Levorphanol prodrugs and processes for making and using them
Inventors
Mickle, Travis • Guenther, Sven • Bera, Sanjib
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11234975-B2
Publication Date
2022-02-01
Expiration Date
Abstract
The presently described technology provides compositions of one or more of oxoacids, amino acids, polyethylene glycols, and/or vitamin compounds chemically conjugated to levorphanol ((−)-17-methylmorphinan-3-ol) to form novel prodrugs and compositions of levorphanol.
Core Innovation
The invention relates to levorphanol prodrug/conjugate compositions formed by covalently bonding levorphanol to ligands where the ligand includes an oxoacid and may include polyethylene glycols (PEG/PEO) and/or vitamin compounds. The bonding occurs at the N-17 tertiary amine and/or the C-3 hydroxyl of levorphanol, optionally through a linker. The resulting conjugates are described using general Formula IA and general Formula IB with substituent and linker parameters including L1/L2, Y1/Y2, G1/G2, and integers such as m, n, k, p, and q.
The ligand and oxoacid components are defined broadly to include at least one oxoacid and encompass multiple oxoacid subtypes, including benzoates, hydroxybenzoates, salicylic acid, acetylsalicylic acid, heteroaryl carboxylic acids, phenylacetates, benzylacetates, cinnamates, polycarboxylic acids, and dicarboxylic acids. The disclosure also characterizes certain example conjugate classes such as N-alkyl levorphanolium quaternary ammonium salts.
The document describes pharmaceutical formulation options for levorphanol conjugates and levorphanol prodrugs, including chewable tablet, film coated tablet, and compressed tablet types, together with pharmaceutically acceptable carriers and excipients. It also states therapeutic use cases for pain relief, anesthesia, hyperalgesia, opioid-induced hyperalgesia, neuropathic pain, central sensitization, Alzheimer’s disease, pseudobulbar affect, PTSD, and opioid rotation based on opioid receptor and NMDA receptor modulation.
The disclosure further states that the prodrug behavior is directed to enzymatic and/or metabolic hydrolysis to release active levorphanol in vivo. The intended effects include abuse-resistant or abuse-deterrent behavior with reduced crush and resistance to non-oral misuse routes, altered pharmacokinetics such as delayed T_max and lower C_max, potential reductions in opioid-induced constipation, and reduced variability in plasma levels.
Claims Coverage
The consolidated set includes three independent claims directed to compound families defined by general formulas, selected R-group classes, q and m ranges, and the presence of at least one oxoacid in G2 and/or G1. Pharmaceutically acceptable salts are included, and the claims are supported by dependent refinements involving substituent selections, oxoacid type selections, compound form, and pharmaceutical compositions.
General formula compound with oxoacid and substituent constraints
A compound having the general formula, wherein R3 and R4 are each independently selected from H, alkyl, aryl, alkyl aryl, alkoxy, haloalkyl, or haloaryl; q is 1-4; G2 is at least one oxoacid; and m is 1-3, or a pharmaceutically acceptable salt thereof.
General formula compound with oxoacid including q and k
A compound having the general formula, wherein R1, R2, R3, and R4 are each independently selected from H, alkyl, aryl, alkyl aryl, alkoxy, haloalkyl, or haloaryl; q and k are independently selected from 1-4; G2 is at least one oxoacid and m is 1-3, or a pharmaceutically acceptable salt therefor.
General formula compound with at least one oxoacid at two positions
A compound having the general formula, wherein R3 and R4 are each independently selected from H, alkyl, aryl, alkyl aryl, alkoxy, haloalkyl, or haloaryl; q is 1-4; G1 is at least one oxoacid and G2 is at least one oxoacid; and m is 1-4 or a pharmaceutically acceptable salt thereof.
Across the independent claims, the coverage centers on levorphanol prodrug or conjugate-type compounds defined by general formulas with selected R substituent classes, defined ranges for q and k where present, and the requirement that G1 and/or G2 include at least one oxoacid, with pharmaceutically acceptable salts included in each independent claim.
Stated Advantages
Abuse-resistant or abuse-deterrent behavior with reduced crush and resistance to non-oral misuse routes.
Altered pharmacokinetics including delayed T_max and lower C_max.
Potential reductions in opioid-induced constipation (OIC).
Reduced variability in plasma levels.
Documented Applications
Dosing and dosage forms for oral administration of prodrug or conjugate compositions, with contexts for intravenous injection and intranasal administration.
Treatment of pain and CNS conditions.
Pain relief.
Anesthesia.
Hyperalgesia and opioid-induced hyperalgesia (OIH).
Neuropathic pain and central sensitization.
Alzheimer’s disease.
Pseudobulbar affect (PBA).
PTSD.
Combination or potentiation with quinidine and certain opioids such as oxycodone.
Opioid rotation based on opioid receptor and NMDA receptor modulation.
Interested in licensing this patent?