Dextrorphan prodrugs and processes for making and using them
Inventors
Mickle, Travis • Guenther, Sven • Bera, Sanjib
Assignees
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Publication Number
US-11214544-B2
Publication Date
2022-01-04
Expiration Date
Abstract
The presently described technology provides compositions of one or more of oxoacids, polyethylene glycols, and/or vitamin compounds chemically conjugated to dextrorphan, (+)-17-methylmorphinan-3-ol), to form novel prodrugs and compositions of dextrorphan.
Core Innovation
The disclosed subject matter relates to dextrorphan prodrugs, conjugates, and derivatives and pharmaceutically acceptable salts. Dextrorphan ((+)-17-methylmorphinan-3-ol) is covalently conjugated at the C-3 hydroxyl and/or the N-17 tertiary amine to oxoacid, polyethylene glycol (PEG/PEO), vitamin moieties, amino-acid/peptide structures, and other substituents through linker/spacer groups and carbonate or ether motifs.
Representative dextrorphan conjugates include 3-Val-dextrorphan, 3-(N-acetyl-Val)-dextrorphan, PEG-conjugates, biotin-conjugates, hippuryl, cinnamoyl, benzoate/butanoyl, lys/val/tyr analogs, biotinyl, PEGyl, and O-acyl or O-alkyl carbonate and methylated ether derivatives. The disclosure also includes quaternary ammonium salt forms and synthetic routes to related dextrorphan conjugates and chloride salt forms.
A central concept is that the conjugate approach supports hydrolysis-triggered or enzymatic/metabolic cleavage to release active dextrorphan under physiological conditions. The disclosure further relates this design to plasma PK-related outcomes such as Tmax, Cmax, and AUC, and to oral and non-oral routes in the context of abuse resistance, abuse deterrent, reduced manipulation, control release, safety, and side-effect profile.
Claims Coverage
The claim coverage centers on a compound having a chemical structure selected from a group and a pharmaceutically acceptable salt thereof. The inventive features repeatedly reflected across the items are the structural selection, pharmaceutical composition context, salt selection, a quantitative compound threshold, and enumerated dosage forms.
Chemical structure selected from a group and pharmaceutically acceptable salts
A compound having a chemical structure selected from the group and a pharmaceutically acceptable salt thereof.
Pharmaceutical composition including the compound or its pharmaceutically acceptable salt
A pharmaceutical composition that includes the compound of the chemical structure selection or a pharmaceutically acceptable salt of that compound.
Salt form selection from an enumerated pharmaceutically acceptable salt group
The pharmaceutical composition uses a pharmaceutically acceptable salt selected from an enumerated group of salt options, including hydrochloride/chloride and combinations thereof.
Quantitative threshold for compound content in the composition
The pharmaceutical composition specifies that the compound is present at an amount of about 0.5 mg or higher.
Enumerated dosage forms for delivering the composition
The pharmaceutical composition specifies a dosage form selected from tablets, capsules, caplets, suppositories, troches, lozenges, oral powders, solutions, syrups, oral films, thin strips, slurries, or suspensions.
Overall, the claims coverage centers on selected dextrorphan-related compound structures and pharmaceutically acceptable salts, with dependent scope limited to pharmaceutical compositions, selected salt forms, a minimum compound amount, and specified dosage forms.
Stated Advantages
Aims to reduce abuse or provide abuse resistance/abuse deterrent for non-oral routes such as intravenous injection and intranasal administration.
Aims to reduce manipulation, including reduced ability to rapidly crush non-oral forms.
Aims to release dextrorphan in vivo via enzymatic/metabolic cleavage.
Aims to improve pharmacokinetic variability and control release.
Potentially lessens side effects.
Control plasma PK (Tmax, Cmax, AUC).
Reduce crush.
Improve safety/side-effect profile.
Potentially reduce abuse/depot effects across oral and non-oral routes.
Documented Applications
In vivo pharmacokinetic comparisons in rats for oral and intranasal dosing of dextrorphan conjugates versus a dextrorphan tartrate comparator, with LC-MS/MS plasma concentration profiling.
Non-oral use contexts addressed include intravenous injection and intranasal administration, in connection with abuse resistance/abuse deterrent and reduced rapid crush behavior.
Therapeutic use/rationale related to NMDA receptor antagonists and NMDA receptor-related indications, including levo/dextrorphan conjugates.
Oral and intranasal pharmacokinetic comparison in rats using LC-MS/MS against a dextrorphan tartrate comparator, for multiple described conjugates.
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