficult to genericize in view of its expected abuse deterrent label. In the E.U, we believe Levorphanol ER will be eligible for 10-year data exclusivity. We intend to cement our market exclusivity through additional patents based on the pharmaceutical and clinical characteristics of our drug and through the introduction of line extensions with non-opioids.