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-12076316-B2
Publication Date
2024-09-03
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 prodrugs and conjugates formed by covalently conjugating the opioid levorphanol to ligands. The ligands include oxoacids, amino acids, polyethylene glycols (PEG/PEO), and vitamin compounds, and the conjugates are configured to release active levorphanol in vivo via enzymatic or metabolic breakdown.
The conjugation is positioned at the N-17 tertiary amine and/or at both the N-17 and the C-3 hydroxyl, directly or via linkers. The disclosure provides Formula 1, Formula IA, and Formula IB frameworks with variable moieties, including repeating subunits in which Y1, Y2, J, Gm1, and Gm2 are defined by the stated structural options.
The disclosure also covers pharmaceutically acceptable salt forms of the levorphanol conjugates and lists ligand classes and subtypes, including benzoates and hydroxybenzoic acids, heteroaryl carboxylic acids, phenylacetates, benzylacetates, cinnamates, aliphatic, dicarboxylic, and tricarboxylic acids, standard, non-standard, and synthetic amino acids, PEG structures, and water-soluble or fat-soluble vitamin categories.
Therapeutic and physiological benefits are stated for oral administration, including abuse-deterrence by resistance to IV and intranasal misuse. The disclosure further states that the conjugates can provide controlled/sustained or immediate release characteristics, may reduce overdose and abuse potential, reduce opioid-induced constipation risk, and reduce patient-to-patient pharmacokinetic variability, with broad indications such as pain and other CNS conditions.
Claims Coverage
The provided claims include one independent claim. It defines a Formula 1 compound with variable ligand, oxoacid, PEG, and vitamin moieties and an optional pharmaceutically acceptable salt; additional inventive refinements are addressed in dependent claims.
Formula 1 compound with variable moieties
A compound of Formula 1 with independently variable L1, L2, Y1, Y2, J, Gm1, Gm2, and repeating-unit parameters, where repeating subunits are independently selected from H, oxoacid, polyethylene glycol having from 2 to 5 ethylene oxide units, or a vitamin compound, and the compound includes an optionally present pharmaceutically acceptable salt.
Oxoacid selected from amino acid and carboxylic acid options
The oxoacid is selected as either at least one amino acid, at least one carboxylic acid, or a combination of at least one carboxylic acid and at least one amino acid.
Carboxylic acid class selection
The carboxylic acid component is selected from aliphatic carboxylic acids, aryl carboxylic acids, dicarboxylic acids, polycarboxylic acids, benzoate, phenylacetate, branched phenylpropionate, unbranched phenylpropionate, phenylpropenoate, and heteroaryl carboxylic acids, including salts thereof and combinations thereof.
Pharmaceutically acceptable salt selection
The pharmaceutically acceptable salt is selected from a listed group of specific salt forms, including acetate, aspartate, besylate, bicarbonate, carbonate, camphorsulfonate derivatives, citrate, edisylate, formate, fumarate, gluconate, and many other enumerated salts, and combinations thereof.
Minimum compound amount in a composition
The compound is present at an amount of about 0.5 mg or higher in the composition.
Dosage form selection
The compound is formulated in a dosage form chosen from tablets, capsules, caplets, suppositories, troches, lozenges, oral powders, solutions, oral films, thin strips, slurries, suspensions, or transdermal patches.
Overall, the claims cover a Formula 1 compound defined by variable ligand, oxoacid, PEG, and vitamin moieties with an optional pharmaceutically acceptable salt, and they refine oxoacid and carboxylic acid selection, enumerate permissible salt forms, specify a minimum compound amount, and restrict the dosage forms to a stated list.
Stated Advantages
Abuse-deterrence by resisting IV and intranasal misuse.
Controlled/sustained or immediate release characteristics via oral administration.
Reduced overdose and abuse potential.
Reduced risk of opioid-induced constipation.
Reduced patient-to-patient pharmacokinetic variability.
Documented Applications
Treatment of pain.
Use for other CNS conditions.
Oral administration of levorphanol conjugates/prodrugs.
Interested in licensing this patent?