Use of (2R, 6R)-hydroxynorketamine, (S)-dehydronorketamine and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine in the treatment of depression and neuropathic pain
Inventors
Wainer, Irving W. • Moaddel, Ruin • Bernier, Michel • Zarate, Carlos A. • Torjman, Marc C. • Goldberg, Michael E. • Tanga, Mary J.
Assignees
SRI International Inc • Cooper Health System Inc • Office of Technology Transfer
Publication Number
US-9867830-B2
Publication Date
2018-01-16
Expiration Date
2032-10-15
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Abstract
The disclosure provides pharmaceutical preparations containing (2R,6R)-hydroxynorketamine, or (R)- or (S)-dehydronorketamine, or other stereoisomeric dehydro or hydroxylated ketamine metabolite. (2R,6R)-hydroxynorketamine The disclosure also provides novel ketamine metabolite prodrugs. The disclosure provides methods of treating, bipolar depression, major depressive disorder, neuropathic and chronic pain, including complex regional pain synthetic pain disorder (CRPD) by administering a purified ketamine metabolite or a ketamine metabolite prodrug directly to patients in need of such treatment.
Core Innovation
The invention provides pharmaceutical preparations containing purified ketamine metabolites, specifically (2R,6R)-hydroxynorketamine, (R)- or (S)-dehydronorketamine, and other stereoisomeric dehydro or hydroxylated ketamine metabolites. It also introduces novel ketamine metabolite prodrugs and methods of treating bipolar depression, major depressive disorder, neuropathic pain, chronic pain including complex regional pain syndrome (CRPS) by administering these metabolites or their prodrugs directly to patients.
Ketamine is currently used to treat treatment-resistant bipolar depression, major depressive disorder, neuropathic and chronic pain including CRPS, but its use is limited by unwanted central nervous system (CNS) effects and poor response in approximately 30% of patients. The traditional understanding attributes ketamine and norketamine as the active agents producing analgesic effects, though they also cause CNS side effects and have abuse potential.
Recent studies revealed that the primary circulating metabolites during ketamine infusion in patients are (R,S)-dehydronorketamine and (2S,6S;2R,6R)-hydroxynorketamine. These metabolites appear responsible for ketamine's therapeutic effects with fewer side effects, as they are not active at the NMDA receptor. This discovery addresses the need for therapeutics with ketamine's efficacy but reduced CNS side effects and lower abuse liability by administering these metabolites or their prodrugs directly, enhancing patient response rates and reducing adverse effects.
Claims Coverage
The patent contains one independent claim, focusing on a method of treating bipolar depression or major depressive disorder using specific ketamine metabolites.
Use of specific ketamine metabolites for treating depression
Administering a pharmaceutical composition containing an effective amount of one or more of the following compounds: (2S,6S)-hydroxynorketamine, (2R,6R)-hydroxynorketamine, (2S,6R)-hydroxynorketamine, (2R,6S)-hydroxynorketamine, (S)-dehydronorketamine, or (R)-dehydronorketamine, or any combination thereof, to a patient in need for the treatment of bipolar depression or major depressive disorder.
The claims primarily cover methods of treating bipolar depression or major depressive disorder by administering specific purified ketamine metabolites or their pharmaceutically acceptable salts, with emphasis on (2R,6R)-hydroxynorketamine and related stereoisomers, optionally in combination with other active agents and in various pharmaceutical formulations.
Stated Advantages
The ketamine metabolites have reduced central nervous system side effects compared to ketamine, as they are not active at the NMDA receptor.
They provide therapeutic efficacy in a higher percentage of patients, including those who are ketamine non-responders.
The metabolites have long plasma half-lives and oral bioavailability, facilitating convenient oral administration.
Documented Applications
Treatment of bipolar depression, major depressive disorder, schizophrenia, Alzheimer's dementia, amyotrophic lateral sclerosis, complex regional pain syndrome (CRPS), chronic pain, and neuropathic pain by administration of purified ketamine metabolites or their prodrugs.
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